Cannabinoid Es 3d4272
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Contents 1
Cannabinoid 1.1
1.2
3
Cannabinoid receptors
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.1.1
Cannabinoid receptor type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.1.2
Cannabinoid receptor type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2.1
Cannabis-derived cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2.2
Cannabinoids from other plants
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
1.2.3
Cannabis plant profile
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
1.2.4
Pharmacology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.2.5
Separation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.2.6
Natural occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.2.7
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
Endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.3.1
Types of endocannabinoid ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.3.2
Function
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
1.4
Synthetic cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
1.5
Table of natural cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
1.6
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
1.7
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
1.8
Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.9
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
1.9.1
Cannabinoid information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
1.9.2
Cannabinoid research organizations
10
1.3
2
1
Phytocannabinoids
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Entourage effect
11
2.1
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
2.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
Synthetic cannabis
12
3.1
Misnomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
3.2
Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.2.1
Artificial cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.3
i
ii
CONTENTS 3.4
Drug testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5
Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5.1
Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5.2
South America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.3
Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.4
Australasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.5
North America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.6.1
Slang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.8
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.6
4
5
6
7
8
9
4-HTMPIPO
21
4.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5F-PB-22
22
5.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
5.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
A-40174
23
6.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
6.2
References
23
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-41988
24
7.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
7.2
References
24
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-796,260
25
8.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
8.2
References
25
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-834,735
26
9.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
9.2
References
26
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10 A-836,339 10.1 References
27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11 AB-001
27 28
11.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
11.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
12 AB-005 12.1 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29 29
CONTENTS
iii
12.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
12.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
13 AB-CHMINACA
30
13.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 AB-FUBINACA
30 31
14.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
14.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
15 AB-PINACA
32
15.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
15.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
16 Abnormal cannabidiol
33
16.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
16.2 References
33
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17 ADB-FUBINACA
35
17.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
17.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
18 ADB-PINACA
36
18.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
18.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
19 ADBICA
37
19.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
19.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
20 Ajulemic acid 20.1 References
38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21 AM-087
38 39
21.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
21.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
22 AM-1220
40
22.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
22.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
23 AM-1221
41
23.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
23.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
24 AM-1235
42
iv
CONTENTS 24.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.1.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
25 AM-1241
43
25.1 Effects in bone cancer model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
25.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
25.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
26 AM-1248
45
26.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
26.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
27 AM-1714
46
27.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
27.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
28 AM-2201
47
28.1 Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
29 AM-2232
48
29.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48
29.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48
30 AM-2233
49
30.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
30.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
31 AM-2389
50
31.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
31.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
32 AM-4030
51
32.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
32.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
33 AM-411 33.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52 52
CONTENTS
v
33.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 AM-630
52 53
34.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
34.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
35 AM-6545
54
35.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
35.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
36 AM-679 (cannabinoid)
55
36.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
36.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
37 AM-694
56
37.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
37.1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
37.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
37.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
38 AM-855
57
38.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 AM-905
57 58
39.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 AM-906
58 59
40.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
40.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
41 AM-919
60
41.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
41.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
42 AM-938
61
42.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
42.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
43 AM404
62
43.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
43.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
43.3 References
62
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44 AMG-1 44.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63 63
vi
CONTENTS
45 AMG-3
64
45.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 AMG-36
64 65
46.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 AMG-41
65 66
47.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 APINACA
66 67
48.1 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
48.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
48.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
49 AR-231,453
68
49.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
68
49.2 References
68
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50 Arachidonyl-2'-chloroethylamide 50.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Arachidonylcyclopropylamide 51.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 N-Arachidonylglycine
69 69 70 70 71
52.1 Synthesis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2 Research
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.1 Effects on the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.2 Effects on the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.3 Cell migration
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.4 Other targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
52.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
53 AZ-11713908
74
53.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
53.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
54 BAY 38-7271 54.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 BAY 59-3074 55.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 BML-190 56.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75 75 76 76 77 77
CONTENTS
vii
57 (C6)- 47,497
78
57.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 (C9)- 47,497
78 79
58.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Canbisol
79 80
59.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
80
59.2 References
80
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60 Cannabichromene
81
60.1 Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
81
60.2 References
81
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61 Cannabicyclohexanol
82
61.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
61.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
62 Cannabicyclol
83
62.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
62.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
63 Cannabidiol
84
63.1 Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.1 Antimicrobial actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.2 Neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.3 Psychotropic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.4 Dravet syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.2 CBD-enhanced cannabis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.3 Industrial hemp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.2 Pharmacokinetic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.3 Pharmaceutical preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.5 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.6 Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.6.1 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.7 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.8 US patent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87
63.10External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
64 Cannabidivarin 64.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90 90
viii
CONTENTS 64.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
64.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
65 Cannabigerol
91
65.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
91
65.2 References
91
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66 Cannabinoidergic
92
66.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
66.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
67 Cannabinol
93
67.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
67.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
67.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
68 Cannabivarin 68.1 References
94 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
68.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
68.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
69 Caryophyllene
95
69.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
69.2 Compendial status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
69.3 Notes and references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
70 CB-13
98
70.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
70.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
71 CBS-0550
99
71.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
99
71.2 References
99
72 47,497
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
100
72.1 Homologue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.3 Latvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.4 Lithuania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.5 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.6 Romania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.7 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
CONTENTS
ix
72.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 72.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 73 55,244
102
73.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 73.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 74 55,940
103
74.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 74.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 75 Dexanabinol
104
75.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 76 Dimethylheptylpyran
105
76.1 Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 76.2 Investigation as non-lethal incapacitating agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 76.3 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 76.4 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
77 Docosatetraenoylethanolamide
107
77.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 78 Drinabant
108
78.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 78.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
79 EAM-2201
109
79.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 79.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 79.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 79.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 80 Endocannabinoid reuptake inhibitor
110
80.1 Etymology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.3 Use in medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.4 Examples of eCBRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 81 Endocannabinoid system
112
81.1 Basic overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 81.1.1 Expression of receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 81.1.2 Endocannabinoid synthesis, release, and degradation . . . . . . . . . . . . . . . . . . . . . 112
x
CONTENTS 81.1.3 Binding and intracellular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 81.1.4 Binding and neuronal excitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 81.2 Functions of the endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.1 Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.2 Appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.3 Energy balance & metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.4 Stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 81.2.5 Immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 81.2.6 Female reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.7 Autonomic nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.8 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.9 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.10 Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.3 Experimental use of CB1 -/- phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 81.5 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 81.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
82 Endocannabinoid transporters 82.1 References 83 GW-405,833
120
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 121
83.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 84 GW-842,166X 84.1 References 85 Hemopressin
122 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 123
85.1 Role in diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 85.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 85.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 86 HU-210
124
86.1 Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.2.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.2.2 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.3 Other HU Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 86.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 87 HU-243
126
87.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
CONTENTS 87.2 References
xi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
88 HU-308
127
88.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 88.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 89 HU-331
128
89.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 89.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 89.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 90 11-Hydroxy-THC 90.1 References
130 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
91 9-nor-9β-Hydroxyhexahydrocannabinol
131
91.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 91.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
92 Ibipinabant
132
92.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 92.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 93 IDFP
133
93.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 93.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 94 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene
134
94.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 95 JTE 7-31
135
95.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 95.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 96 JTE-907
136
96.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 96.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 97 JWH-015
137
97.1 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 97.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 98 JWH-051
138
98.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 99 JWH-057
139
99.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
xii
CONTENTS 99.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
100JWH-120
140
100.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 100.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 101JWH-122
141
101.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 101.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 102JWH-133
142
102.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 102.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
102.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 103JWH-148
143
103.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 103.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 104JWH-149
144
104.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 104.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 105JWH-161
145
105.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 106JWH-176
146
106.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 106.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 107JWH-359
147
107.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 108JZL184
148
108.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 108.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 109JZL195
149
109.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 109.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 110KM-233
150
110.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 110.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 111L-759,633
151
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111.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 111.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 112L-759,656
152
112.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 112.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 113LASSBio-881
153
113.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 114LBP-1 (drug)
154
114.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 114.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
115Leelamine
155
115.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 115.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
116Levonantradol
156
116.1Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.2Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.3Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.4Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 116.6Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 116.7References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
117List of AM cannabinoids
158
117.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 117.2Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 117.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 118List of JWH cannabinoids
161
118.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 118.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 119LY-2183240
164
119.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 119.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 120LY-320,135
165
120.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 121MAM-2201
166
121.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
xiv
CONTENTS 121.1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 121.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
122MDA-19
167
122.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 122.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 123Menabitan
168
123.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 123.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
124Methanandamide
169
124.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 125MK-9470
170
125.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 126N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-methoxyindole-3-carboxamide
171
126.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 126.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 126.3Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 127Nabazenil 127.1References 128Nabilone
173 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 174
128.1Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 128.2Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 128.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 128.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 129Nabitan 129.1References 130Nabiximols
176 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 177
130.1Availability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 130.2Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.3Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.4Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 131Naboctate 131.1References
180 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
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132NESS-0327
181
132.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 132.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 133NESS-040C5
182
133.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 133.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 134NMP-7
183
134.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 135Nonabine 135.1References
184 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
13611-nor-9-Carboxy-THC 136.1References 137O-1057
185
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 187
137.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 137.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 138O-1125
188
138.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 139O-1238
189
139.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 140O-1269
190
140.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 141O-1602
191
141.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 141.2References 142O-1812
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 192
142.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 142.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 143O-1871
193
143.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 143.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 144O-1918
194
144.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 144.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
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145O-2050
195
145.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 145.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 146O-2113
196
146.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 146.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 147O-2372
197
147.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 147.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 148O-2545
198
148.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 148.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 149O-2694
199
149.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 149.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 150O-774
200
150.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 150.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 151O-806
201
151.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 152O-823
202
152.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 153Org 27569 153.1References 154Org 28312
203 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 204
154.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 154.2References 155Org 28611
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 205
155.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 155.2References 156Otenabant
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 206
156.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 156.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 157Parahexyl
207
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xvii
157.1Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 157.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 157.3References 158UR-144
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 208
158.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.2History of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.3Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.6Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 159Perrottetinene 159.1References 160PF-03550096
210 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 211
160.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 160.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 161PF-514273
212
161.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 162PipISB
213
162.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 163Pirnabine 163.1References 164PSB-SB-1202
214 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 215
164.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 164.2References 165PSB-SB-487
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 216
165.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 165.2References 166QUCHIC
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 217
166.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 166.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 167QUPIC
218
167.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 167.2Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 167.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 167.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
xviii
CONTENTS
168Rimonabant
219
168.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 168.2Uses/potential uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 168.2.1 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 168.2.2 Smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.2.3 Addiction behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.2.4 Short-term memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.2.5 Blockage of cannabis effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.3Other effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.4Negative side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.5Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.6Brand names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.7References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 169Rosonabant
222
169.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 169.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
170S-444,823
223
170.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 170.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 171SDB-001
224
171.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 171.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 172SDB-006
225
172.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 172.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 173SER-601
226
173.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 173.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
174Serinolamide A
227
174.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 174.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 175SR-144,528
228
175.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 175.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 176Stearoylethanolamide
229
176.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
CONTENTS
xix
177STS-135 (drug)
230
177.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 177.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 177.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 178Surinabant
231
178.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 178.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 179Taranabant
232
179.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 179.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 180Tedalinab
233
180.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 180.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
181Tetrad test
234
181.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 182Tetrahydrocannabinol 182.1Effects
235
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.1.1 Appetite and taste
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.2Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.2.1 Discovery and structure identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.2.2 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.3Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.3.1 Multiple sclerosis symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.3.2 Neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.3.3 Other neurological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.3.4 Other studies in humans
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.4Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.4.1 Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.4.2 Cognitive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 182.4.3 Impact on psychosis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.4.4 Other potential long-term effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 182.4.5 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 182.5Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.5.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.6Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.7Chemical synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.8Marinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.8.1 Comparisons with medical marijuana
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
xx
CONTENTS 182.9Regulatory history
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
182.10See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 182.11References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
182.12Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 182.13External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 183Tetrahydrocannabinol-C4
246
183.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 183.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
184Tetrahydrocannabinolic acid
247
184.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 184.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
185Tetrahydrocannabivarin
249
185.1Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 185.2Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 185.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 185.4References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.5External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 186THC-O-acetate
250
186.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 187THC-O-phosphate 187.1References 188Tinabinol
251
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 252
188.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 188.2References 189URB602
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 253
189.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 190URB754
254
190.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 191VCHSR
255
191.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 192VDM-11
256
192.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 192.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 193WIN 54,461
257
193.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
CONTENTS 193.2References
xxi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
194WIN 55,212-2
258
194.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 194.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
194.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 195WIN 56,098
260
195.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 195.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
196XLR-11 (drug)
261
196.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.2Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.3Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 197AM251
263
197.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 197.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
198Aminoalkylindole
264
198.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 198.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 198.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 199Cannabipiperidiethanone
265
199.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 199.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 200JWH-193
266
200.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 200.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 201JWH-198
267
201.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 201.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 202JWH-200
268
202.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 202.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 203Pravadoline
269
203.1Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
xxii
CONTENTS
203.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 203.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 204RCS-4
270
204.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 204.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 204.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 205Anandamide
271
205.1History
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
205.2Physiological functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 205.3Synthesis and degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 205.4Medical benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 205.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 205.6References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 206N-Arachidonoyl dopamine
274
206.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 206.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
206.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 2072-Arachidonoylglycerol
275
207.1Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.2Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.4Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.6.1 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 207.6.2 General references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 2082-Arachidonyl glyceryl ether
277
208.1Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.2Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.5References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.6External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 209Oleamide
279
209.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 209.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
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210RVD-Hpα
280
210.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 211Virodhamine
281
211.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 211.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 212HU-320
282
212.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 212.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 213HU-336
283
213.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 213.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 214HU-345
284
214.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 214.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 215Raphael Mechoulam
285
215.1Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 215.2Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 215.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 215.4Podcasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 216John W. Huffman
286
216.1Law enforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 216.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 216.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 217JWH-007
287
217.1Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 217.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 217.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 218Naphthoylindole 218.1History
288
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 218.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 218.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 218.4Detection in biological fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 218.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 218.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 218.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
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218.8References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 219JWH-019
292
219.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.1 Poland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.2 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.3 UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.4 USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 220JWH-030
293
220.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 220.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 221JWH-047
294
221.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 221.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 222JWH-048
295
222.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 222.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 223JWH-073
296
223.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.2Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3.2 Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3.3 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 223.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 223.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 224JWH-081
298
224.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 224.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 225JWH-098
299
225.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 225.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 226JWH-116
300
226.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
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226.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 227JWH-147
301
227.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 227.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 228JWH-164
302
228.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 229Phenylacetylindole
303
229.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 230JWH-175
304
230.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 230.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 231JWH-184
305
231.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 231.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 232JWH-185
306
232.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 232.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 233JWH-196
307
233.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 233.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 234JWH-203
308
234.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 234.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 235JWH-210
309
235.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 235.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 236JWH-249
310
236.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 236.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 237JWH-250
311
237.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 237.2References 238JWH-251
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 312
238.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
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239JWH-302
313
239.1References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
240JWH-307
314
240.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 240.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 241JWH-398
315
241.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 241.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 242JWH-424
316
242.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 242.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 243Naphthoylindole 243.1History
317
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 243.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 243.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 243.4Detection in biological fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.8References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 244Phenylacetylindole
321
244.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 245RCS-8
322
245.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 245.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 246Intravenous Marijuana Syndrome
323
246.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 247Mellow Yellow coffeeshop
324
247.1Citations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 247.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
247.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 248The Night Train Seizure
325
248.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 248.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
CONTENTS 249PSN-375,963
xxvii 326
249.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 249.2References 250PSN-632,408
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 327
250.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 250.2References 251Soma Seeds 251.1References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 328 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
251.2External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 252TM-38837
329
252.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 252.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
252.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 252.4Text and image sources, contributors, and licenses . . . . . . . . . . . . . . . . . . . . . . . . . . 330 252.4.1 Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 252.4.2 Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 252.4.3 Content license . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Chapter 1
Cannabinoid Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain. These receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals),[1] the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured chemically). The most notable cannabinoid is the phytocannabinoid ∆9 -tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis.[2][3] Cannabidiol (CBD) is another major constituent of the plant, representing up to 40% in extracts of the plant resin.[4] There are at least 85 different cannabinoids isolated from cannabis, exhibiting varied effects.[5]
including the hippocampus.[1] They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not the risk of respiratory or cardiovascular failure that can be produced by some drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
Synthetic cannabinoids encom a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5diarylpyrazoles, quinolines, and arylsulfonamides, as well as eicosanoids related to the endocannabinoids.[2]
CB2 receptors are predominantly found in the immune system, or immune-derived cells[8] with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.[9] CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.[8]
1.1.2 Cannabinoid receptor type 2 Main article: Cannabinoid receptor type 2
1.1 Cannabinoid receptors 1.2 Phytocannabinoids
Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2 ,[1] with mounting evidence of more.[6] The human brain has more cannabinoid receptors than any other G proteincoupled receptor (GPCR) type.[7]
1.1.1
1.2.1 Cannabis-derived cannabinoids The classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. At least 85 different cannabinoids have been isolated from the Cannabis plant[5] To the right, the main classes of cannabinoids from Cannabis are shown. The best studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).
Types
Cannabinoid receptor type 1
All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.[10] The classical cannabinoids are derived from their respective CB1 receptors are found primarily in the brain, more 2-carboxylic acids (2-COOH) by decarboxylation (catspecifically in the basal ganglia and in the limbic system, alyzed by heat, light, or alkaline conditions).[11] Main article: Cannabinoid receptor type 1
1
2
CHAPTER 1. CANNABINOID Tetrahydrocannabinol Tetrahydrocannabinol
Main
article:
Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta−9tetrahydrocannabinol (Δ9 -THC, THC) and delta−8tetrahydrocannabinol (Δ8 -THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. These two THCs produce the effects associated with cannabis by binding to the CB1 cannabinoid receptors in the brain. THC appears to ease moderate pain (analgesic) and to be neuroprotective, while also offering the potential to reduce neuroinflammation and to stimulate neurogenesis.[12] THC has approximately equal affinity for the CB1 and CB2 receptors.[13] The bracts surrounding a cluster of Cannabis sativa flowers are coated with cannabinoid-laden trichomes
Cannabidiol
Main article: Cannabidiol
Cannabidiol (CBD) is not psychoactive, and was thought not to affect the psychoactivity of THC.[14] However, recent evidence shows that smokers of cannabis with a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms.[15] This is ed by psychological tests, in which participants experience less intense psychotic-like effects when intravenous THC was co-istered with CBD (as measured with a PANSS test).[16] Cannabidiol has little affinity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists.[17] Recently it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[18] Cannabidiol has also been shown to act as a 5-HT₁A receptor agonist,[19] an action that is involved in its antidepressant,[20][21] anxiolytic,[21][22] and neuroprotective[23][24] effects.
Cannabis indica plant
• CBG (Cannabigerol) • CBC (Cannabichromene) • CBL (Cannabicyclol) • CBV (Cannabivarin) • THCV (Tetrahydrocannabivarin) • CBDV (Cannabidivarin) • CBCV (Cannabichromevarin) • CBGV (Cannabigerovarin) • CBGM (Cannabigerol Monomethyl Ether)
It appears to relieve convulsion, inflammation, anxiety, and nausea.[17] CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.[17] CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains. CBD apparently plays a role in preventing the short-term memory loss associated with THC in mammals. Some research suggests that the antipsychotic effects of cannabidiol potentially represent a novel mechanism in the treatment of schizophrenia.[25] Researchers at California Pacific Medical Center discovered CBD’s ability to “turn off” the activity of ID1, the gene responsible for metastasis in breast and other types of cancers, including the particularly aggressive triple negative breast cancer.[26][27][28] The researchers hope to start human trials soon.[29]
Cannabinol
Main article: Cannabinol
1.2. PHYTOCANNABINOIDS
3
Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB2 receptor is higher than for the CB1 receptor.[30] Cannabigerol
Main article: Cannabigerol
There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ9 -THC, while the minor form is called Δ8 THC. Under the alternate terpene numbering system, these same compounds are called Δ1 -THC and Δ6 -THC, respectively.
Length Most classical cannabinoids are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain attached to the aromatic ring. In THC, CBD, and CBN, this side-chain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3-carbon) chain. Cannabinoids with the propyl side-chain are named using the suffix varin, and are desarticle: ignated, for example, THCV, CBDV, or CBNV.
Cannabigerol (CBG) is non-psychotomimetic but still affects the overall effects of Cannabis. It acts as an α2 adrenergic receptor agonist, 5-HT₁A receptor antagonist, and CB1 receptor antagonist.[31] It also binds to the CB2 receptor.[31] Tetrahydrocannabivarin Tetrahydrocannabivarin
Main
Tetrahydrocannabivarin (THCV) is prevalent in cer- 1.2.2 Cannabinoids from other plants tain central Asian and southern African strains of Cannabis.[32][33] It is an antagonist of THC at CB1 recep- Phytocannabinoids are known to occur in several plant species besides cannabis. These include Echinacea tors and attenuates the psychoactive effects of THC.[34] purpurea, Echinacea angustifolia, Echinacea pallida, Acmella oleracea, Helichrysum umbraculigerum, and Cannabidivarin Main article: Cannabidivarin Radula marginata.[36] The best-known cannabinoids that are not derived from Cannabis are the lipophilic alka[36] At Although cannabidivarin (CBDV) is usually a minor mides (alkylamides) from Echinacea species. least 25 different alkylamides (dodeca-2E,4E,8Z,10E/Zconstituent of the cannabinoid profile, enhanced levels of CBDV have been reported in feral cannabis plants tetraenoic-acid-isobutylamides) have been identified, and them have shown affinities to the CB2 from the northwest Himalayas, and in hashish from some of[37][38] receptor. In Echinacea species, cannabinoids are [33][35] Nepal. found throughout the plant structure, but are most concentrated in the roots and flowers.[39][40] Yangonin found in the Kava plant is a ligand on the CB1 receptor.[41] Cannabichromene Main article: Cannabichromene Tea (Camellia sinensis) catechins have an affinity for human cannabinoid receptors.[42] A widespread dietary Cannabichromene (CBC) is non-psychoactive and does cannabinoid, beta-caryophyllene, a component from the not affect the psychoactivity of THC.[14] More comessential oil of cannabis and other medicinal plants, has mon in tropical cannabis varieties. Effects include antialso been identified as a selective agonist of peripheral inflammatory and analgesic. CB2 -receptors, in vivo.[43] Biosynthesis Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBGA. Next, CBGA is independently converted to either CBG, THCA, CBDA or CBCA by four separate synthase, FAD-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the propyl homologues (THCVA, CBDVA and CBCVA), there is a similar pathway that is based on CBGVA from divarinolic acid instead of olivetolic acid.
Most of the phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents.
1.2.3 Cannabis plant profile
Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant’s cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (comDouble bond position In addition, each of the com- monly called hemp) are bred such that they are low in psypounds above may be in different forms depending on the choactive chemicals like THC. Strains used in medicine position of the double bond in the alicyclic carbon ring. are often bred for high CBD content, and strains used for
4
CHAPTER 1. CANNABINOID
recreational purposes are usually bred for high THC con- 1.2.6 Natural occurrence tent or for a specific chemical balance. Quantitative analysis of a plant’s cannabinoid profile is of- Main article: Medical_cannabis § Difference between ten determined by gas chromatography (GC), or more re- C. indica and C. sativa liably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, and, unlike GC methods, can differentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.
Cannabis indica may have a CBD:THC ratio 4–5 times that of Cannabis sativa.
1.2.7 History Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964.
Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural pre1.2.4 Pharmacology cursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant Cannabinoids can be istered by smoking, vaporizfrom the precursor CBG. ing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, especially by cytochrome P450 mixed-function oxidases, 1.3 Endocannabinoids mainly CYP 2C9. Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication. For more details on the roles and regulation of the endoSome is also stored in fat in addition to being metabo- cannabinoids, see Endocannabinoid system. lized in the liver. Δ9 -THC is metabolized to 11-hydroxy- Endocannabinoids are substances produced from within Δ9 -THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body several weeks after istration. These metabolites are the chemicals recognized by common antibody-based “drug tests"; in the case of THC or others, these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous blood alcohol levels), but an integration of past consumption over an approximately month-long window. This is because they are fat-soluble, lipophilic molecules that accumulate in fatty tissues.[44]
1.2.5
Separation
Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures (73 atmospheres or more), there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high-purity cannabinoids, chemical synthesis or semisynthesis is generally required.
Anandamide, an endogenous ligand of CB1 and CB2
the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand for the receptor.
1.3.1 Types of endocannabinoid ligands Arachidonoylethanolamine (Anandamide or AEA) Main article: Arachidonoylethanolamine In 1992, in Raphael Mechoulam's lab, the first such compound was identified as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit
1.3. ENDOCANNABINOIDS word for bliss and -amide. Anandamide is derived from arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to the central (CB1 ) and, to a lesser extent, peripheral (CB2 ) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor.[45] Anandamide is found in nearly all tissues in a wide range of animals.[46] Anandamide has also been found in plants, including small amounts in chocolate.[47] Two analogs of anandamide, 7,10,13,16docosatetraenoylethanolamide and homo-γlinolenoylethanolamine, have similar pharmacology. All of these are of a family of signalling lipids called N-acylethanolamines, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide, which possess anti-inflammatory and orexigenic effects, respectively. Many Nacylethanolamines have also been identified in plant seeds[48] and in molluscs.[49]
2-Arachidonoylglycerol (2-AG)
5 N-Arachidonoyl dopamine (NADA) Main article: N-Arachidonoyl dopamine Discovered in 2000, NADA preferentially binds to the CB1 receptor.[54] Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.[55][56]
Virodhamine (OAE) Main article: Virodhamine A fifth endocannabinoid, virodhamine, or Oarachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1 , it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.[57]
Main article: 2-Arachidonoylglycerol Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both.[45] 2-AG is present at significantly higher concentrations in the brain than anandamide,[50] and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo.[1] In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.[51]
2-Arachidonyl glyceryl ether (noladin ether) Main article: 2-Arachidonyl glyceryl ether
Lysophosphatidylinositol (LPI) Recent evidence has highlighted lysophosphatidylinositol as the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid.[58]
1.3.2 Function Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons. Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
In 2001, a third, ether-type endocannabinoid, 2arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain.[52] Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at “any appreciable amount” in the brains of several different mammalian species.[53] It binds to the CB1 cannabinoid receptor (Kᵢ = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and The endocannabinoid 2-AG has been found in bovine and human maternal milk.[59] only weakly to the CB2 receptor.[45]
6 Retrograde signal
CHAPTER 1. CANNABINOID • Dronabinol (Marinol), is Δ9 -tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on • Nabilone (Cesamet, Canemes), a synthetic cannabia ‘postsynaptic’ cell, where presynaptic and postsynaptic noid and an analog of Marinol. It is Schedule II undesignate the sending and receiving sides of a synapse, like Marinol, which is Schedule III respectively. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most • Sativex, a cannabinoid extract oral spray containing commonly travel ‘backward’ against the usual synaptic THC, CBD, and other cannabinoids used for neutransmitter flow. They are, in effect, released from the ropathic pain and spasticity in 22 countries includpostsynaptic cell and act on the presynaptic cell, where ing England, Canada and Spain. Sativex develops the target receptors are densely concentrated on axonal whole-plant cannabinoid medicines terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid re• Rimonabant (SR141716), a selective cannabinoid ceptors temporarily reduces the amount of conventional (CB1 ) receptor inverse agonist once used as an antineurotransmitter released. This endocannabinoid mediobesity drug under the proprietary name Acomplia. ated system permits the postsynaptic cell to control its It was also used for smoking cessation own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For Other notable synthetic cannabinoids include: instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the ex• JWH-018, a potent synthetic cannabinoid agonist citability of the endocannabinoid-releasing cell. On the discovered by Dr. John W. Huffman at Clemson converse, when release of the excitatory neurotransmitUniversity. It is being increasingly sold in legal ter glutamate is reduced, the net effect is a decrease in smoke blends collectively known as “spice”. Several the excitability of the endocannabinoid-releasing cell. countries and states have moved to ban it legally. Range Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
1.4 Synthetic cannabinoids Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids. Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.
• JWH-073 • -55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC. • Dimethylheptylpyran • HU-210, about 100 times as potent as THC[60] • HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II. • SR144528, a CB2 receptor antagonist • WIN 55,212-2, a potent cannabinoid receptor agonist • JWH-133, a potent selective CB2 receptor agonist • Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine • AM-2201, a potent cannabinoid receptor agonist
1.5 Table of natural cannabinoids
Medications containing natural or synthetic cannabinoids From es:Cannabinoide#Tabla de cannabinoides naturales. or cannabinoid analogs:
1.7. REFERENCES
1.6 See also • Cannabinoid receptor antagonist • Cancer and nausea
1.7 References
7
doi:10.1046/j.1432-1327.2001.02030.x/j.14321327.2001.02030.x.pdf;jsessionid=3E999436DFF039CE743A44B5D42533C PMID 11248677. (subscription required (help)). |first2= missing |last2= in Authors list (help); |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help) ICID: 55687 [11] Patentdocs. Patent application title: Controlled cannabis decarboxylation. US Patent application number: 20120046352. Retrieved 28 December, 2013
[1] Pacher, P.; Bátkai, S; Kunos, G (2006). “The Endocannabinoid System as an Emerging Target of Pharmacotherapy”. Pharmacological Reviews 58 (3): 389– 462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
[12] Campbell, V A; Gowran, A (2007). “Alzheimer’s disease; taking the edge off with cannabinoids?". British Journal of Pharmacology 152 (5): 655–62. doi:10.1038/sj.bjp.0707446. PMC 2190031. PMID 17828287.
[2] Lambert, Didier M.; Fowler, Christopher J. (2005). “The Endocannabinoid System: Drug Targets, Lead Compounds, and Potential Therapeutic Applications”. Journal of Medicinal Chemistry 48 (16): 5059–87. doi:10.1021/jm058183t. PMID 16078824.
[13] Huffman, J. (2000). “The Search for Selective Ligands for the CB2 Receptor”. Current Pharmaceutical Design 6 (13): 1323–37. doi:10.2174/1381612003399347. PMID 10903395.
[3] Pertwee, Roger, ed. (2005). Cannabinoids. SpringerVerlag. p. 2. ISBN 3-540-22565-X. [4] “Bulletin on Narcotics - 1962 Issue 3 - 004”. UNODC (United Nations Office of Drugs and Crime). 1962-0101. Retrieved 2014-01-15. [5] El-Alfy, Abir T.; Ivey, Kelly; Robinson, Keisha; Ahmed, Safwat; Radwan, Mohamed; Slade, Desmond; Khan, Ikhlas; Elsohly, Mahmoud; Ross, Samir (2010). “Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”. Pharmacology Biochemistry and Behavior 95 (4): 434– 42. doi:10.1016/j.pbb.2010.03.004. PMC 2866040. PMID 20332000. [6] Begg, Malcolm; Pacher, Pál; Batkai, Sándor; Oseihyiaman, Douglas; Offertaler, László; Mo, Fong Ming; Liu, Jie; Kunos, George (2005). “Evidence for novel cannabinoid receptors”. Pharmacology & Therapeutics 106 (2): 133–45. doi:10.1016/j.pharmthera.2004.11.005. PMID 15866316.
[14] Ilan, A. B.; Gevins, A.; Coleman, M.; Elsohly, M. A.; De Wit, H. (2005). “Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids”. Behavioural Pharmacology 16 (5– 6): 487–96. doi:10.1097/00008877-200509000-00023. PMID 16148455. [15] Morgan, C. J. A.; Curran, H. V. (2008). “Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis”. The British Journal of Psychiatry 192 (4): 306–7. doi:10.1192/bjp.bp.107.046649. PMID 18378995. [16] “Should I Smoke Dope?". British Broadcasting Corporation. Retrieved 2008-05-24. [17] Mechoulam, Raphael; Peters, Maximilian; MurilloRodriguez, Eric; Hanuš, Lumír O. (2007). “Cannabidiol – Recent Advances”. Chemistry & Biodiversity 4 (8): 1678– 92. doi:10.1002/cbdv.200790147. PMID 17712814.
[7] Boron, Walter F.; Boulpaep, Emile L., eds. (2009). Medical Physiology: A Cellular and Molecular Approach. Saunders. p. 331. ISBN 978-1-4160-3115-4.
[18] Ryberg, E; Larsson, N; Sjögren, S; Hjorth, S; Hermansson, N-O; Leonova, J; Elebring, T; Nilsson, K; Drmota, T; Greasley, P J (2009). “The orphan receptor GPR55 is a novel cannabinoid receptor”. British Journal of Pharmacology 152 (7): 1092–101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302.
[8] Pacher, P.; Mechoulam, R. (2011). “Is lipid signaling through cannabinoid 2 receptors part of a protective system?". Progress in Lipid Research 50 (2): 193– 211. doi:10.1016/j.plipres.2011.01.001. PMC 3062638. PMID 21295074.
[19] Russo, Ethan B.; Burnett, Andrea; Hall, Brian; Parker, Keith K. (2005). “Agonistic Properties of Cannabidiol at 5-HT1a Receptors”. Neurochemical Research 30 (8): 1037–43. doi:10.1007/s11064-005-6978-1. PMID 16258853.
[9] Núñez, Estefanía; Benito, Cristina; Pazos, M. Ruth; Barbachano, Antonio; Fajardo, Otto; González, Sara; Tolón, Rosa M.; Romero, Julián (2004). “Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: An immunohistochemical study”. Synapse 53 (4): 208–13. doi:10.1002/syn.20050. PMID 15266552.
[20] Zanelati, TV; Biojone, C; Moreira, FA; Guimarães, FS; Joca, SRL (2010). “Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors”. British Journal of Pharmacology 159 (1): 122–8. doi:10.1111/j.1476-5381.2009.00521.x. PMC 2823358. PMID 20002102.
[10] Zenk, H. (2001). “Biosynthesis of cannabinoids”. Eur. J. Biochem 268 (6): 1596–1604.
[21] Resstel, Leonardo B.M.; Tavares, Rodrigo F.; Lisboa, Sabrina F.S.; Joca, Sâmia R.L.; Corrêa, Fernando M.A.; Guimarães, Francisco S. (2009). “5-HT1Areceptors are
8
CHAPTER 1. CANNABINOID
involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats”. British Journal of Pharmacology 156 (1): 181–8. doi:10.1111/j.1476-5381.2008.00046.x. PMC 2697769. PMID 19133999. [22] Campos, Alline Cristina; Guimarães, Francisco Silveira (2008). “Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats”. Psychopharmacology 199 (2): 223–30. doi:10.1007/s00213-008-1168-x. PMID 18446323. [23] Mishima, K.; Khoutorova, K.; Zhao, K.; Vigdorchik, T.; Belayev, N.; Busto, K.; Magal, M.; Ginsberg, MD (2005). “Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine1A Receptor-Dependent Mechanism”. Stroke 36 (5): 1071– 6. doi:10.1161/01.STR.0000163083.59201.34. PMID 15845890. [24] Hayakawa, Kazuhide; Mishima, Kenichi; Nozako, Masanori; Ogata, Ayumi; Hazekawa, Mai; Liu, An-Xin; Fujioka, Masayuki; Abe, Kohji; Hasebe, Nobuyoshi; Egashira, Nobuaki; Iwasaki, Katsunori; Fujiwara, Michihiro (2007). “Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance”. Neuropharmacology 52 (4): 1079– 87. doi:10.1016/j.neuropharm.2006.11.005. PMID 17320118. [25] Leweke, F M; Piomelli, D; Pahlisch, F; Muhl, D; Gerth, C W; Hoyer, C; Klosterkötter, J; Hellmich, M; Koethe, D (2012). “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia”. Translational Psychiatry 2 (3): e94–. doi:10.1038/tp.2012.15. PMC 3316151. PMID 22832859. [26] “Pot compound seen as tool against cancer”. SFGate. [27] McAllister, S. D.; Christian, R. T.; Horowitz, M. P.; Garcia, A.; Desprez, P.-Y. (2007). “Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells”. Molecular Cancer Therapeutics 6 (11): 2921–7. doi:10.1158/1535-7163.MCT-07-0371. PMID 18025276. [28] Ligresti, A.; Moriello, AS; Starowicz, K; Matias, I; Pisanti, S; De Petrocellis, L; Laezza, C; Portella, G; Bifulco, M; Di Marzo, V (2006). “Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma”. Journal of Pharmacology and Experimental Therapeutics 318 (3): 1375–87. doi:10.1124/jpet.106.105247. PMID 16728591. [29] “Marijuana Compound Fights Cancer; Human Trials Next”. NBC Bay Area. [30] Mahadevan, Anu; Siegel, Craig; Martin, Billy R.; Abood, Mary E.; Beletskaya, Irina; Razdan, Raj K. (2000). “Novel Cannabinol Probes for CB1 and CB2 Cannabinoid Receptors”. Journal of Medicinal Chemistry 43 (20): 3778–85. doi:10.1021/jm0001572. PMID 11020293.
[31] Cascio, MG; Gauson, LA; Stevenson, LA; Ross, RA; Pertwee, RG (2010). “Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist”. British Journal of Pharmacology 159 (1): 129–41. doi:10.1111/j.1476-5381.2009.00515.x. PMC 2823359. PMID 20002104. [32] Baker, PB; Gough, TA; Taylor, BJ (1980). “Illicitly imported Cannabis products: Some physical and chemical features indicative of their origin”. Bulletin on narcotics 32 (2): 31–40. PMID 6907024. [33] Hillig, K. W.; Mahlberg, P. G. (2004). “A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae)". American Journal of Botany 91 (6): 966–75. doi:10.3732/ajb.91.6.966. PMID 21653452. [34] Thomas, Adèle; Stevenson, Lesley A; Wease, Kerrie N; Price, Martin R; Baillie, Gemma; Ross, Ruth A; Pertwee, Roger G (2005). “Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1and CB2receptor antagonist”. British Journal of Pharmacology 146 (7): 917–26. doi:10.1038/sj.bjp.0706414. PMC 1751228. PMID 16205722. [35] Merkus, Frans W. H. M. (1971). “Cannabivarin and Tetrahydrocannabivarin, Two New Constituents of Hashish”. Nature 232 (5312): 579–80. doi:10.1038/232579a0. PMID 4937510. [36] Bauer, Rudolf; Salo-Ahen, Karin; Bauer, Outi (2008). “CB Receptor Ligands from Plants”. Current Topics in Medicinal Chemistry 8 (3): 173–86. doi:10.2174/156802608783498023. PMID 18289087. [37] Bauer, R.; Remiger, P. (2007). “TLC and HPLC Analysis of Alkamides inEchinaceaDrugs1,2”. Planta Medica 55 (4): 367–71. doi:10.1055/s-2006-962030. PMID 17262436. [38] Raduner, S; Majewska, A; Chen, J; Xie, X; Hamon, J; Faller, B; Altmann, K; Gertsch, J (2006). “Alkylamides from Echinacea Are a New Class of Cannabinomimetics: CANNABINOID TYPE 2 RECEPTOR-DEPENDENT AND -INDEPENDENT IMMUNOMODULATORY EFFECTS” (PDF). J. Biol. Chem. 281 (20): 14192–14206. doi:10.1074/jbc.M601074200. PMID 16547349. [39] Perry, Nigel; Van Klink, John; Burgess, Elaine; Parmenter, Graeme (2007). “Alkamide Levels inEchinacea purpurea: A Rapid Analytical Method Revealing Differences among Roots, Rhizomes, Stems, Leaves and Flowers”. Planta Medica 63 (1): 58–62. doi:10.1055/s-2006957605. PMID 17252329. [40] He, X; Lin, L; Bernart, MW; Lian, L (1998). “Analysis of alkamides in roots and achenes of Echinacea purpurea by liquid chromatography–electrospray mass spectrometry”. Journal of Chromatography A 815 (2): 205–11. doi:10.1016/S0021-9673(98)00447-6. [41] Ligresti, A.; Villano, R.; Allarà, M.; Ujváry, I. N.; Di Marzo, V. (2012). “Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB1
1.8. FURTHER READING
receptor ligand”. Pharmacological Research 66 (2): 163– 169. doi:10.1016/j.phrs.2012.04.003. PMID 22525682. [42] Korte, G.; Dreiseitel, A.; Schreier, P.; Oehme, A.; Locher, S.; Geiger, S.; Heilmann, J.; Sand, P.G. (2010). “Tea catechins’ affinity for human cannabinoid receptors”. Phytomedicine 17 (1): 19–22. doi:10.1016/j.phymed.2009.10.001. PMID 19897346. [43] Gertsch, J; Leonti, M; Raduner, S; Racz, I; Chen, J; Xie, X; Altmann, K; Karsak, M; Zimmer, A (2008). “Beta-caryophyllene is a dietary cannabinoid”. PNAS 105 (26): 9099–9104. doi:10.1073/pnas.0803601105. PMC 2449371. PMID 18574142. [44] Ashton CH (February 2001). “Pharmacology and effects of cannabis: a brief review”. Br J Psychiatry 178 (2): 101–106. doi:10.1192/bjp.178.2.101. PMID 11157422. “Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4-5 days. They are then slowly released back into other body compartments, including the brain. They are then slowly released back into other body compartments, including the brain. Because of the sequestration in fat, the tissue elimination half-life of THC is about 7 days, and complete elimination of a single dose may take up to 30 days.”
9
[52] Hanuš, Lumír; Abu-Lafi, Saleh; Fride, Ester; Breuer, Aviva; Vogel, Zvi; Shalev, Deborah E.; Kustanovich, Irina; Mechoulam, Raphael (2001). “2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor”. Proceedings of the National Academy of Sciences 98 (7): 3662–5. doi:10.1073/pnas.061029898. PMC 31108. PMID 11259648. [53] Oka, Saori; Tsuchie, Akiko; Tokumura, Akira; Muramatsu, Mayumi; Suhara, Yoshitomo; Takayama, Hiroaki; Waku, Keizo; Sugiura, Takayuki (2003). “Etherlinked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species”. Journal of Neurochemistry 85 (6): 1374– 81. doi:10.1046/j.1471-4159.2003.01804.x. PMID 12787057. [54] Bisogno, Tiziana; Melck, Dominique; Bobrov, Mikhail Yu.; Gretskaya, Natalia M.; Bezuglov, Vladimir V.; De Petrocellis, Luciano; Di Marzo, Vincenzo (2000). “N-acyl-dopamines: Novel synthetic CB1 cannabinoidreceptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo”. Biochemical Journal 351 (3): 817–24. doi:10.1042/02646021:3510817. PMC 1221424. PMID 11042139.
[45] Grotenhermen, Franjo (2005). “Cannabinoids”. Current Drug Target -CNS & Neurological Disorders 4 (5): 507. doi:10.2174/156800705774322111.
[55] Bisogno, T; Ligresti, A; Dimarzo, V (2005). “The endocannabinoid signalling system: Biochemical aspects”. Pharmacology Biochemistry and Behavior 81 (2): 224– 38. doi:10.1016/j.pbb.2005.01.027. PMID 15935454.
[46] Martin, B.R.; Mechoulam, R.; Razdan, R.K. (1999). “Discovery and characterization of endogenous cannabinoids”. Life Sciences 65 (6–7): 573. doi:10.1016/S00243205(99)00281-7.
[56] Ralevic, Vera (2003). “Cannabinoid modulation of peripheral autonomic and sensory neurotransmission”. European Journal of Pharmacology 472 (1–2): 1–21. doi:10.1016/S0014-2999(03)01813-2. PMID 12860468.
[47] Di Tomaso, Emmanuelle; Beltramo, Massimiliano; Piomelli, Daniele (1996). “Brain cannabinoids in chocolate”. Nature 382 (6593): 677–8. doi:10.1038/382677a0. PMID 8751435.
[57] Porter, A. C.; Sauer, JM; Knierman, MD; Becker, GW; Berna, MJ; Bao, J; Nomikos, GG; Carter, P; Bymaster, FP; Leese, AB; Felder, CC (2002). “Characterization of a Novel Endocannabinoid, Virodhamine, with Antagonist Activity at the CB1 Receptor”. Journal of Pharmacology and Experimental Therapeutics 301 (3): 1020–4. doi:10.1124/jpet.301.3.1020. PMID 12023533.
[48] Chapman, K. D.; Venables, B; Markovic, R; Blair Jr, RW; Bettinger, C (1999). “N-Acylethanolamines in Seeds. Quantification of Molecular Species and Their Degradation upon Imbibition”. Plant Physiology 120 (4): 1157– 64. doi:10.1104/pp.120.4.1157. PMC 59349. PMID 10444099. [49] Sepe, Nunzio; De Petrocellis, Luciano; Montanaro, sca; Cimino, Guido; Di Marzo, Vincenzo (1998). “Bioactive long chain N-acylethanolamines in five species of edible bivalve molluscs”. Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism 1389 (2): 101–11. doi:10.1016/S0005-2760(97)00132-X. PMID 9461251. [50] Piomelli, Daniele; Schweitzer, Nephi; Piomelli, Paul (1997). “A second endogenous cannabinoid that modulates long-term potentiation”. Nature 388 (6644): 773–8. doi:10.1038/42015. PMID 9285589. [51] Savinainen, Juha R; Järvinen, Tomi; Laine, Krista; Laitinen, Jarmo T (2001). “Despite substantial degradation, 2arachidonoylglycerol is a potent full efficacy agonist mediating CB1receptor-dependent G-protein activation in rat cerebellar membranes”. British Journal of Pharmacology 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC 1572991. PMID 11588122.
[58] Piñeiro, Roberto; Falasca, Marco (2012). “Lysophosphatidylinositol signalling: New wine from an old bottle”. Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids 1821 (4): 694–705. doi:10.1016/j.bbalip.2012.01.009. PMID 22285325. [59] Fride, E; Bregman, T; Kirkham, TC (2005). “Endocannabinoids and food intake: Newborn suckling and appetite regulation in adulthood”. Experimental biology and medicine 230 (4): 225–34. PMID 15792943. [60] “More medicinal uses for marijuana”. Marijuana.org. October 18, 2005. Archived from the original on 200512-21. Retrieved 2014-01-15.
1.8 Further reading • De Meijer, EP; Bagatta, M; Carboni, A; Crucitti, P; Moliterni, VM; Ranalli, P et al. (2003). “The inheritance of chemical phenotype in Cannabis sativa L”.
10
CHAPTER 1. CANNABINOID Genetics 163 (1): 335–46. PMC 1462421. PMID 12586720.
• Devane, W.; Hanus, L; Breuer, A; Pertwee, R.; Stevenson, L.; Griffin, G et al. (1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science 258 (5090): 1946– 9. doi:10.1126/science.1470919. PMID 1470919. • Elsohly, Mahmoud A.; Slade, Desmond (2005). “Chemical constituents of marijuana: The complex mixture of natural cannabinoids”. Life Sciences 78 (5): 539–48. doi:10.1016/j.lfs.2005.09.011. PMID 16199061.
• Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.; Rehnelt, J.; Martín, M. et al. (2008). “Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain”. Journal of Neuroscience 28 (46): 12125–35. doi:10.1523/JNEUROSCI.3400-08.2008. PMC 3844839. PMID 19005077. • Turner, C. E.; Mole, M. L.; Hanus, L.; Elsohly, H. N. (1981). “Constituents of Cannabis sativa. XIX. Isolation and Structure Elucidation of Cannabiglendol, A Novel Cannabinoid from an Indian Variant”. Journal of Natural Products 44 (1): 27–33. doi:10.1021/np50013a005.
• Hanus, Lumir; Gopher, Asher; Almog, Shlomo; Mechoulam, Raphael (1993). “Two new unsaturated fatty acid ethanolamides in brain 1.9 that bind to the cannabinoid receptor”. Journal of Medicinal Chemistry 36 (20): 3032–4. 1.9.1 doi:10.1021/jm00072a026. PMID 8411021. • Hanus, L (1987). “Biogenesis of cannabinoid substances in the plant”. Acta Universitatis Palackianae Olomucensis Facultatis Medicae 116: 47–53. PMID 2962461. • Hanuš, L.; Krejčí, Z. (1975). “Isolation of two new cannabinoid acids from Cannabis sativa L. of Czechoslovak origin”. Acta Univ. Olomuc., Fac. Med 74: 161–166. • Hanuš, L.; Krejčí, Z.; Hruban, L. (1975). “Isolation of cannabidiolic acid from Turkish variety of cannabis cultivated for fibre”. Acta Univ. Olomuc., Fac. Med 74: 167–172.
External links Cannabinoid information
• Bela Szabo: Pharmacology of Cannabinoid Receptors BIOTREND Reviews No. 02, February 2008 • Marijuana and Medicine – Assessing the Science Base (Institute of Medicine) – 1999 at National Academies Press • House of Lords Report – Cannabis (United Kingdom) – 1998 at Parliament of the United Kingdom • Cannabis: A Health Perspective and Research Agenda – 1997 at World Health Organization • Chemical Ecology of Cannabis (J. Intl. Hemp Assn. - 1994)
• Köfalvi, Attila, ed. (2008). “Cannabinoids and the Brain”. doi:10.1007/978-0-387-74349-3. ISBN 978-0-387-74348-6.
• THC (tetrahydrocannabinol) accumulation in glands of Cannabis (Cannabaceae)
• Nicoll, Roger A.; Alger, Bradley E. (2004). “The Brain’s Own Marijuana”. Scientific American 291 (6): 68–75. doi:10.1038/scientificamerican120468. PMID 15597982.
• Therapeutic Potential in Spotlight at Cannabinoid Researchers’ Meeting at California Cannabis Research Medical Group
• Non-psychotropic plant cannabinoids: new thera• Mechoulam, Raphael; Ben-Shabat, Shimon; Hanus, peutic opportunities from an ancient herb Lumir; Ligumsky, Moshe; Kaminski, Norbert E.; Schatz, Anthony R. et al. (1995). “Identification of an endogenous 2-monoglyceride, present 1.9.2 Cannabinoid research organizations in canine gut, that binds to cannabinoid recep• International Cannabinoid Research Society tors”. Biochemical Pharmacology 50 (1): 83– 90. doi:10.1016/0006-2952(95)00109-D. PMID • The Canadian Consortium for the Investigation of 7605349. Cannabinoids
• Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.; Rehnelt, J.; Martín, M. et al. (2008). “Interferonis a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain”. Journal of Neuroscience 28 (46): 12136–45. doi:10.1523/JNEUROSCI.3402-08.2008. PMC 3844840. PMID 19005078.
Chapter 2
Entourage effect Entourage effect is a phrase that was introduced in cannabinoid science in 1998 by S. Ben-Shabat, with Raphael Mechoulam, to represent a novel endogenous cannabinoid molecular regulation route. Biological activity assayed together with inactive compounds. References whole plant and whole person caregiver synergy treatments over isolated compound pharmacological dosages.[1][2][3][4][5][6][7][8]
2.1 External links • Dr. Sanjay Gupta: Medical marijuana and 'the entourage effect'
2.2 References [1] Lee, Martin A. (Sep 13, 2013). Smoke Signals: A Social History of Marijuana-Medical, Recreational and Scientific. Scribner. p. 465. ISBN 978-1439102619. [2] Ben-Shabat, Shimon (July 17, 1998). “An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity”. European Journal of Pharmacology 353 (1): 23–31. doi:10.1016/S0014-2999(98)00392-6. [3] Andersson, Karl-Erik (Feb 4, 2011). Urinary Tract. eBook: Springer Science & Business Media. p. 438. [4] Newnes (March 5, 2010). Comprehensive Natural Products II: Chemistry and Biology:. eBook: Google. p. 220. [5] Guy, Geoffrey William (July 1, 2004). The Medicinal Uses of Cannabis and Cannabinoids (1st ed.). Pharmaceutical Press. p. 114. ISBN 978-0853695172. [6] Castle, David (May 27, 2004). Marijuana and Madness: Psychiatry and Neurobiology. eBook: Google. p. 8. [7] Russo, Ethan B (Aug 2011). “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”. Br J Pharmacol 163 (7): 1344–1364. doi:10.1111/j.1476-5381.2011.01238.x. [8] Gardner, Fred (2011). “Terpenoids, 'minor' cannabinoids contribute to 'entourage effect' of Cannabis-based medicines”. The Journal of Cannavis in Clinical Practice: 1.
11
Chapter 3
Synthetic cannabis its metabolites in human urine. The synthetic cannabinoids contained in synthetic cannabis products have been made illegal in many European countries. On November 24, 2010, the US Drug Enforcement istration announced it would use emergency powers to ban many synthetic cannabinoids within a month.[4] Prior to the announcement, several US states had already made them illegal under state law. In the US, as of March 1, 2011, five cannabinoids, JWH-018, JWH-073, 47,497, JWH-200, and cannabicyclohexanol have been placed on Schedule I of the Controlled Substances Act (and are therefore illegal to possess or use in the US); the Drug Enforcement istration claims that said action is “to avoid an imminent hazard to the public safety.”[5][6] In July 2012, the Synthetic Drug Abuse Prevention Act of A bag of Spice brand herbal incense 2012 was signed into law. It banned synthetic compounds commonly found in synthetic cannabis, placing them unCommercially known as Synthetic cannabis (synthetic der Schedule I of the Controlled Substances Act.[7] marijuana), or technically cannabinoid research chemicals, is any designer drug that mimics the effects of cannabis.[1] There are several psychoactive artificial cannabinoid families (eg AM-xxx, HU-xxx, JWHxxx, xx) that are used as designer drugs sprayed on herbs and sold as natural highs under brand names like K2[2] and Spice,[3] both of which are genericized trade- 3.1 Misnomer marks used for any synthetic cannabis product. Synthetic cannabis is often termed spice product. There is controversy about calling Spice and K2 synthetic When synthetic cannabis blends first went on sale in the cannabis. Synthetic marijuana is a misnomer accordearly 2000s, it was thought that they achieved an effect ing to Lewis Nelson, MD, a medical toxicologist at the through a mixture of natural herbs. Laboratory anal- NYU School of Medicine. “It’s really quite different, ysis in 2008 showed that this is not the case, and that and the effects are much more unpredictable. It’s danthey in fact contain synthetic cannabinoids that act on the gerous, and there is no quality control in what you are body in a similar way to cannabinoids naturally found in getting.”[8] Since the term synthetic does not apply to the cannabis, such as THC. A large and complex variety of plant but rather to the chemical that the plant contains synthetic cannabinoids, most often cannabicyclohexanol, (tetrahydrocannabinol), the term synthetic cannabinoid is JWH-018, JWH-073, or HU-210, are used in an attempt more appropriate.[9] Research on the safety of synthetic to avoid the laws that make cannabis illegal, making syn- cannabinoids is now becoming available. Initial studthetic cannabis a designer drug. It has been sold under ies are focused on the role of synthetic cannabinoids in various brand names, online, in head shops, and at some psychosis. Synthetic cannabis may precipitate psychosis gas stations. and in some cases it may be prolonged. Some studies sugIt is often marketed as "herbal incense"; however, some gest that synthetic cannabinoid intoxication is associated brands market their products as “herbal smoking blends”. with acute psychosis, worsening of previously stable psyIn either case, the products are usually smoked by s. chotic disorders, and it may trigger a chronic (long-term) Although synthetic cannabis does not produce positive re- psychotic disorder among vulnerable individuals such as sults in drug tests for cannabis, it is possible to detect those with a family history of mental illness.[10][11] 12
3.3. SAFETY
3.2 Ingredients Synthetic cannabis is claimed by the manufacturers to contain a mixture of traditionally used medicinal herbs, each of which producing mild effects, with the overall blend resulting in the cannabis-like intoxication produced by the product. Herbs listed on the packaging of Spice include Canavalia maritima (Coastal Jackbean), Nymphaea caerulea (Blue Egyptian water lily), Scutellaria nana (dwarf skullcap), Pedicularis densiflora (Indian warrior), Leonotis leonurus (lion’s tail), Zornia latifolia (maconha brava), Nelumbo nucifera (lotus), and Leonurus sibiricus (honeyweed). However, when the product was analyzed by laboratories in and elsewhere, it was found that many of the characteristic “fingerprint” molecules expected to be present from the claimed plant ingredients were not present. There were also large amounts of synthetic tocopherol present. This suggested that the actual ingredients might not be the same as those listed on the packet, and a German government risk assessment of the product conducted in November 2008 concluded that it was unclear as to what the actual plant ingredients were, where the synthetic tocopherol had come from, and whether the subjective cannabis-like effects were actually produced by any of the claimed plant ingredients or instead caused by a synthetic cannabinoid drug.
3.2.1
Artificial cannabinoids
In January 2009, researchers at the University of Freiburg in announced that an active substance in Spice was an undisclosed analogue of the synthetic cannabinoid 47,497.[12] Later that month, 47,497 along with its dimethylhexyl, dimethyloctyl and dimethylnonyl homologues, were added to the German controlled drug schedules.[13][14] In May the analogue of 47,497 was named cannabicyclohexanol.[15] In July 2010, it was announced that JWH-018 is one of the active components in at least three versions of Spice, which had been sold in a number of countries around the world since 2002, often marketed as incense.[16][17][18][19] Another potent synthetic cannabinoid, HU-210, has been reported to have been found in Spice seized by U.S. Customs and Border Protection.[20] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[21] Different ratios of JWH-018 and 47,497 and their analogues have been found in different brands of synthetic cannabis[22] and manufacturers constantly change the composition of their products.[23] The amount of JWH-018 in Spice has been found to vary from 0.2% to 3%.[24]
13 not produce classical cannabis intoxication effects. This includes substituted cathinone derived stimulant drugs such as 4-methylbuphedrone and 4-methyl-alpha-PPP, and psychedelic tryptamine derivatives such as 4-HODET.[25][26] In 2013 a designer opioid drug AH-7921 was detected in smoking blends in Japan, along with several novel cannabinoids and a cathinone analogue.[27] New Zealand An analysis of 41 different synthetic cannabis blends sold commercially in New Zealand, conducted by the Institute of Environmental Science and Research and released in July 2011, found 11 different synthetic cannabinoid ingredients used: including JWH-018, JWH-073, AM-694, AM-2201, RCS-4, RCS-4 butyl homologue, JWH-210, JWH-081, JWH-250 (or possibly JWH-302, isomer not determined), JWH-203, and JWH-122— with between one and five different active ingredients, though JWH-018 was present in 37 of the 41 blends tested. In two brands the benzodiazepine anxiolytic drug phenazepam was also found, which is classified as a prescription medicine in New Zealand, and so these brands were ordered to be removed from the market by emergency recall.[28][29] Since this time, a further 15 cannabinoid compounds have been detected as ingredients of synthetic cannabis blends in New Zealand and banned as temporary class drugs.[30] In 2013 another hypnotic medication, zaleplon was found to have been used as an active ingredient in a blend that had been sold in New Zealand during 2011-2012.[31]
3.3 Safety No official studies have been conducted on the effects of synthetic cannabinoids on humans (as is usually the case with known toxic and/or illegal compounds).[36] However, reports describing effects seen in patients seeking medical care after taking synthetic cannabinoids have been published. Compared to cannabis and its active cannabinoid THC, the adverse effects are often much more severe and can include hypertension, tachycardia, myocardial infarction,[37] agitation, vomiting, hallucinations, psychoses, seizures, convulsions[38] and panic attacks.[39][40][41][42][43] Among individuals who need emergency treatment after using synthetic cannabis, the most common symptoms are accelerated heartbeat, high blood pressure, nausea, blurred vision, hallucination and agitation.[44] Other symptoms included epileptic seizures, acute psychosis, and heart attacks.[44]
At least one death has been linked to overdose of synthetic cannabinoids[45] and in Colorado three deaths in September 2013 have been investigated for being linked to synthetic cannabinoids.[46] In December 2012, after two weeks of daily synthetic cannabis use, a 17-year old Other non-cannabinoid ingredients have also been found girl suffered multiple strokes and subsequent brain damin synthetic cannabis blends around the world, but they do age, leaving her blind and paralyzed.[47]
14
CHAPTER 3. SYNTHETIC CANNABIS
These more severe adverse effects in contrast to use of 3.5 Legal status marijuana are believed to stem from the fact that many of the synthetic cannabinoids are full agonists to the 3.5.1 Europe cannabinoid receptors, CB1R and CB2R, compared to THC which is only a partial agonist and thus not able Austria The Austrian Ministry of Health announced on to saturate and activate all of the receptor population no December 18, 2008 that Spice would be controlled [48] matter of dose and resulting concentration. It has also under Paragraph 78 of their drug law on the grounds been seen that phase 1 metabolism of JWH-018 results that it contains an active substance that affects the in at least nine monohydroxylated metabolites and with functions of the body, and the legality of JWH-018 at least three of the metabolites shown to have full agois under review.[55][56][57] nistic effect on CB1R which compared to metabolism of THC only results in one psychoactive monohydroxylated JWH-018, 47,497 and the C6, C8 and C9 metabolite. This may further explain the increased toxihomologues of 47,497 are illegal in city of synthetic cannabinoids compared to THC.[45] since January 22, 2009.[14][58] Professor John W. Huffman, who first synthesised many of the cannabinoids used in synthetic cannabis, is quoted Finland Spice blends are classified as a medicine in Finland, and, therefore, it is illegal to order them withas saying, “People who use it are idiots.”[36] “You don't out a prescription. In practice, it is not possible to know what it’s going to do to you.”[49] A who conget a prescription. sumed 3 g of Spice Gold every day for several months showed withdrawal symptoms, similar to those associated with withdrawing from the use of narcotics. Doc- JWH-018, 47,497 (and its homologues) and HU-210 were all made illegal in on February tors treating the also noted that his use of the [50] 24, 2009.[59] product showed signs associated with addiction. One case has been reported wherein a , who had previwith a variety ously suffered from cannabis-induced recurrent psychotic Ireland From June 2010, JWH-018, along [60] of other designer drugs, is illegal. episodes, suffered reactivation of his symptoms after using Spice. Psychiatrists treating him have suggested Latvia JWH-018, JWH-073, 47,497 (and its homothat the lack of an antipsychotic chemical, similar to logues) and HU-210 are all banned in Latvia as well cannabidiol found in natural cannabis, may make synas leonotis leonurus.[61] thetic cannabis more likely to induce psychosis than natural cannabis.[51] Poland JWH-018 and many of the herbs mentioned on the ingredient lists of Spice and similar preparaStudies are currently available which suggest an assotions were made illegal in May 2009. The bill was ciation between synthetic cannabinoids and psychosis. ed by Polish Sejm,[62][63] Polish Senat[64] and Physicians should be aware that the use of synthetic was signed by the President.[65] cannabinoids can be associated with psychosis and investigate possible use of synthetic cannabinoids in patients with inexplicable psychotic symptoms. In contrast Romania Spice was made illegal in Romania on February 15, 2010.[66] to most other recreational drugs, the dramatic psychotic state induced by use of synthetic cannabinoids has been reported in multiple cases to persist for several weeks, Russia On April 9, 2009, the Chief Medical Officer of the Russian Federation issued a resolution on reand in one case for seven months, after complete cessa[52] inforcing control over the sales of smoking blends. tion of drug use. Individuals with risk factors for psyThese blends, marketed under the trade names AMchotic disorders should be counseled against using syn[53] HI-CO, Dream, Spice (Gold, Diamond), Zoom, Exthetic cannabinoids. ses, Yucatán Fire and others, have been declared to contain Salvia divinorum, Hawaiian Wood Rose, and Blue Lotus, and are prohibited to be sold. These substances have been found to have “psychotropic, 3.4 Drug testing narcotic effects, contain poisonous components and represent potential threat for humans”. The resoluSpice does not cause a positive drug test for cannabis tion does not mention JWH-018 or other synthetic or other illegal drugs using GC-MS-screening with cannabinoids.[67] On January 14, 2010, the Russian library search, multi-target screening by LC-MS/MS, government issued a statement including 23 synor immunological screening procedures.[22][50] A study thetic cannabinoids found in smoking blends Hawaihas been conducted into the detection of metabolites of ian Rose and Blue Lotus on the list of prohibited JWH-018 in urine; the metabolites are mainly conjugates narcotic and psychotropic substances. Thus, all of with glucuronic acid and can be reliably detected by GC– these plants and compounds are now illegal in the MS/MS and LC–MS/MS.[54] Russian Federation.[68]
3.5. LEGAL STATUS Slovakia Spice is legal in Slovakia. The National AntiDrug Unit is considering adding it to the list of controlled substances.[69] The latest anti-drug law version (468/2009) valid since January 2010 still does not mention active compounds of Spice.[70]
15 ed on September 18, 2013 that bans entire families of synthetic drugs instead of only banning existing compounds that have been identified.[82][83] The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.[83]
Sweden 47,497-C6, 47,497-C7, 47,497-C8, 47,497-C9, JWH-018, JWH-073 and HU-210 it is claswere all made illegal in Sweden on September 15, New Zealand Spice is illegal in New Zealand, [84] sified as a Class C controlled drug. The New 2009. The bill was accepted on July 30, 2009 and Zealand Parliament ed a law in July 2013 ban[71] was put in effect on September 15, 2009. ning the sale of legal highs in dairies and supermarkets, but allowing some “low risk” drugs to continue Switzerland Spice has been banned in Switzerland.[72] to be sold through speciality licensed shops.[85] SynTurkey Spice a.k.a Bonzai added to the list of drugs thetic cannabinoids, as well as all other 'legal highs’ and psychotropic substances in 07.01.2011 by the were outlawed at midnight on 7 May 2014, after a law which numbered as 2011/1310 B.K.K. (Februlaw was ed a week prior by the New Zealand ary 13, 2011 and the Official Gazette No. 27845) government.[86] [73]
United Kingdom Spice was legal in the United King3.5.5 North America dom until December 2009, when it was classified as [74] a Class B drug. Canada
3.5.2
South America
Chile The Chilean Ministry of Health on April 24, 2009 declared the sale of synthetic cannabis to be illegal.[75]
Spice and specific forms of JWHxxx are not specifically prohibited in Canada, but synthetic cannabis is listed as a schedule II drug.[87][88] Health Canada is debating on the subject.[89][90] United States
3.5.3
Asia
See also: JWH-018 § United States South Korea South Korea officially added JWH-018, 47,497 and HU-210 to the controlled substance The case of David Mitchell Rozga, an American teenager list on July 1, 2009, effectively making these chem- from Indianola, Iowa, United States, brought internaicals illegal.[76] tional attention to K2. Rozga shot himself in the head Japan Japan has banned JWH-018, 47, 497, and ho- with a family owned hunting rifle in an apparent suicide in June 6, 2010. After news of Rozga’s death, it was remologues, and HU-210 since October 2009 ported by friends that they had smoked K2 with Rozga United Arab Emirates The United Arab Emirates had approximately one hour before his death. The nature of stated that Spice was an illegal substance and posses- his death and reports from numerous family , sion or intent to sell would be a jailable offense.[77] had led investigators to believe that it was likely Rozga was under the influence of a mind-altering substance, at the time of his death. The death of Rozga has been used 3.5.4 Australasia as a face of political lobbying against the continuation of K2, and other legal synthetic drugs, such as bath salts.[91] Australia On June 17, 2011, the Western Australian government banned all of the synthetic cannabi- Following the incident, an act to ban the use and distribunoids found in already existing products, including tion of the drug was proposed by the US Senator Chuck brands such as Kronic, Kalma, Voodoo, Kaos, and Grassley of Iowa as the David Mitchell Rozga Act. It was legislation by the United States Congress Mango Kush. Western Australia was the first state approved into [92] in June 2011. On July 10, 2012, President Barack in Australia to prohibit the sale of certain synthetic signed the Synthetic Drug Abuse Prevention Act Obama [78][79] On June 18, 2013, an interim cannabinoids. of 2012 into law. It banned synthetic compounds comban made a large list of product brands and synthetic monly found in synthetic marijuana, placing them under [80] substances illegal to sell anywhere in Australia. Schedule I of the Controlled Substances Act.[7] This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[81] Synthetic Prior to that, some compounds within synthetic cannabis cannabis remains illegal in NSW, where a bill was (HU-210) were scheduled in the USA under federal law,
16 while others (JWH-073) have been temporarily scheduled until final determination of their status can be made.[93][94][95][96] The Drug Enforcement istration (DEA) considers it to be a “drug of concern”,[97] citing "...a surge in emergency-room visits and calls to poison-control centers. Adverse health effects associated with its use include seizures, hallucinations, paranoid behavior, agitation, anxiety, nausea, vomiting, racing heartbeat, and elevated blood pressure.”[98][99] Several states independently ed acts making it illegal under state law, including Kansas in March 2010,[100] Georgia and Alabama in May 2010,[101][102] Tennessee and Missouri in July 2010,[103][104] Louisiana in August 2010, Mississippi in September 2010, and Iowa.[105] An emergency order was ed in Arkansas in July 2010 banning the sale of synthetic cannabis.[106] In October 2010, the Oregon Board of Pharmacy listed synthetic cannabinoid chemicals on its Schedule 1 of controlled substance, which means that the sale and possession of these substances is illegal under the Oregon Uniform Controlled Substances Act.[107] According to the National Conference of State Legislatures, several other states are also considering legislation, including New Jersey, New York, Florida, and Ohio.[104] Illinois ed a law on July 27, 2010 banning all synthetic cannabinoids that goes into effect January 1, 2011.[108] Michigan banned synthetic cannabinoids in October 2010,[109] and the South Dakota Legislature ed a ban on these products which was signed into law by Gov. Dennis Daugaard on February 23, 2012 (and which took immediate effect under an emergency clause of the state constitution).[110] Indiana banned synthetic cannabinoids in a law which became effective in March 2012.[111] North Carolina banned synthetic cannabis by a unanimous vote of the state senate, due to concerns that its contents and effects are reasonably similar to natural cannabis, and may cause equal effects in of psychological dependency.[112][113] Following cases in Japan involving the use of synthetic cannabis by Navy, Army and Marine Corps personnel resulted in the official banning of it,[114] a punitive general order issued on January 4, 2010 by the Commander Marine Corps Forces, Pacific prohibits the actual or attempted possession, use, sale, distribution or manufacture of synthetic cannabis as well as any derivative, analogue or variant of it.[115] On June 8, 2010, the U.S. Air Force issued a memorandum that banned the possession and use of Spice, or any other mood-altering substance except alcohol or tobacco, among its service .[116] On November 24, 2010, the DEA announced that it would make JWH-018, JWH-073, JWH-200, 47,497, and cannabicyclohexanol, which are often found in synthetic cannabis, illegal using emergency powers.[117] They will be placed in Schedule I of the Controlled Substances Act, within a month of the announcement, and the ban will last for at least a year.[118][119] The temporary ban, for at least a year, came into effect on
CHAPTER 3. SYNTHETIC CANNABIS March 1, 2011.[120] On October 20, 2011, the Louisiana State University football program announced that it had suspended three players, including star cornerback Tyrann Mathieu, who tested positive for synthetic cannabis.[121]
3.6 History According to the Psychonaut Web Mapping Research Project, synthetic cannabis products, sold under the brand name Spice, first appeared in Europe in 2004.[122] The brand “Spice” was released in 2004 by the now-dormant company The Psyche Deli in London, UK. In 2006 the brand gained popularity. According to the Financial Times, the assets of The Psyche Deli rose from £65,000 in 2006 to £899,000 in 2007.[123] The EMCDDA reported in 2009 that 'Spice' products were identified in 21 of the 30 participating countries. Because 'Spice' was the dominant brand until 2009, the competing brands that started to appear from 2008 on were also dubbed 'Spice'. Spice can, therefore, refer to both the brand 'Spice', as to all herbal blends with synthetic cannabinoids added. A survey of readers of Mixmag in the UK in 2009 found that one in eight respondents had used synthetic cannabis, compared to 85% who had used cannabis.[124]
3.6.1 Slang In addition to K2 and Spice, other street names include Black Mamba (Turnera diffusa), Bombay Blue, Genie, and Zohai.[7] According to Partnership at Drugfree.org, other names also include Bliss, Blaze, JWH −018, −073, −250, Yucatan Fire, Skunk, Moon Rocks[125] and Bonzai (esp. in Turkey)[73]
3.7 References [1] Roland Macher; Tod W. Burke, Ph.D, Stephen S. Owen, Ph.D. “Synthetic Marijuana”. FBI Law Enforcement Bulletin. Retrieved 22 July 2012. [2] Mary Carmichael (March 4, 2010). “K2: Scary Drug or Another Drug Scare?". Newsweek. Retrieved November 24, 2010. [3] “What’s the buzz?: Synthetic marijuana, K2, Spice, JWH018 : Terra Sigillata”. Scienceblogs.com. Retrieved November 24, 2010. [4] Grim, Ryan (November 24, 2010). “K2 Crackdown: DEA Using Emergency Powers To Ban Fake Pot”. The Huffington Post. Retrieved November 25, 2010. [5] Jeanne Meserve (February 28, 2011). “DEA imposes “emergency” ban to control synthetic marijuana”. CNN.
3.7. REFERENCES
[6] Citing Imminent Hazard to Public Safety, DEA Temporarily Places Synthetic Cannabinoids Into Schedule I [7] Vashi, Sonam (September 26, 2012). K2 Trend Not Slowing Down WebMD Medical News via KOKI-TV [8] http://www.npr.org/blogs/health/2012/03/30/ 149679528/new-york-bans-synthetic-marijuana [9] www.emed-journal.com Lapoint J, Nelson LS. Synthetic Cannabinoids: The Newest, Almost Illicit Drug of Abuse. Emergency Medicine 2011;43(2):26-28 [10] Cannabis, synthetic cannabinoids, and psychosis risk: What the evidence says [11] Synthetic Cannabis May Pose an Even Greater Psychosis Risk [12] 19, 2009.19/ Hauptwirkstoff von “Spice Girl” identifiziert. W was here. January 19, 2009 (German) [13] “Modedroge “Spice” ist verboten!" (in German). Bmg.bund.de. March 10, 2009. Retrieved August 24, 2010. [14] BGBl I Nr. 3 vom January 21, 2009, 22. BtMÄndV vom 19. Jan 2009, S. 49–50. [15] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda Y (May 2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1–3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892. [16] “Gefährlicher Kick mit Spice (German)". Fr-online.de. Retrieved August 24, 2010. [17] “Erstmals Bestandteile der Modedroge “Spice” nachgewiesen (German)". Haz.de. Retrieved August 24, 2010. [18] “Spice enthält chemischen Wirkstoff (German)". Badische-zeitung.de. Retrieved August 24, 2010. [19] Schifano, F.; Corazza, O.; Deluca, P.; Davey, Z.; Di Furia, L.; Farre', M.; Flesland, L.; Mannonen, M.; Pagani, S.; Peltoniemi, T.; Pezzolesi, C.; Scherbaum, N.; Siemann, H.; Skutle, A.; Torrens, M.; Van Der Kreeft, P. (2009). “Psychoactive drug or mystical incense? Overview of the online available information on Spice products”. International Journal of Culture and Mental Health 2 (2): 137. doi:10.1080/17542860903350888. [20] “Spice” – Plant material(s) laced with synthetic cannabinoids or cannabinoid mimicking compounds (U.S. Drug Enforcement istration) [21] Lindigkeit, Rainer; Boehme, A; Eiserloh, I; Luebbecke, M; Wiggermann, M; Ernst, L; Beuerle, T (October 30, 2009). “Spice: A never-ending story?". Forensic Science International 191 (1): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [22] Auwärter, V., et al. (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. Free version
17
[23] Emanuel, C. E. J.; Ellison, B.; Banks, C. E. (2010). “Spice up your life: screening the illegal components of ‘Spice’ herbal products”. Analytical Methods 2 (6): 614. doi:10.1039/c0ay00200c. [24] Stafford, Ned. Synthetic Cannabis Mimic Found in Herbal Incense. Royal Society of Chemistry: Chemistry World. January 15, 2009. Accessed: June 17, 2010 [25] Kikura-Hanajiri, R.; Uchiyama, N.; Goda, Y. (2011). “Survey of current trends in the abuse of psychotropic substances and plants in Japan”. Legal Medicine 13 (3): 109–115. doi:10.1016/j.legalmed.2011.02.003. PMID 21377397. [26] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [27] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [28] Whitworth, Chris (July 7, 2011). “Kronic ingredients secret to stop industry 'cowboys’". 3 News. Retrieved November 16, 2011. [29] 'Herbal High' synthetic Cannabinoid composition, released by ESR July 2011. (PDF) . Retrieved on August 7, 2011. [30] Temporary Class Drug Notices. New Zealand Ministry of Health [31] Conviction for sale of herbal smoking material containing a prescription medicine. MedSafe Media release, 28 March 2013 [32] Aung, M. M.; Griffin, G.; Huffman, J. W.; Wu, M. J.; Keel, C.; Yang, B.; Showalter, V. M.; Abood, M. E.; Martin, B. R. (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [33] Devane, W. A., et al. (1992). “A novel probe for the cannabinoid receptor”. Journal of Medical Chemistry 35 (11): 2065–2069. doi:10.1021/jm00089a018. PMID 1317925. [34] Compton, D.; Johnson, M.; Melvin, L.; Martin, B. (1992). “Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents”. The Journal of Pharmacology and Experimental Therapeutics 260 (1): 201–209. PMID 1309872. [35] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted June 7, 2001
18
[36] “Fake pot that acts real stymies law enforcement”. Associated Press. February 17, 2010. Retrieved April 21, 2010. [37] Mir, A; Obafemi, A; Young, A; Kane, C (December 2011). “Myocardial infarction associated with use of the synthetic cannabinoid k2.”. Pediatrics 128 (6): e1622–7. doi:10.1542/peds.2010-3823. PMID 22065271. [38] Schneir, AB; Baumbacher, T (December 13, 2011). “Convulsions Associated with the Use of a Synthetic Cannabinoid Product.”. Journal of Medical Toxicology 8 (1): 62–4. doi:10.1007/s13181-011-0182-2. PMID 22160733. [39] Jeanna Bryner (March 3, 2010). “Fake Weed, Real Drug: K2 Causing hallucinations in Teens”. LiveScience. Retrieved April 21, 2010. [40] Vardakou, I; Pistos, C; Spiliopoulou, Ch (2010). “Spice drugs as a new trend: Mode of action, identification and legislation”. Toxicology Letters 197 (3): 157–62. doi:10.1016/j.toxlet.2010.06.002. PMID 20566335. [41] Auwärter, V., et al. (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. [42] Every-Palmer, S (2010). “Warning: Legal synthetic cannabinoid-receptor agonists such as JWH-018 may precipitate psychosis in vulnerable individuals”. Addiction 105 (10): 1859–60. doi:10.1111/j.13600443.2010.03119.x. PMID 20840203. [43] Müller, H.; Sperling, W.; Köhrmann, M.; Huttner, H.; Kornhuber, J.; Maler, J. (2010). “The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes”. Schizophrenia research 118 (1–3): 309–310. doi:10.1016/j.schres.2009.12.001. PMID 20056392. [44] “Legal highs linked to psychosis”. New Zealand Herald. Apr 5, 2014. [45] Brents, L. K.; Reichard, E. E.; Zimmerman, S. M.; Moran, J. H.; Fantegrossi, W. E.; Prather, P. L. (2011). “Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity”. PLoS ONE 6 (7): e21917. doi:10.1371/journal.pone.0021917. PMC 3130777. PMID 21755008. [46] Coffman, K. (6 September 2013). “Colorado probes three deaths possibly linked to synthetic marijuana”. Reuters (Denver). Retrieved 30 January 2014. [47] Taylor, V. (14 September 2013). “Teen makes miraculous progress nine months after synthetic marijuana nearly kills her”. NY Daily News. Retrieved 30 January 2014. [48] Fantegrossi, W. E.; Moran, J. H.; Radominska-Pandya, A; Prather, P. L. (2014). “Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9 -THC: Mechanism underlying greater toxicity?". Life Sciences 97 (1): 45–54. doi:10.1016/j.lfs.2013.09.017. PMID 24084047.
CHAPTER 3. SYNTHETIC CANNABIS
[49] “Fake Weed, Real Drug: K2 Causing Hallucinations in Teens”. LiveScience. Retrieved November 24, 2010. [50] Zimmermann, U., et al. (2009). “Withdrawal phenomena and dependence syndrome after the consumption of “spice gold"". Deutsches Arzteblatt international 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [51] Müller, H.; Sperling, W.; Köhrmann, M.; Huttner, H.; Kornhuber, J.; Maler, J. (2010). “The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes”. Schizophrenia research 118 (1–3): 309–310. doi:10.1016/j.schres.2009.12.001. PMID 20056392. [52] Hurst, D; Loeffler, G; McLay, R (October 2011). “Psychosis associated with synthetic cannabinoid agonists: a case series.”. The American Journal of Psychiatry 168 (10): 1119. doi:10.1176/appi.ajp.2011.11010176. PMID 21969050. [53] Every-Palmer, S (September 1, 2011). “Synthetic cannabinoid JWH-018 and psychosis: an explorative study.”. Drug and alcohol dependence 117 (2-3): 152–7. doi:10.1016/j.drugalcdep.2011.01.012. PMID 21316162. [54] Sobolevsky, T.; Prasolov, I.; Rodchenkov, G. (2010). “Detection of JWH-018 metabolites in smoking mixture post-istration urine”. Forensic Science International 200 (1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [55] “Kräutermischung “Spice": Gesundheitsministerium stoppt Handel, December 18, 2008”. Derstandard.at. December 19, 2008. Retrieved June 19, 2010. [56] (AFP) (December 18, 2008). “Austria bans herbal incense 'Spice'". Google. Retrieved June 19, 2010. [57] “Gesundheitsministerium setzt Maßnahme zum Verbot von “Spice"". Bmgfj.gv.at. December 18, 2008. Retrieved June 19, 2010. [58] “Betäubungsmittelrecht: Modedroge Spice wird per Eilverordnung verboten”. Der Spiegel. Retrieved June 19, 2010. [59] “Arrêté du 24 février 2009 modifiant l’arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants”. Journal Officiel De La République Française. February 27, 2009. Retrieved June 19, 2010. [60] “Move on head shops 'not enough' – The Irish Times — Wed, Mar 3, 2010”. The Irish Times. March 3, 2010. Retrieved August 24, 2010. [61] “Noteikumi par Latvijā kontrolējamajām narkotiskajām vielām, psihotropajām vielām un prekursoriem” (in Latvian). likumi.lv. Retrieved June 19, 2010. [62] http://orka.sejm.gov.pl/Druki6ka.nsf/wgdruku/1547 [63] mm, PAP (February 12, 2009). “Sejm za delegalizacją 'dopalaczy'". Wiadomosci.gazeta.pl. Retrieved June 19, 2010.
3.7. REFERENCES
[64] “Senat poparł ustawę zakazującą handlu “dopalaczami” – Wiadomości — WP.PL”. Wiadomosci.wp.pl. Retrieved June 19, 2010. [65] http://www.prezydent.pl/x.node?id=26543130 [66] “OUG 6/2010 pentru modificarea si completarea Legii nr. 143/2000 privind prevenirea si combaterea traficului si consumului ilicit de droguri si pentru completarea Legii nr. 339/2005 privind regimul juridic al plantelor, substantelor si preparatelor stupefiante si psihotrope. Ordonanta de urgenta nr. 6/2010”. Dreptonline.ro. August 3, 2000. Retrieved June 19, 2010. [67] "О запрещении реализации продукции с содержанием шалфея предсказателей, гавайской розы и голубого лотоса". Rospotrebnadzor.ru. Retrieved June 19, 2010. [68] "Постановление от 31 декабря 2009 г. № 1186 О внесении изменений в некоторые постановления Правительства Российской Федерации по вопросам, связанным с оборотом наркотических средств". Government.ru. Retrieved June 19, 2010. [69] “Po ketamíne by sa mala zakázať bylinná zmes Spice”. SME.sk. Retrieved June 19, 2010. [70] [71] “Regeringen förbjuder nätdrogen “Spice” from the website of the Government Offices of Sweden”. Regeringen.se. Retrieved June 19, 2010. [72] Adams, Stephen (February 13, 2009). “Teens in Britain getting legally high on synthetic cannabis banned across Europe”. The Daily Telegraph (UK). Retrieved August 13, 2009. [73] “Sentetik Cannabinoid (Bonzai)". www. uyusturucumaddeler.com. Retrieved 12 August 2014. [74] Portal, Gaetan (December 23, 2009). "'Legal high' drugs banned in UK”. BBC News. Retrieved May 23, 2010. [75] “Chile prohibe uso de spice, La Nacion 24 de Abril 2009”. Lanacion.cl. Retrieved June 19, 2010. [76]
(July 2, 2009). “1 '5- - ’ " (in Korean). . Retrieved February 18, 2010.
[77] Dubai Customs foil 126 attempts to smuggle narcotic [78] Jerga, Josh (June 13, 2011). “Fake cannabis to be outlawed in WA”. The Sydney Morning Herald. Retrieved June 15, 2011. [79] O'Brien, Amanda (April 11, 2011). “Miners working high on synthetic grass”. The Australian. Retrieved April 17, 2011.
19
[82] “NSW law to ban synthetic drugs ed”. September 18, 2013. Retrieved October 28, 2013. [83] Coultan, Mark (September 10, 2013). “NSW law to ban synthetic drugs to stop 'legal highs’". The Australian. Retrieved October 28, 2013. [84] “Cannabis substitute “Spice” now illegal”. TVNZ. April 1, 2009. Retrieved March 2, 2011. [85] Heather, Ben (October 6, 2013). “Kronic king gets the green light”. Retrieved October 28, 2013. [86] “Legal highs banned from midnight”. May 7, 2014. Retrieved May 8, 2014. [87] “Controlled Drugs and Substances Act”. Laws.justice.gc.ca. November 15, 2010. Retrieved November 24, 2010. [88] “Consolidated Index of Drugs and Substances”. Isomerdesign.com. April 24, 2010. Retrieved June 19, 2010. [89] “Ian Bussières : Le spice: la capitale craque pour les “herbes magiques” | Société". Cyberpresse.ca. Retrieved June 19, 2010. [90] “Une pilule une petite granule : Le Spice, un substitut au cannabis ?". Pilule.telequebec.tv. Retrieved June 19, 2010. [91] “K2 Drug Facts”. K2drugfacts.com. Retrieved 2012-0909. [92] “The David Mitchell Rozga Act (S.605 - Dangerous Synthetic Drug Control Act of 2011)". Opencongress.org. Retrieved 2012-09-09. [93] “HU-210”. USDOJ.gov. Retrieved September 16, 2010. [94] Cook, Morgan (February 28, 2011). “Synthetic marijuana illegal as of Tuesday”. North County Times (San Diego). Retrieved February 28, 2011. [95] [96] “Drug Scheduling from the US Drug Enforcement istration website”. Justice.gov. Retrieved June 19, 2010. [97] Donna Leinwand (May 24, 2010). 24, 2010-k2_N.htm “Places race to outlaw K2 'Spice' drug”. USA Today. Retrieved July 26, 2010. [98] Meserve, Jeanne (February 28, 2011). “DEA imposes “emergency” ban to control synthetic marijuana”. CNN. Retrieved March 1, 2011. [99] Ben Paynter: The Big Business of Synthetic Highs, Bloomerg Businessweek June, 2011
[80] Bradbury, David (June 18, 2013). “Competition and Consumer Act 2010 - Consumer Protection Notice No. 3 of [100] The Associated Press. How major issues fared in Kansas Legislature. CNBC. May 23, 2010. Accessed: May 23, 2013 - Imposition of Interim Ban on Certain Consumer 2010 Goods Containing Synthetic Drug Substances”. Retrieved October 28, 2013. [101] Simmons, Andria (May 24, 2010). “Governor signs bill [81] “Synthetic drug substances - national interim ban”. to outlaw synthetic marijuana”. ajc.com. Retrieved June ACCC. Retrieved October 28, 2013. 19, 2010.
20
CHAPTER 3. SYNTHETIC CANNABIS
[102] May 20, 2010 (May 20, 2010). “Alabama Coalition Gets [120] Meserve, Jeanne (February 28, 2011). “DEA imposes Salvia and K2 Banned in Their State”. CADCA. Re“emergency” ban to control synthetic marijuana”. CNN. trieved August 24, 2010. Retrieved March 1, 2011. [103] Haas, Brian. 'K2', 'K3' synthetic drugs are illegal in TN [121] Schlabach, Mark (October 20, 2011). “Sources: LSU starting July 1. The Tennessean. May 30, 2010. Alayers had positive tests”. ESPN.com. Retrieved Novemcessed: June 17, 2010 ber 4, 2011. [104] Gay, Malcolm. (2010-07-10) Synthetic Marijuana Spurs [122] Spice Report Psychonaut Web Mapping Research Project State Bans. New York Times. Retrieved on August 7, [123] “The story of Spice”. Financial Times. February 13, 2011. 2009. Retrieved September 19, 2010. [105] Iowa Code § 124.204(4)(u) (defining a Schedule I controlled substance to include “synthetic equivalents of the [124] Winstock, A.; Mitcheson, L.; Deluca, P.; Davey, Z.; Corazza, O.; Schifano, F. (2010). “Mephedrone, new substances contained in the Cannabis plant, or in the kid for the chop?". Addiction (Abingdon, England) 106 resinous extractives of such plant, and synthetic sub(1): 154–161. doi:10.1111/j.1360-0443.2010.03130.x. stances, derivatives, and their isomers with similar chemPMID 20735367. ical structure and pharmacological activity to those substances contained in the plant....”) [125] K2 – Spice via Partnership at Drugfree.org [106] Gavin Lesnick (July 2, 2010). “Beebe signs emergency ban on K2”. Arkansas Online (Arkansas Democrat Gazette). Retrieved July 26, 2010.
3.8 External links
[107] “Synthetic Cannabis — Controlled Substance Information”. Retrieved October 16, 2010.
• Erowid
[108] Daniel Martynowicz. “Illinois Bans Synthetic Cannabinoids”. Retrieved September 14, 2010.
• Synthetic cannabinoid profile European Monitoring Centre for Drugs and Drug Addiction
[109] http://www.michigan.gov/lara/0,4601,7-154-10573_ 11472-280858--,00.html [110] Argus Leader, "New law bans synthetic drugs,” by John Hult (February 23rd 2012 - retrieved on May 14th, 2012). [111] http://www.in.gov/attorneygeneral/2974.htm [112] “NC Senate OKs synthetic pot ban”. WRAL-TV. 10 February 2011. Retrieved 27 September 2012. [113] “Make Synthetic Cannabinoids Illegal”. General Assembly of North Carolina. 31 January 2011. Retrieved 27 September 2012. [114] Allan, David; Fisher, Cindy. Ruling Clarifies 'Legal' Drug Policy. Stars and Stripes via Military.com. May 23, 2010. Accessed: May 23, 2010 [115] Marines Ban Spice Drug. Military.com. May 23, 2010. Accessed: May 23, 2010 [116] “Air Force officials ban use and possession of spice, mood-altering substances. Air Force News. June 17, 2010. Accessed: June 18, 2010”. Af.mil. Retrieved June 19, 2010. [117] “DEA Moves to Emergency Control Synthetic Marijuana”. DEA Public Affairs. U.S. Drug Enforcement istration. November 24, 2010. Retrieved February 19, 2011. [118] Grim, Ryan (November 24, 2010). “K2 Crackdown: DEA Using Emergency Powers To Ban Fake Pot”. Huffington Post. Retrieved November 24, 2010. [119] By the CNN Wire Staff (November 24, 2010). “Feds move to ban 'fake pot'". CNN. Retrieved November 24, 2010.
Chapter 4
4-HTMPIPO 4-HTMPIPO is a synthetic cannabinoid drug first identified in smoking products purchased from online vendors in 2012.[1] 4-HTMPIPO is the product resulting from the electrophilic addition of water to the cyclopropane moiety of synthetic cannabinoid UR-144.[1] Nothing is known about the in vitro or in vivo pharmacology of 4HTMPIPO.
4.1 See also • AB-001 • JWH-018 • UR-144 • XLR-11
4.2 References [1] Kavanagh, P.; Grigoryev, A.; Savchuk, S.; Mikhura, I.; Formanovsky, A. (2013). “UR-144 in products soldviathe Internet: Identification of related compounds and characterization of pyrolysis products”. Drug Testing and Analysis: n/a. doi:10.1002/dta.1456.
21
Chapter 5
5F-PB-22 5F-PB-22 or Quinolin-8-yl 1-(5-fluoropentyl)−1Hindole-3-8-carboxylate is a designer drug and a possible cannabinoid agonist. The structure of 5F-PB-22 appears to have been designed with an understanding of structure-activity relationships within the indole class of cannabinoids on the Forendex website of potential drugs of abuse.[1] In January 2014, 5F-PB-22 was designated as a Schedule I controlled substance in the United States.[2]
5.1 See also • AM-2201 • JWH-018 • QUCHIC • QUPIC • SDB-001
5.2 References [1] 5F-PB-22 page on Forendex [2] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G; Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C (2014). “Four Postmortem Case Reports with Quantitative Detection of the Synthetic Cannabinoid, 5F-PB-22”. Journal of analytical toxicology. doi:10.1093/jat/bku048. PMID 24876364.
22
Chapter 6
A-40174 A-40174 (SP-1) is an analgesic drug which acts as a potent cannabinoid receptor agonist, and was developed by Abbott Laboratories in the 1970s.[1]
6.1 See also • A-41988 • Menabitan
6.2 References [1] Reggio, Patricia H., ed. (2009). “The Cannabinoid Receptors”. doi:10.1007/978-1-59745-503-9. ISBN 978-158829-712-9.
23
Chapter 7
A-41988 A-41988 (BW29Y) is an analgesic drug which acts as a cannabinoid agonist. It was developed by Abbott Laboratories in the 1970s,[1][2] and researched for potential use in the treatment of glaucoma,[3] but never commercialised.
7.1 See also • A-40174 • Menabitan
7.2 References [1] Winn, M.; Arendsen, D.; Dodge, P.; Dren, A.; Dunnigan, D.; Hallas, R.; Hwang, K.; Kyncl, J.; Lee, Y. H.; Plotnikoff, N.; Young, P.; Zaugg, H. (1976). “Drugs derived from cannabinoids. 5. Delta6a,10aTetrahydrocannabinol and heterocyclic analogs containing aromatic side chains”. Journal of Medicinal Chemistry 19 (4): 461–471. doi:10.1021/jm00226a003. PMID 817021. [2] Guterman A, Somani P, Bachand RT. Clinical Pharmacology and Therapeutics 1979; 25:227. [3] Tiedeman, J. S.; Shields, M. B.; Weber, P. A.; Crow, J. W.; Cocchetto, D. M.; Harris, W. A.; Howes, J. F. (1981). “Effect of synthetic cannabinoids on elevated intraocular pressure”. Ophthalmology 88 (3): 270–277. doi:10.1016/s0161-6420(81)35052-0. PMID 7015221.
24
Chapter 8
A-796,260 A-796,260 is a drug developed by Abbott Laboratories that acts as a potent and selective cannabinoid CB2 receptor agonist. Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids with the 3-tetramethylcyclopropylmethanone group, imparts significant selectivity for CB2 , and A-796,260 was found to be a highly selective CB2 agonist with little affinity for CB1 , having a CB2 Kᵢ of 4.6 nM vs 945 nM at CB1 .[1] It has potent analgesic and anti-inflammatory actions in animal models, being especially effective in models of neuropathic pain, but without producing cannabis-like behavioral effects.[2]
8.1 See also • A-834,735 • A-836,339 • JWH-200 • UR-144 • XLR-11
8.2 References [1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781. [2] Yao BB, et al. (January 2008). “In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models”. British Journal of Pharmacology 153 (2): 390–401. doi:10.1038/sj.bjp.0707568. PMC 2219533. PMID 17994110.
25
Chapter 9
A-834,735 A-834,735 is a drug developed by Abbott Laboratories that acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors, with a Kᵢ of 12nM at CB1 and 0.21nM at CB2 . Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids, with the 3tetramethylcyclopropylmethanone group of A-834,735 and related compounds, imparts significant selectivity for CB2 , with most compounds from this group found to be highly selective CB2 agonists with little affinity for CB1 . However low nanomolar CB1 binding affinity is retained with certain heterocyclic 1-position substituents such as (N-methylpiperidin-2-yl)methyl (cf. AM-1220, AM1248), or the (tetrahydropyran-4-yl)methyl substituent of A-834,735, resulting in compounds that still show significant affinity and efficacy at both receptors despite being CB2 selective overall.[1][2][3][4][5]
9.1 See also • A-796,260 • AB-001 • JTE 7-31 • UR-144 • XLR-11
9.2 References [1] Dart M, et al. (2006). 1-Alkyl-3-keto-indoles: identification and in vitro characterization of a series of potent cannabinoid ligands. In 2006 Symposium on the Cannabinoids. International Cannabinoid Research Society: Burlington, VT. [2] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473.
26
[3] Chin CL, et al. (January 2008). “Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI”. British Journal of Pharmacology 153 (2): 367–79. doi:10.1038/sj.bjp.0707506. PMC 2219521. PMID 17965748. [4] Frost, J. M., et al. (2008). “Indol-3-yltetramethylcyclopropyl Ketones: Effects of Indole Ring Substitution on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 51 (6): 1904. doi:10.1021/jm7011613. PMID 18311894. [5] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781.
Chapter 10
A-836,339 A-836,339 is a drug developed by Abbott Laboratories that acts as a potent cannabinoid receptor full agonist. It is selective for CB2 , with Kᵢ values of 0.64nM at CB2 vs 270nM at the psychoactive CB1 receptor, but while it exhibits selective analgesic, anti-inflammatory and antihyperalgesic effects at low doses,[1] its high efficacy at both targets results in typical cannabis-like effects appearing at higher doses, despite its low binding affinity for CB1 .[2]
10.1 References [1] McGaraughty, S., et al. (2009). “A CB(2) receptor agonist, A-836339, modulates wide dynamic range neuronal activity in neuropathic rats: contributions of spinal and peripheral CB(2) receptors”. Neuroscience 158 (4): 1652– 1661. doi:10.1016/j.neuroscience.2008.11.015. PMID 19063946. [2] Yao, B., et al. (2009). “Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 2,2,3,3tetramethyl-cyclopropanecarboxylic acid 3-(2-methoxyethyl)−4,5-dimethyl-3H-thiazol-(2Z)-ylidene-amide, using in vitro pharmacological assays, in vivo pain models, and pharmacological magnetic resonance imaging”. The Journal of Pharmacology and Experimental Therapeutics 328 (1): 141–151. doi:10.1124/jpet.108.145011. PMID 18931146.
27
Chapter 11
AB-001 AB-001 or 1-pentyl-3-(1-adamantoyl)indole is a designer drug that was found as an ingredient in synthetic cannabis smoking blends in Ireland in 2010 and Hungary and in 2011.[1][2][3] It is unclear who AB-001 was originally developed by, but it is structurally related to compounds such as AM-1248 and its corresponding 1-(tetrahydropyran-4-ylmethyl) analogue, which are known to be potent cannabinoid agonists with moderate to high selectivity for CB2 over CB1 .[4][5] The first published synthesis and pharmacological evaluation of AB-001 revealed that it acts as a full agonist at CB1 (EC50 = 35 nM) and CB2 receptors (EC50 = 48 nM).[6] However, AB-001 was found to possess only weak cannabimimetic effects in rats at doses up to 30 mg/kg, making it less potent than carboxamide analogue SDB001, which possesses potent cannabimimetic activity at doses of 3 mg/kg.[6]
11.1 See also • A-834,735
and identification of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary”. Forensic Science International 214 (1–3): 27–32. doi:10.1016/j.forsciint.2011.07.011. PMID 21813254. [2] Research on Head Shop drugs in Dublin: Part 2 [3] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012). “The detection of the urinary metabolites of 3-\(adamantan1-yl)carbonyl]−1-pentylindole (AB-001), a novel cannabimimetic, by gas chromatography-mass spectrometry”. Drug Testing and Analysis 4 (6): 519–524. doi:10.1002/dta.350. PMID 22102533. [4] US patent 7820144, Makriyannis A, Deng H, “Receptor selective cannabimimetic aminoalkylindoles”, granted 2010-10-26 [5] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781. [6] Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. (2013). “The synthesis and pharmacological evaluation of adamantanederived indoles: Novel cannabimimetic drugs of abuse”. ACS Chemical Neuroscience 4 (7): 130403084729007. doi:10.1021/cn400035r.
• AB-005 • AM-1248 • JWH-018 • JWH-250 • RCS-4 • RCS-8 • SDB-001 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • (1-Pentylindol-3-yl)-(2,2,3,3tetramethylcyclopropyl)methanone
11.2 References [1] Jankovics, P. T.; Váradi, A. S.; Tölgyesi, L. S.; Lohner, S.; Németh-Palotás, J. L.; Balla, J. Z. (2012). “Detection
28
Chapter 12
AB-005 AB-005 or [1-[(1-methyl-2-piperidinyl)methyl]−1Hindol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone is a designer drug offered by online vendors as a cannabimimetic agent. The structure and pharmacological activity of AB-005 was published in 2010, prior to its commercial availability in 2012, where it was reported to have high affinity for both CB1 (Kᵢ = 5.5 nM) and CB2 receptors (Kᵢ = 0.48 nM).[1] AB-005 features groups found in other previously reported synthetic cannabinoids: the tetramethylcyclopropane group of UR-144 and XLR-11 as well as the (1-methyl2-piperidinyl)methyl substituent of AM-1248 and AM-1220. No information regarding the in vivo activity of AB-005 has been published, and only anecdotal reports are known of its psychoactivity in humans.
12.1 Legal status Psychoactive products in New Zealand containing this drug have been given interim approval under recent psychoactive substances legislation.[2]
12.2 See also • AB-001 • AM-1248 • AM-1220 • JWH-018 • UR-144 • XLR-11
12.3 References [1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781.
29
[2] Ministry of Health – Manatū Hauora “Interim Product Approvals”, Ministry of Health NZ, New Zealand, 2 January 2013. Retrieved on 2 January 2013.
Chapter 13
AB-CHMINACA AB-CHMINACA is an indazole-based synthetic cannabinoid. It is a potent agonist of the CB1 receptor.[1]
13.1 References [1] AB-CHMINACA, Cayman Chemicals
30
Chapter 14
AB-FUBINACA AB-FUBINACA is a drug that acts as a potent agonist for the cannabinoid receptors, with Kᵢ values of 0.9nM at CB1 and 23.2nM at CB2 . It was originally developed by Pfizer in 2009 as an analgesic medication,[1] but was never pursued for human use. Subsequently in 2012, this compound was discovered as an ingredient in synthetic cannabis blends in Japan,[2] along with a related compound AB-PINACA which had not previously been reported. In January 2014, AB-FUBINACA was designated as a Schedule I controlled substance in the United States.[3]
14.1 See also • AB-PINACA • ADB-FUBINACA • ADBICA • APICA • APINACA • Benzydamine • NESS-040C5 • PF-03550096
14.2 References [1] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106982 [2] Uchiyama, N.; Matsuda, S.; Wakana, D.; KikuraHanajiri, R.; Goda, Y. (2012). “New cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan2-yl)−1-pentyl-1H-indazole-3-carboxamide (ABPINACA) and N-(1-amino-3-methyl-1-oxobutan-2yl)−1-(4-fluorobenzyl)−1H-indazole-3-carboxamide (AB-FUBINACA) identified as designer drugs in illegal products”. Forensic Toxicology 31: 93. doi:10.1007/s11419-012-0171-4.
31
[3] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G; Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C (2014). “Four Postmortem Case Reports with Quantitative Detection of the Synthetic Cannabinoid, 5F-PB-22”. Journal of analytical toxicology. doi:10.1093/jat/bku048. PMID 24876364.
Chapter 15
AB-PINACA AB-PINACA is a compound that was first identified as a component of synthetic cannabis products in Japan in 2012.[1] The pharmacological properties of this compound have not been formally studied or reported in the scientific literature, but it is presumably a cannabinoid agonist as it was found alongside a structurally related compound AB-FUBINACA which had previously been reported as a cannabinoid agonist in a 2009 Pfizer patent.[2][3]
15.1 See also • AB-FUBINACA • ADB-PINACA • APINACA • PF-03550096
15.2 References [1] Uchiyama, N.; Matsuda, S.; Wakana, D.; KikuraHanajiri, R.; Goda, Y. (2012). “New cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan2-yl)−1-pentyl-1H-indazole-3-carboxamide (ABPINACA) and N-(1-amino-3-methyl-1-oxobutan-2yl)−1-(4-fluorobenzyl)−1H-indazole-3-carboxamide (AB-FUBINACA) identified as designer drugs in illegal products”. Forensic Toxicology 31: 93. doi:10.1007/s11419-012-0171-4. [2] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106980 [3] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106982
32
Chapter 16
Abnormal cannabidiol Abnormal cannabidiol (abn-cbd) is a synthetic regioisomer of cannabidiol, which unlike most other cannabinoids produces vasodilator effects, lowers blood pressure, and induces cell migration, cell proliferation and mitogen-activated protein kinase activation in microglia, but without producing any psychoactive effects.[1][2] It has been shown that the actions of abnormal cannabidiol are mediated through a site separate from the CB1 and CB2 receptors,[2][3] which responds to abnormal cannabidiol, O-1602, and the endogenous ligands: anandamide (AEA), N-arachidonoyl glycine (NAGly) and N-arachidonoyl L-serine.[2][4][5][6] Multiple lines of evidence the proposed identification of this novel target in microglia as the previously “orphan” receptor GPR18.[2] Another possible target of abnormal cannabidiol is GPR55, which has also received much attention as a putative cannabinoid receptor,[7][8] although a growing body of evidence points to lysophosphatidylinositol (LPI) as the endogenous ligand for GPR55.[9][10] Further research suggests there are yet more additional cannabinoid receptors.[11][12][13][14]
the putative abnormal cannabidiol receptor”. BMC Neuroscience 11: 44. doi:10.1186/1471-2202-11-44. PMC 2865488. PMID 20346144. [3] Jarai, Z. (1999). “Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from Proceedings of the NaCB1 or CB2 receptors”. tional Academy of Sciences 96 (24): 14136–14141. doi:10.1073/pnas.96.24.14136. PMC 24203. PMID 10570211. [4] Walter, L; Franklin, A; Witting, A; Wade, C; Xie, Y; Kunos, G; MacKie, K; Stella, N (2003). “Nonpsychotropic cannabinoid receptors regulate microglial cell migration”. Journal of Neuroscience 23 (4): 1398–1405. PMID 12598628. [5] Offertáler, L; Mo, FM; Bátkai, S; Liu, J; Begg, M; Razdan, RK; Martin, BR; Bukoski, RD; Kunos, G (2003). “Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor”. Molecular Pharmacology 63 (3): 699–705. doi:10.1124/mol.63.3.699. PMID 12606780. [6] Milman, G; Maor, Y; Abu-Lafi, S; Horowitz, M; Gallily, R; Batkai, S; Mo, FM; Offertaler, L; Pacher, P; Kunos, G; Mechoulam, R (2006). “N-arachidonoyl l-serine, an endocannabinoid-like brain constituent with vasodilatory properties”. Proceedings of the National Academy of Sciences of the United States of America 103 (7): 2428–2433. doi:10.1073/pnas.0510676103. PMC 1413724. PMID 16467152.
16.1 See also • Cannabinoids • Cannabinoid receptors • Cannabidiol
[7] McCollum, L; Howlett, AC; Mukhopadhyay, S (2007). “Anandamide-mediated CB1/CB2 cannabinoid receptor—independent nitric oxide production in rabbit aortic endothelial cells”. The Journal of Pharmacology and Experimental Therapeutics 321 (3): 930–937. doi:10.1124/jpet.106.117549. PMID 17379772.
• O-1918
16.2 References [1] Adams, MD; Earnhardt, JT; Martin, BR; Harris, LS; Dewey, WL; Razdan, RK (1977). “A cannabinoid with cardiovascular activity but no overt behavioral effects”. Experientia 33 (9): 1204–1205. doi:10.1007/BF01922330. PMID 891878.
[8] Ryberg, E; Larsson, N; Sjögren, S; Hjorth, S; Hermansson, NO; Leonova, J; Elebring, T; Nilsson, K; Drmota, T; Greasley, PJ (2007). “The orphan receptor GPR55 is a novel cannabinoid receptor”. British Journal of Pharmacology 152 (7): 1092–1101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302.
[2] McHugh D, Hu SS, Rimmerman N, Juknat A, Vogil Z, Walker JM, Bradshaw HB (March 2010). “Narachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18,
[9] Kapur, A; Zhao, P; Sharir, H; Bai, Y; Caron, MG; Barak, LS; Abood, ME (2009). “Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands”. The Journal of Biological Chemistry 284 (43): 29817–29827.
33
34
CHAPTER 16. ABNORMAL CANNABIDIOL
doi:10.1074/jbc.M109.050187. PMC 2785612. PMID 19723626. [10] Henstridge, CM; Balenga, NA; Ford, LA; Ross, RA; Waldhoer, M; Irving, AJ (2009). “The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoAdependent Ca2+ signaling and NFAT activation”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 (1): 183– 193. doi:10.1096/fj.08-108670. PMID 18757503. [11] Brown AJ (November 2007). “Novel cannabinoid receptors”. British Journal of Pharmacology 152 (5): 567– 575. doi:10.1038/sj.bjp.0707481. PMC 2190013. PMID 17906678. [12] Johns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.; Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.; Yue, T. -L.; Brown, A. J.; Morrison, A. D.; Douglas, S. A. (2009). “The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects”. British Journal of Pharmacology 152 (5): 825–831. doi:10.1038/sj.bjp.0707419. PMC 2190033. PMID 17704827. [13] McHugh, D; Tanner, C; Mechoulam, R; Pertwee, RG; Ross, RA (2008). “Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2”. Molecular Pharmacology 73 (2): 441–450. doi:10.1124/mol.107.041863. PMID 17965195. [14] Kreutz, S; Koch, M; Böttger, C; Ghadban, C; Korf, HW; Dehghani, F (2009). “2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells”. Glia 57 (3): 286–294. doi:10.1002/glia.20756. PMID 18837048.
Chapter 17
ADB-FUBINACA ADB-FUBINACA is a designer drug identified in synthetic cannabis blends in Japan in 2013.[1] The (S) enantiomer of ADB-FUBINACA is claimed in Pfizer patent WO 2009/106982, with a Kᵢ value of 0.36nM at CB1 .[2] ADB-FUBINACA features a carboxamide group at the 3-indazole position, like SDB-001 and STS-135. ADB-FUBINACA appears to be the product of rational drug design, since it differs from AB-FUBINACA only by the replacement of the isopropyl group with a tertbutyl group. The stereochemistry of the tert-butyl sidechain in the illicitly sold product is unresolved. Nothing is known of the pharmacological activity of ADBFUBINACA in humans or other animals.
17.1 See also • AB-FUBINACA • ADB-PINACA • ADBICA • APINACA • PF-03550096 • SDB-001 • STS-135
17.2 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106982
35
Chapter 18
ADB-PINACA ADB-PINACA is a cannabinoid designer drug that is an ingredient in some synthetic cannabis products.[1][2] It has been linked to multiple hospitalizations due to its use.[3] In the United States, it is a Schedule I controlled substance.[4]
18.1 See also • AB-PINACA • APINACA • ADB-FUBINACA
18.2 References [1] “ADB-PINACA”. Forendex. [2] “ADB-PINACA”. Forensic Drug Review. [3] “CDC: 221 sickened by synthetic pot in Colorado”. USA Today. December 12, 2013. [4] “Schedules of controlled substances: temporary placement of four synthetic cannabinoids into Schedule I. Final order”. Fed Regist. 79 (27): 7577–7582. Feb 10, 2014. PMID 24605391.
36
Chapter 19
ADBICA ADBICA is a designer drug identified in synthetic cannabis blends in Japan in 2013.[1] ADBICA had not previously been reported in the scientific literature prior to its sale as a component of synthetic cannabis blends. ADBICA features a carboxamide group at the 3-indole position, like SDB-001 and STS-135. The stereochemistry of the tert-butyl side-chain in the illicitly sold product is unresolved, though in a large series of indazole derivatives structurally similar to ADBICA that are disclosed in Pfizer patent WO 2009/106980, activity resides exclusively in the (S) enantiomers.[2] Nothing is known of the pharmacological activity of ADBICA in humans or other animals.
19.1 See also • AB-FUBINACA • ADB-FUBINACA • APINACA • PF-03550096 • SDB-001 • STS-135
19.2 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106980
37
Chapter 20
Ajulemic acid Ajulemic acid (AB-III-56, HU-239, IP-751, L 7075, CT-3, Resunab) is a synthetic cannabinoid derivative of the non-psychoactive THC metabolite 11-nor-9-carboxyTHC that shows useful analgesic and anti-inflammatory effects without causing a subjective “high”.[1] It is being developed for the treatment of neuropathic pain and inflammatory conditions such as arthritis.[2] It does not however share the anti-emetic effects of other cannabinoids but may be useful for treating pain and chronic inflammatory conditions where nausea is not present.[3] Side effects include dry mouth, tiredness and dizziness. The mechanism of action has not yet been fully established, but ajulemic acid may activate the CB2 receptor in the periphery leading to production of resolving eicosanoids. Studies in animals at doses up to 40 mg/kg show minimal psychoactivity of ajulemic acid, comparable to that produced by tetrahydrocannabinol,.[4] Likewise, there was no difference between ajulemic acid and placebo on the “cannabimimetic” assay when used in humans at therapeutic doses.[5][6] A new highly purified composition of ajulemic acid named Resunab is being developed by Corbus Pharmaceuticals (formerly JB Therapeutics)for the treatment of orphan life-threatening inflammatory diseases.
20.1 References [1] Burstein, S.; Karst, M.; Schneider, U.; Zurier, R. (2004). “Ajulemic acid: A novel cannabinoid produces analgesia without a “high"". Life Sciences 75 (12): 1513–1522. doi:10.1016/j.lfs.2004.04.010. PMID 15240185. [2] Mitchell, V.; Aslan, S.; Safaei, R.; Vaughan, C. (2005). “Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain”. Neuroscience letters 382 (3): 231–235. doi:10.1016/j.neulet.2005.03.019. PMID 15925096. [3] Burstein, S. (2005). “Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials”. The AAPS journal 7 (1): E143–E148. doi:10.1208/aapsj070115. PMC 2751505. PMID 16146336. [4] Vann, R.; Cook, C.; Martin, B.; Wiley, J. (2007). “Cannabimimetic properties of ajulemic acid”. The Jour-
38
nal of Pharmacology and Experimental Therapeutics 320 (2): 678–686. doi:10.1124/jpet.106.111625. PMC 2633725. PMID 17105826. [5] Sumariwalla, P.; Gallily, R.; Tchilibon, S.; Fride, E.; Mechoulam, R.; Feldmann, M. (2004). “A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis”. Arthritis and rheumatism 50 (3): 985–998. doi:10.1002/art.20050. PMID 15022343. [6] Sumariwalla, P.F., et al. (2004). “Reply”. Arthritis & Rheumatism 50 (12): 4079. doi:10.1002/art.20806.
Chapter 21
AM-087 AM-087 is an analgesic drug that is a cannabinoid agonist. It is a derivative of Δ8THC substituted on the 3-position side chain. AM-087 is a potent CB1 agonist with a Ki of 0.43nM, making it around 100x more potent than THC itself. This is most likely due to the bulky bromine substituent on the side chain.[1][2][3]
21.1 See also • AM-411
21.2 References [1] Charalambous A, et al. Pharmacological evaluation of halogenated delta 8-THC analogs. Pharmacology, Biochemistry and Behaviour. 1991 Nov;40(3):509-12. PMID 1666915 [2] Nikas SP, et al. The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model. AAPS Journal. 2004 Oct 19;6(4):e30. PMID 15760095 [3] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X
39
Chapter 22
AM-1220 AM-1220 is a drug that acts as a potent and moderately selective agonist for the cannabinoid receptor CB1 , with around 19x selectivity for CB1 over the related CB2 receptor.[1] It was originally invented in the early 1990s by a team led by Thomas D'Ambra at Sterling Winthrop,[2] but has subsequently been researched by many others, most notably the team led by Alexandros Makriyannis at the University of Connecticut. The (piperidin-2-yl)methyl side chain of AM-1220 contains a stereocenter, so there are two enantiomers with quite different potency, the (R) enantiomer having a Kᵢ of 0.27nM at CB1 while the (S) enantiomer has a much weaker Kᵢ of 217nM.[3] A number of related compounds are known with similar potent cannabinoid activity, with modifications such as substitution of the indole ring at the 2- or 6- positions, the naphthoyl ring substituted at the 4- position or replaced by substituted benzoyl rings or other groups, or the 1-(N-methylpiperidin-2-ylmethyl) group replaced by similar heterocyclic groups such as N-methylpyrrolidin-2-ylmethyl or N-methylmorpholin3-ylmethyl.[4][5][6] AM-1220 was first detected as an ingredient of synthetic cannabis smoking blends in 2010.[7]
• AM-2201 • AM-2233 • Cannabipiperidiethanone
22.2 References [1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] US patent 5068234, Thomas E. D'Ambra et al., “3arylcarbonyl-1-(C-attached-N-heteryl)−1H-indoles”, granted 1991-11-26 [3] D'ambra, T. (1996). “C-Attached aminoalkylindoles: potent cannabinoid mimetics”. Bioorganic & Medicinal Chemistry Letters 6: 17–14. doi:10.1016/0960894X(95)00560-G. [4] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut. [5] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D. B.; Mukhin, A. G.; Horti, A. G. (2005). “Synthesis and Structure−Activity Relationship of a Novel Series of Aminoalkylindoles with Potential for Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography”. Journal of Medicinal Chemistry 48 (18): 5813. doi:10.1021/jm0502743. PMID 16134948. [6] US patent 7820144, Alexandros Makriyannis, et al., “Receptor selective cannabimimetic aminoalkylindoles”, granted 2010-10-26
Related 1-(N-methylpyrrolidin-2-ylmethyl) methylmorpholin-3-ylmethyl) derivatives
and
[7] Head Shop ‘Legal Highs’ Active Constituents Identification Chart (July - August 2010)
1-(N-
22.1 See also • A-834,735 • AM-1221 • AM-1248 40
Chapter 23
AM-1221 AM-1221 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2 , with a Kᵢ of 0.28nM at CB2 and 52.3nM at the CB1 receptor, giving it around 180x selectivity for CB2 .[1] The 2-methyl and 6-nitro groups on the indole ring both tend to increase CB2 affinity while generally reducing affinity at CB1 , explaining the high CB2 selectivity of AM-1221. However despite this relatively high selectivity for CB2 , its CB1 affinity is still too strong to make it useful as a truly selective CB2 agonist, so the related compound AM-1241 is generally preferred for research purposes.[2][3]
23.1 See also • AM-630 • AM-1220 • AM-1235 • AM-2233 • UR-144 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
23.2 References [1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut. [3] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
41
Chapter 24
AM-1235 AM-1235 (1-(5-fluoropentyl)−3-(naphthalen-1oyl)−6-nitroindole) is a drug that acts as a potent and reasonably selective agonist for the cannabinoid receptor CB1 .
24.3 References
[2] Deng, Hongfeng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut.
24.1 Pharmacology 24.1.1
Pharmacodynamics
AM-1235 is a cannabinoid receptor agonist with Kᵢ of 1.5nM at CB1 compared to 20.4nM at CB2 .[1] While the 6-nitro substitution on the indole ring reduces affinity for both CB1 and CB2 relative to the unsubstituted parent compound AM-2201, CB2 affinity is reduced much more, resulting in a CB1 selectivity of around 13x.[2] This is in contrast to other related compounds such as AM1221 where a 6-nitro substitution instead confers significant selectivity for CB2 .[3]
24.1.2
[1] US patent 7241799, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200707-10
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 are generally applicable to AM-1235. AM-1235 metabolism differs only slightly from that of JWH-018. AM-1235 N-dealkylation produces fluoropentane instead of pentane (or plain alkanes in general). It has been speculated that the fluoropentane might function as an alkylating agent or is further metabolized into toxic fluoroacetic acid. This is not true since fluoroalkanes do not act as alkylating agents under normal conditions and uneven fluoroalkane chains metabolize into substantially less toxic fluoropropanoic acid.[4][5]
24.2 See also • AM-906 • AM-2389 • O-1812 42
[3] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [4] Millington JE, Pattison FLM. TOXIC FLUORINE COMPOUNDS: XII. ESTERS OF ωFLUOROALCOHOLS. Canadian Journal of Chemistry. 1956 Nov;34(11):1532-1541. [5] Pattison FLM, Howell WC, Woolford RG. TOXIC FLUORINE COMPOUNDS: XIII. ω-FLUOROALKYL ETHERS. Canadian Journal of Chemistry. 1957 Feb;35(2):141-148.
Chapter 25
AM-1241 AM-1241 (1-(methylpiperidin-2-ylmethyl)−3-(2iodo-5-nitrobenzoyl)indole) is a chemical from the aminoalkylindole family that acts as a potent and selective agonist for the cannabinoid receptor CB2 ,[1][2] with a Kᵢ of 3.4nM at CB2 and 80x selectivity over the related CB1 receptor.[3][4] It has analgesic effects in animal studies, particularly against “atypical” pain such as hyperalgesia and allodynia.[5] This is thought to be mediated through CB2 -mediated peripheral release of endogeous opioid peptides,[6] as well as direct activation of the TRPA1 channel.[7] It has also shown efficacy in the treatment of amyotrophic lateral sclerosis in animal models.[8][9]
25.1 Effects in bone cancer model The antihyperalgesic effects of AM-1241 were investigated in a murine bone cancer model. Sarcoma cells were injected into the femur of a mouse, and then mice were injected twice daily with AM-1241. Treatment with AM1241 reduced both spontaneous and evoked pain, as well as reducing the bone loss and subsequent fractures due to the tumor. Pretreatment with the CB2 antagonist SR144,528 reversed the acute effects of AM-1241 on both spontaneous and evoked pain, while having no effect on its own.[10]
25.2 See also
[2] Bingham B, et al. (August 2007). “Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers”. British Journal of Pharmacology 151 (7): 1061– 70. doi:10.1038/sj.bjp.0707303. PMC 2042933. PMID 17549048. [3] Ibrahim MM, et al. (September 2003). “Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS”. Proceedings of the National Academy of Sciences of the United States of America 100 (18): 10529–33. doi:10.1073/pnas.1834309100. PMC 193595. PMID 12917492. [4] Marriott KS, Huffman JW (2008). “Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor”. Current Topics in Medicinal Chemistry 8 (3): 187–204. doi:10.2174/156802608783498014. PMID 18289088. [5] Beltramo M, et al. (March 2006). “CB2 receptormediated antihyperalgesia: possible direct involvement of neural mechanisms”. The European Journal of Neuroscience 23 (6): 1530–8. doi:10.1111/j.14609568.2006.04684.x. PMID 16553616. [6] Ibrahim MM, et al. (February 2005). “CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids”. Proceedings of the National Academy of Sciences of the United States of America 102 (8): 3093– 8. doi:10.1073/pnas.0409888102. PMC 549497. PMID 15705714. [7] Akopian AN, Ruparel NB, Patwardhan A, Hargreaves KM (January 2008). “Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation”. Journal of Neuroscience 28 (5): 1064– 75. doi:10.1523/JNEUROSCI.1565-06.2008. PMID 18234885.
• AM-1220 • AM-1248 • AM-2233
25.3 References [1] Yao BB, et al. (September 2006). “In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor?". British Journal of Pharmacology 149 (2): 145–54. doi:10.1038/sj.bjp.0706838. PMC 2013801. PMID 16894349.
43
[8] Kim K, Moore DH, Makriyannis A, Abood ME (August 2006). “AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis”. European Journal of Pharmacology 542 (1-3): 100–5. doi:10.1016/j.ejphar.2006.05.025. PMID 16781706. [9] Shoemaker JL, et al (April 2007). “The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic
44
CHAPTER 25. AM-1241
mouse model of amyotrophic lateral sclerosis when initiated at symptom onset”. Journal of Neurochemistry 101 (1): 87–98. doi:10.1111/j.1471-4159.2006.04346.x. PMC 2819701. PMID 17241118. [10] Lozano, Alysia (April 2010). “A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss”. Life Sciences 86 (17-18): 646–53. doi:10.1016/j.lfs.2010.02.014. PMC 2871326. PMID 20176037. Retrieved 18 December 2011.
Chapter 26
AM-1248 AM-1248 is a drug that acts as a moderately potent agonist for both the cannabinoid receptors CB1 and CB2 , but with some dispute between sources over its exact potency and selectivity. Replacing the 3-(1-naphthoyl) group found in many indole derived cannabinoid ligands, with an adamantoyl group, generally confers significant CB2 selectivity,[1] but reasonable CB1 affinity and selectivity is retained when an N-methylpiperidin-2-ylmethyl substitution is used at the indole 1-position.[2][3] The related compound 1-pentyl-3-(1-adamantoyl)indole was identified as having been sold as a cannabinoid designer drug in Hungary in 2011, along with another synthetic cannabinoid AM-679.[4]
26.1 See also • A-834,735 • AB-001 • AM-411 • AM-1220 • AM-2233 • Cannabipiperidiethanone
26.2 References [1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781. [2] US patent 7820144, Makriyannis A, Deng H, “Receptor selective cannabimimetic aminoalkylindoles”, granted 2010-10-26 [3] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607
45
[4] Jankovics P, et al. (August 2011). “Detection and identification of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary”. Forensic Science International 214 (1-3): 27–32. doi:10.1016/j.forsciint.2011.07.011. PMID 21813254.
Chapter 27
AM-1714 AM-1714 is a drug that acts as a reasonably selective agonist of the peripheral cannabinoid receptor CB2 , with sub-nanomolar affinity and 490x selectivity over the related CB1 receptor. In animal studies it has both analgesic and anti-allodynia effects. The 9-methoxy derivative AM-1710 has similar CB2 affinity but only 54x selectivity over CB1 .[1][2]
27.1 See also • Cannabinol • Canbisol
27.2 References [1] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur GA, Malan TP Jr, Porreca F, Veerappan V, Tian X, George C, Parrish DA, Papahatjis DP, Makriyannis A. Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. Journal of Medicinal Chemistry. 2007 Dec 27;50(26):6493-500. PMID 18038967 [2] Rahn EJ, Zvonok AM, Thakur GA, Khanolkar AD, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats. Journal of Pharmacology and Experimental Therapeutics. 2008 Nov;327(2):584-91. doi: 10.1124/jpet.108.141994. PMID 18664590
46
Chapter 28
AM-2201 AM-2201 (1-(5-fluoropentyl)−3-(1- AM-2201 metabolism differs only slightly from that naphthoyl)indole) is a research chemical that acts as a of JWH-018. AM-2201 N-dealkylation produces fluopotent but nonselective full agonist for the cannabinoid ropentane instead of pentane (or plain alkanes in general). receptor. It is part of the AM series of cannabinoids discovered by Alexandros Makriyannis at Northeastern University. 28.3 Detection A forensic standard of AM-2201 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[5]
28.1 Hazards AM-2201 is widely regarded by recreational s of synthetic cannabinoids as one of the most potent and possibly the most potent substance available in this class of drugs. As the dosage is much smaller than other synthetic cannabinoids, accidental overdose becomes more likely. There have been anecdotal reports of individuals experiencing panic attacks and vomiting at doses as small as 2 mg. Convulsions have been reported[1] including at doses as low as 10 mg.[2] Caution should be taken if using this substance as it is active at doses as small as 500 µg, has a very steep dose-response curve, and tolerance builds up very quickly to the effects. Recreational use of AM-2201 in the United States has led to it being specifically listed in a proposed 2011 amendment to the Controlled Substances Act, aiming to add a number of synthetic drugs into Schedule I.[3] As of November 2011, there have been no reports of death associated with the drug. The acute toxicity and long term side effects associated with the use of AM-2201 are unknown.
28.4 See also • AM-2233 • AM-694 • AM-1235 • AM-2232 • JWH-018
28.5 References [1] David McQuade, Simon Hudson, Paul I. Dargan, David M. Wood (March 2013). “First European case of convulsions related to analytically confirmed use of the synthetic cannabinoid receptor agonist AM-2201”. European Journal of Clinical Pharmacology 69 (3): 373–376. [2] ekaJ (20 February 2011). “The Night I Killed My Friends”. Erowid.org. Retrieved 11 June 2012.
28.2 Pharmacology AM-2201 is a full agonist for cannabinoid receptors. Affinities are: with a Kᵢ of 1.0nM at CB1 and 2.6nM at CB2 .[4] The 4-methyl functional analog MAM-2201 probably has similar affinities.
[3] Synthetic Drug Control Act of 2011. H.R. 1254, 112th Congress, 1st Session (2011). [4] WO patent 0128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200106-07 [5] Southern Association of Forensic Scientists
28.2.1
Pharmacokinetics
See also: JWH-018 § Pharmacokinetics
47
Chapter 29
AM-2232 AM-2232 (1-(4-cyanobutyl)−3-(naphthalen-1oyl)indole) is a drug that acts as a potent but unselective agonist for the cannabinoid receptors, with a Kᵢ of 0.28nM at CB1 and 1.48nM at CB2 .[1]
29.1 See also • AM-2201 • O-1057 • O-1812
29.2 References [1] US patent 7241799, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200707-10
48
Chapter 30
AM-2233 AM-2233 is a drug that acts as a highly potent full agonist for the cannabinoid receptors, with a Kᵢ of 1.8nM at CB1 and 2.2nM at CB2 as the active (R) enantiomer.[1] It was developed as a selective radioligand for the cannabinoid receptors and has been used as its 131 I derivative for mapping the distribution of the CB1 receptor in the brain.[2][3][4][5][6][7] AM-2233 was found to fully substitute for THC in rats, with a potency lower than that of JWH-018 but higher than WIN 55,212-2.[8]
30.1 See also
[5] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.; Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gifford, A. N. (2006). “Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233”. Synapse 60 (2): 93–101. doi:10.1002/syn.20277. PMID 16715483. [6] Leung K (Dec 12, 2006). “R-2-[131I]Iodophenyl(1-(1-methylpiperidin-2-ylmethyl)−1H-indol-3yl)methanone”. Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. PMID 20641836. [7] Pei, Y., et al. (2008). “Ligand-Binding Architecture of Human CB2 Cannabinoid Receptor: Evidence for Receptor Subtype-Specific Binding Motif and Modeling GPCR Activation”. Chemistry & Biology 15: 1207. doi:10.1016/j.chembiol.2008.10.011.
• AM-679 • AM-694 • AM-1220
[8] Järbe TU, Deng H, Vadivel SK, Makriyannis A (September 2011). “Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (Δ9-tetrahydrocannabinol) discrimination for rats”. Behavioural Pharmacology 22 (5-6): 498–507. doi:10.1097/FBP.0b013e328349fbd5. PMC 3212432. PMID 21836461.
• AM-1221 • AM-1241 • Cannabipiperidiethanone
30.2 References [1] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD Dissertation). University of Connecticut. [2] Deng H, et al. (October 2005). “Potent cannabinergic indole analogues as radioiodinatable brain imaging agents for the CB1 cannabinoid receptor”. Journal of Medicinal Chemistry 48 (20): 6386–92. doi:10.1021/jm050135l. PMID 16190764. [3] Hanuš, L. R. O.; Mechoulam, R. (2005). “Cannabinoid chemistry: an overview”. “Cannabinoids as Therapeutics”. Milestones in Drug Therapy MDT. p. 23. doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6. [4] Shen , et al. (February 2006). “F200A substitution in the third transmembrane helix of human cannabinoid CB1 receptor converts AM2233 from receptor agonist to inverse agonist”. European Journal of Pharmacology 531 (1–3): 41–6. doi:10.1016/j.ejphar.2005.12.026. PMID 16438957.
49
Chapter 31
AM-2389 AM-2389 is a classical cannabinoid derivative which acts as a potent and reasonably selective agonist for the CB1 receptor, with a Kᵢ of 0.16 nM, and 26x selectivity over the related CB2 receptor. It has high potency in animal tests of cannabinoid activity, and a medium duration of action.[1][2] Replacing the 1',1'-dimethyl substitution of the dimethylheptyl side chain of classical cannabinoids with cyclopropyl or cyclopentyl results in higher potency than cyclobutyl, but only the cyclobutyl derivatives show selectivity for CB1 over CB2 .[3] High selectivity for CB1 over CB2 is difficult to achieve (cf. AM-906, AM-1235), as almost all commonly used CB1 agonists have similar or greater affinity for CB2 than CB1 , and the only truly highly selective CB1 agonists known as of 2012 are eicosanoid derivatives such as O-1812.
31.1 See also • HHC • AMG-36 • AMG-41
31.2 References [1] Nikas SP, et al. Novel 1',1'-chain substituted hexahydrocannabinols: 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)hexahydrocannabinol (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist. Journal of Medicinal Chemistry. 2010 Oct 14;53(19):6996-7010. PMID 20925434 [2] Järbe TU, et al. AM2389, a high-affinity, in vivo potent CB(1)-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice. Psychopharmacology (Berlin). 2011 Oct 12. PMID 21989802 [3] Papahatjis DP, et al. C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols. Journal of Medicinal Chemistry. 2007 Aug 23;50(17):4048-60. PMID 17672444
50
Chapter 32
AM-4030 AM-4030 is an analgesic drug which is a cannabinoid receptor agonist. It is a derivative of HU-210 which has been substituted with a 6β-((E)−3-hydroxyprop-1-enyl) group. This adds a “southern” aliphatic hydroxyl group to the molecule as seen in the -series of nonclassical cannabinoid drugs, and so AM-4030 represents a hybrid structure between the classical and nonclassical cannabinoid families,[1] with the 6-hydroxyalkyl chain rigidified with a double bond with defined stereochemistry. This gives AM-4030 a greater degree of selectivity, so while it is still a potent agonist at both CB1 and CB2 , it is reasonably selective for CB1 , with a Kᵢ of 0.7nM at CB1 and 8.6nM at CB2 , a selectivity of around 12x.[2][3] Resolution of the enantiomers of AM-4030 yields an even more potent compound, although with less selectivity, with the (-) enantiomer AM-4030a having a Kᵢ of 0.6nM at CB1 and 1.1nM at CB2 .[4]
32.1 See also • AM-919 • AM-938
32.2 References [1] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X [2] Tius MA, Hill WA, Zou XL, Busch-Petersen J, Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji V, Makriyannis A. Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain. Life Sciences. 1995;56(23-24):200712. PMID 7776825 [3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK, Concepcion Fernandez-Garcia M, Fan P, Makriyannis A, Tius MA. Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues. Journal of Medicinal Chemistry. 1998 Sep 10;41(19):3596-608. PMID 9733485 [4] Thakur GA, Palmer SL, Harrington PE, Stergiades IA, Tius MA, Makriyannis A. Enantiomeric resolution of a
51
novel chiral cannabinoid receptor ligand. Journal of Biochemical and Biophysical Methods. 2002 Dec 31;54(13):415-22. PMID 12543516
Chapter 33
AM-411 AM-411 is an analgesic drug that is a cannabinoid agonist. It is a derivative of Δ8THC substituted with an adamantyl group at the 3-position, demonstrating that the binding pocket for the alkyl chain at this position can accommodate significant bulk. AM-411 is a potent and fairly selective CB1 full agonist with a Kᵢ of 6.80nM, but is still also a moderately potent CB2 agonist with a Kᵢ of 52.0nM.[1] It produces similar effects to other cannabinoid agonists such as analgesia, sedation, and anxiolysis.[2][3]
33.1 See also • AM-087 • AM-1248 • KM-233
33.2 References [1] Lu D, et al. Adamantyl cannabinoids: a novel class of cannabinergic ligands. Journal of Medicinal Chemistry. 2005 Jul 14;48(14):4576-85. PMID 15999995 [2] Järbe TU, DiPatrizio NV, Lu D, Makriyannis A. (-)Adamantyl-delta8-tetrahydrocannabinol (AM-411), a selective cannabinoid CB1 receptor agonist: effects on open-field behaviors and antagonism by SR-141716 in rats. Behavioural Pharmacology. 2004 Nov;15(7):51721. PMID 15472574 [3] McLaughlin PJ, et al. Behavioral effects of the novel cannabinoid full agonist AM 411. Pharmacology, Biochemistry and Behaviour. 2005 May;81(1):78-88. PMID 15894067
52
Chapter 34
AM-630 AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2 , with a Kᵢ of 32.1nM at CB2 and 165x selectivity over CB1 , at which it acted as a weak partial agonist.[1][2] It is used in the study of CB2 mediated responses and has been used to investigate the possible role of CB2 receptors in the brain.[3][4] AM-630 is significant as one of the first indole derived cannabinoid ligands substituted on the 6-position of the indole ring, a position that has subsequently been found to be important in determining affinity and efficacy at both the CB1 and CB2 receptors, and has led to the development of a large number of related derivatives.[5][6][7][8][9]
34.1 See also
974–82. doi:10.1016/j.biopsych.2009.09.024. 19931854.
PMID
[5] Eissenstat, M. A.. et al. (1995). “Aminoalkylindoles: Structure-Activity Relationships of Novel Cannabinoid Mimetics”. Journal of Medicinal Chemistry 38 (16): 3094. doi:10.1021/jm00016a013. PMID 7636873. [6] Hongfeng Deng. Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs. PhD Dissertation, University of Connecticut, 2000. [7] Hynes J, et al. (September 2002). “C-3 Amidoindole cannabinoid receptor modulators”. Bioorganic & Medicinal Chemistry Letters 12 (17): 2399– 402. doi:10.1016/S0960-894X(02)00466-3. PMID 12161142. [8] Frost, J. M., et al. (2008). “Indol-3-yltetramethylcyclopropyl Ketones: Effects of Indole Ring Substitution on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 51 (6): 1904. doi:10.1021/jm7011613. PMID 18311894.
• WIN 48,098 (Pravadoline) • WIN 54,461 (6-Bromopravadoline) • AM-1221
[9] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a.
34.2 References [1] Ross RA, et al. (February 1999). “Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630”. British Journal of Pharmacology 126 (3): 665–72. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID 10188977. [2] Murataeva, N.; MacKie, K.; Straiker, A. (2012). “The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons”. Pharmacological Research 66 (5): 437–42. doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID 22921769. [3] Morgan NH, Stanford IM, Woodhall GL (September 2009). “Functional CB2 type cannabinoid receptors at CNS synapses”. Neuropharmacology 57 (4): 356– 68. doi:10.1016/j.neuropharm.2009.07.017. PMID 19616018. [4] Ishiguro H, et al. (May 2010). “Brain cannabinoid CB2 receptor in schizophrenia”. Biological Psychiatry 67 (10):
53
Chapter 35
AM-6545 AM-6545 is a drug which acts as a peripherally selective silent antagonist for the CB1 receptor, and was developed for the treatment of obesity. Other cannabinoid antagonists such as rimonabant have been marketed for this application, but have subsequently been withdrawn from sale because of centrally mediated side effects such as depression and nausea. Because AM-6545 does not cross the blood–brain barrier to any significant extent, it does not produce these kinds of side effects, but has still been shown to effectively reduce appetite and food consumption in animal studies.[1][2][3][4]
35.1 See also • CB-13 – a peripherally selective cannabinoid agonist • O-2050 – a centrally active CB1 silent antagonist • Methylnaltrexone – a peripherally selective mu opioid receptor antagonist • TM-38837 - another peripherally selective cannabinoid antagonist
35.2 References [1] Tam, J.; Vemuri, V. K.; Liu, J.; Bátkai, S. N.; Mukhopadhyay, B.; Godlewski, G.; Osei-Hyiaman, D.; Ohnuma, S.; Ambudkar, S. V.; Pickel, J.; Makriyannis, A.; Kunos, G. (2010). “Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity”. Journal of Clinical Investigation 120 (8): 2953– 2966. doi:10.1172/JCI42551. PMC 2912197. PMID 20664173. PMID 20664173 [2] Randall PA, Vemuri VK, Segovia KN, Torres EF, Hosmer S, Nunes EJ, Santerre JL, Makriyannis A, Salamone JD. The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacology, Biochemistry and Behavior. 2010 Nov;97(1):179-84. PMID 20713079 [3] Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT, Lutz B, Zimmer A, Parker LA,
54
Makriyannis A, Sharkey KA. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. British Journal of Pharmacology. 2010 Oct;161(3):629-42. PMID 20880401 [4] Järbe TU, LeMay BJ, Vemuri VK, Vadivel SK, Zvonok A, Makriyannis A. Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats. Psychopharmacology (Berlin). 2011 Aug;216(3):355-65. PMID 21369753
Chapter 36
AM-679 (cannabinoid) This article is about the cannabinoid agonist. For the FLAP inhibitor, see AM-679 (FLAP inhibitor). AM-679 is a drug that acts as a moderately potent agonist for the cannabinoid receptors, with a Kᵢ of 13.5nM at CB1 and 49.5nM at CB2 .[1] AM-679 was one of the first 3-(2-iodobenzoyl)indole derivatives that was found to have significant cannabinoid receptor affinity, and while AM-679 itself has only modest affinity for these receptors, it was subsequently used as a base to develop several more specialised cannabinoid ligands that are now widely used in research, including the potent CB1 agonists AM-694 and AM-2233, and the selective CB2 agonist AM-1241.[2] AM-679 was first identified as having been sold as a cannabinoid designer drug in Hungary in 2011, along with another novel compound 1-pentyl-3-(1adamantoyl)indole.[3]
36.1 See also • RCS-4 • AM-694 • AM-2233
36.2 References [1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut. [3] Jankovics P, et al. (August 2011). “Detection and identification of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary”. Forensic Science International 214 (1-3): 27–32. doi:10.1016/j.forsciint.2011.07.011. PMID 21813254.
55
Chapter 37
AM-694 AM-694 (1-(5-fluoropentyl)−3-(2-iodobenzoyl)indole) is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB1 . It is used in scientific research for mapping the distribution of CB1 receptors. No public data about AM-694 metabolism is known. AM-694 has already emerged as a designer drug.
37.3 References
37.1 Pharmacology AM-694 is an agonist for cannabinoid receptors. Affinities are: with a Kᵢ of 0.08nM at CB1 and 18x selectivity over CB2 with a Kᵢ 1.44nM.[1] It is unclear what is responsible for this unusually high CB1 binding affinity, but it makes the 18 F radiolabelled derivative of AM-694 useful for mapping the distribution of CB1 receptors in the body.[2]
37.1.1
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 are generally applicable to AM-694. AM-694 metabolism differs only slightly from that of JWH-018. AM-694 N-dealkylation produces fluoropentane instead of pentane (or plain alkanes in general). It has been speculated that the fluoropentane might function as an alkylating agent or is further metabolized into toxic fluoroacetic acid. This is not true since fluoroalkanes do not act as alkylating agents under normal conditions and uneven fluoroalkane chains metabolize into substantially less toxic fluoropropanoic acid.[3][4]
37.2 See also • AM-679 • AM-2201 • AM-2233 56
[1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] Willis PG, Katoch-Rouse R, Horti AG. Regioselective F18 radiolabeling of AM694, a CB1 cannabinoid receptor ligand. Journal of Labelled Compounds and Radiopharmaceuticals 2003;46(9):799-804. doi:10.1002/jlcr.720 [3] Millington JE, Pattison FLM. TOXIC FLUORINE COMPOUNDS: XII. ESTERS OF ωFLUOROALCOHOLS. Canadian Journal of Chemistry. 1956 Nov;34(11):1532-1541. [4] Pattison FLM, Howell WC, Woolford RG. TOXIC FLUORINE COMPOUNDS: XIII. ω-FLUOROALKYL ETHERS. Canadian Journal of Chemistry. 1957 Feb;35(2):141-148.
Chapter 38
AM-855 AM-855 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8 Tetrahydrocannabinol with a conformationally restricted side chain which has been bound into a fourth ring fused to the aromatic A-ring of the cannabinoid skeleton. AM-855 is an agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 22.3nM at CB1 and 58.6nM at CB2 .[1]
38.1 References [1] Khanolkara, Atmaram D.; Dai Lua, Pusheng Fana, Xiaoyu Tiana and Alexandros Makriyannis (August 1999). “Novel conformationally restricted tetracyclic analogs of Δ8 -tetrahydrocannabinol”. Bioorganic & Medicinal Chemistry Letters 9 (15): 2119–24. doi:10.1016/S0960894X(99)00355-8. PMID 10465529.
57
Chapter 39
AM-905 AM-905 is an analgesic drug which is a cannabinoid agonist with a conformationally restricted side chain. It is a potent and reasonably selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 1.2nM at CB1 and 5.3nM at CB2 .[1]
39.1 References [1] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos A, Makriyannis A. Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of Medicinal Chemistry. 1998 Mar 26;41(7):1195-200. PMID 9544219
58
Chapter 40
AM-906 AM-906 is an analgesic drug which is a cannabinoid agonist with a conformationally restricted side chain. It is a potent and selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 0.8nM at CB1 and 9.5nM at CB2 , a selectivity of almost 12x.[1]
40.1 See also • AM-1235 • AM-2389
40.2 References [1] Papahatjis DP, et al. Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of Medicinal Chemistry. 1998 Mar 26;41(7):1195-200. PMID 9544219
59
Chapter 41
AM-919 AM-919 is an analgesic drug which is a cannabinoid receptor agonist. It is a derivative of HU-210 which has been substituted with a 6β-(3-hydroxypropyl) group. This adds a “southern” aliphatic hydroxyl group to the molecule as seen in the -series of nonclassical cannabinoid drugs, and so AM-919 represents a hybrid structure between the classical and nonclassical cannabinoid families.[1] AM-919 is somewhat less potent than HU-210 itself, but is still a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 2.2nM at CB1 and 3.4nM at CB2 .[2][3]
41.1 See also • AM-4030
41.2 References [1] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X [2] Tius MA, Hill WA, Zou XL, Busch-Petersen J, Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji V, Makriyannis A. Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain. Life Sciences. 1995;56(23-24):200712. PMID 7776825 [3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK, Concepcion Fernandez-Garcia M, Fan P, Makriyannis A, Tius MA. Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues. Journal of Medicinal Chemistry. 1998 Sep 10;41(19):3596-608. PMID 9733485
60
Chapter 42
AM-938 AM-938 is an analgesic drug which is a cannabinoid receptor agonist. It is a derivative of HU-210 which has been substituted with a 6β-(3-hydroxyprop-1-ynyl) group. This adds a “southern” aliphatic hydroxyl group to the molecule as seen in the -series of nonclassical cannabinoid drugs, and so AM-938 represents a hybrid structure between the classical and nonclassical cannabinoid families,[1] with the 6-hydroxyalkyl chain rigidified with a triple bond. This gives AM-938 a greater degree of selectivity, so while it is still a potent agonist at both CB1 and CB2 , it is reasonably selective for CB2 , with a Kᵢ of 0.3nM at CB2 and 1.2nM at CB1 , a selectivity of around 4x.[2][3]
42.1 See also • AM-4030
42.2 References [1] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X [2] Tius MA, Hill WA, Zou XL, Busch-Petersen J, Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji V, Makriyannis A. Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain. Life Sciences. 1995;56(23-24):200712. PMID 7776825 [3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK, Concepcion Fernandez-Garcia M, Fan P, Makriyannis A, Tius MA. Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues. Journal of Medicinal Chemistry. 1998 Sep 10;41(19):3596-608. PMID 9733485
61
Chapter 43
AM404 AM404, also known as Narachidonoylaminophenol,[1] is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action.[2] Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.
43.1 Pharmacology AM404 was originally reported to be an endogenous cannabinoid reuptake inhibitor, preventing the transport of anandamide and other related compounds back from the synaptic cleft, much in the same way that common selective serotonin reuptake inhibitor (SSRI) antidepressants prevent the reuptake of serotonin. Earlier work on the mechanism of AM404 suggested that the inhibition of fatty acid amide hydrolase (FAAH) by AM404 was responsible for all of its attributed reuptake properties, since intracellular FAAH hydrolysis of anandamide changes the intra/extracellular anandamide equilibrium.[3] However, this is not the case, as newer research on FAAH knockout mice has found that brain cells internalize anandamide through a selective transport mechanism which is independent of FAAH activity.[4] This mechanism is inhibited by AM404. AM404 is also a TRPV1 agonist and inhibitor of cyclooxygenase COX-1 and COX-2, thus attenuating prostaglandin synthesis. AM404 is thought to induce its analgesic action through its activity on the endocannabinoid, COX, and TRPV systems, all of which are present in pain and thermoregulatory pathways.[5]
43.2 See also • VDM-11
43.3 References [1] Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P (January 2012). “Novel bioactive metabolites of dipyrone (metamizol)". Bioorg. Med.
62
Chem. 20 (1): 101–7. doi:10.1016/j.bmc.2011.11.028. PMC 3248997. PMID 22172309. [2] Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (February 2006). “The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors”. Eur. J. Pharmacol. 531 (1–3): 280–1. doi:10.1016/j.ejphar.2005.12.015. PMID 16438952. [3] Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (April 2003). “Evidence against the presence of an anandamide transporter”. Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4269–74. doi:10.1073/pnas.0730816100. PMC 153082. PMID 12655057. [4] Fegley, D.; Kathuria, S.; Mercier, R.; Li, C.; Goutopoulos, A.; Makriyannis, A.; Piomelli, D. (11 May 2004). “Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysisresistant inhibitor AM1172”. Proceedings of the National Academy of Sciences 101 (23): 8756–8761. doi:10.1073/pnas.0400997101. [5] Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (September 2005). “Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system” (pdf). J. Biol. Chem. 280 (36): 31405–12. doi:10.1074/jbc.M501489200. PMID 15987694.
Chapter 44
AMG-1 AMG-1 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8THC with a rigidified and extended 3-position side chain. AMG-1 is a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 0.6nM at CB1 vs 3.1nM at CB2 .[1]
44.1 References [1] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu W, Pertwee RG, Makriyannis A. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753
63
Chapter 45
AMG-3 AMG-3 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8THC substituted with a dithiolane group on the 3-position side chain.[1] AMG-3 is a potent agonist at both CB1 and CB2 receptors with a Kᵢ of 0.32nM at CB1 and 0.52nM at CB2 ,[2][3] and its particularly high binding affinity has led to it being used as a template for further structural development of novel cannabinoid drugs.[4] It has sedative and analgesic effects, with analgesia lasting for up to 36 hours after istration.[5]
45.1 References [1] Mavromoustakos T, Theodoropoulou E, Zervou M, Kourouli T, Papahatjis D. Structure elucidation and conformational properties of synthetic cannabinoids ()−2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy6H-dibenzo[b,d]pyranyl)−2-hexyl-1,3-dithiolane and its methylated analog. Journal of Pharmaceutical and Biomedical Analysis. 1999 Jan;18(6):947-56. PMID 9925329 [2] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos A, Makriyannis A. Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of Medicinal Chemistry. 1998 Mar 26;41(7):1195-200. PMID 9544219 [3] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu W, Pertwee RG, Makriyannis A. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753 [4] Durdagi S, Papadopoulos MG, Papahatjis DP, Mavromoustakos T. Combined 3D QSAR and molecular docking studies to reveal novel cannabinoid ligands with optimum binding activity. Bioorganic and Medicinal Chemistry Letters. 2007 Dec 15;17(24):6754-63. PMID 17980589 [5] Antoniou K, Galanopoulos A, Vlachou S, Kourouli T, Nahmias V, Thermos K, Panagis G, Daifoti Z, Marselos M, Papahatjis D, Spyraki C. Behavioral pharmacological properties of a novel cannabinoid 1',1'-dithiolane delta8THC analog, AMG-3. Behavioural Pharmacology. 2005 Sep;16(5-6):499-510. PMID 16148456
64
Chapter 46
AMG-36 AMG-36 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8THC substituted with a cyclopentane group on the 3-position side chain. AMG36 is a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 0.4nM at CB1 vs 1.9nM at CB2 .[1][2]
46.1 References [1] Papahatjis DP, et al. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753 [2] Papahatjis DP, et al. C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols. Journal of Medicinal Chemistry. 2007 Aug 23;50(17):4048-60. PMID 17672444
65
Chapter 47
AMG-41 AMG-41 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8-THC substituted with a cyclopropyl group on the C1'-position of the C3-alkyl side chain. AMG-41 is a potent agonist at both CB1 and CB2 , with a Kᵢ of 0.4nM at CB1 vs 0.9nM at CB2 .[1][2][3]
47.1 References [1] Papahatjis DP, Nikas SP, Andreou T, Makriyannis A. Novel 1',1'-chain substituted Delta(8)tetrahydrocannabinols. Bioorganic and Medicinal Chemistry Letters. 2002 Dec 16;12(24):3583-6. PMID 12443781 [2] Papahatjis DP, et al. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753 [3] Papahatjis DP, et al. C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols. Journal of Medicinal Chemistry. 2007 Aug 23;50(17):4048-60. PMID 17672444
66
Chapter 48
APINACA This article is about the synthetic cannabinoid drug. For the Japanese girl group, see AKB48.
48.3 References
AKB48 (APINACA, N-(1-adamantyl)−1-pentyl-1Hindazole-3-carboxamide) is a drug that acts as a reasonably potent agonist for the cannabinoid receptors,[1] with a Kᵢ of 304.5nM and a EC50 of 585nM at CB1 . It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in Japan in March 2012 as an ingredient in synthetic cannabis smoking blends, along with a related compound APICA.[2] Structurally it closely resembles cannabinoid compounds from patent WO 2003/035005 but with a simple pentyl chain on the indazole 1-position, and AKB48 falls within the claims of this patent despite not being disclosed as an example. AKB48 was made illegal in Japan in 2012,[3] and was banned as a temporary class drug in New Zealand from 13 July 2012.[4] It has been banned in Latvia since 14 November 2013. The DEA announced its intent to schedule 16 May 2013. [5]
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [2] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “Identification of two newtype synthetic cannabinoids, N-(1-adamantyl)−1pentyl-1H-indole-3-carboxamide (APICA) and N-(1adamantyl)−1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products”. Forensic Toxicology 30 (2): 114. doi:10.1007/s11419-012-01367. [3] “Designation of “Shitei Yakubutsu” (designated substances) based on the provision of the Pharmaceutical Affairs Law (1960, Law No.145)" (PDF). [4] “Temporary Class Drug Notice”. Department of Internal Affairs. New Zealand. 5 July 2012.
48.1 Detection A forensic standard of AKB48 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[6]
[5] url=http://www.justice.gov/dea/divisions/hq/2013/ hq051613.shtml [6] http://forendex.southernforensic.org/index.php/detail/ index/1221
• http://www.gpo.gov/fdsys/pkg/FR-2013-04-12/ html/2013-08671.htm
48.2 See also • AB-001 • AB-FUBINACA • AB-PINACA • ADB-FUBINACA • ADB-PINACA • RCS-4 • RCS-8 • SDB-001 • STS-135 67
Chapter 49
AR-231,453 AR-231,453 is an agonist for the suggested novel cannabinoid receptor GPR119.[1]
49.1 See also • PSN-375,963 • PSN-632,408
49.2 References [1] Semple G, Fioravanti B, Pereira G, Calderon I, Uy J, Choi K, Xiong Y, Ren A, Morgan M, Dave V, Thomsen W, Unett DJ, Xing C, Bossie S, Carroll C, Chu ZL, Grottick AJ, Ha EK, Leonard J, Jones RM. (2008). “Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119.”. J Med Chem. 51 (17): 5172–5175. doi:10.1021/jm8006867. PMID 18698756.
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Chapter 50
Arachidonyl-2'-chloroethylamide Arachidonyl-2'-chloroethylamide (ACEA) is a synthetic agonist of the cannabinoid receptor 1 (CB1R). ACEA is considered to be a selective cannabinoid agonist as it binds primarily to the CB1R and has low affinity to the cannabinoid receptor 2 (CB2R) (Kᵢ = 1.4 nM for CB1R; Kᵢ = 3100 nM for CB2R). [1]
50.1 References [1] Hillard, CJ; Manna, S; Greenberg, MJ; Dicamelli, R; Ross, RA; Stevenson, LA; Murphy, V; Pertwee, RG; Campbell, WB (1999). “Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1)". The Journal of Pharmacology and Experimental Therapeutics 289 (3): 1427–33. PMID 10336536.
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Chapter 51
Arachidonylcyclopropylamide Arachidonylcyclopropylamide (AA) is a synthetic agonist of the cannabinoid receptor 1 (CB1R). AA is considered to be a selective cannabinoid agonist as it binds primarily to the CB1R and has low affinity to the cannabinoid receptor 2 (CB2R) (Kᵢ = 2.2 nM for CB1R; Kᵢ = 700 nM for CB2R).[1]
51.1 References [1] Hillard, CJ, et al. (1999). “Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1)". The Journal of Pharmacology and Experimental Therapeutics 289 (3): 1427–33. PMID 10336536.
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Chapter 52
N-Arachidonylglycine N-Arachidonylglycine (NAGly) is a carboxylic analog of the endocannabinoid anandamide.[1] Since it was first synthesized in 1996,[2] NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids.[3] Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor.[4][5] NaGly is found throughout the body and research on its explicit functions is on going.
52.1 Synthesis The exact biosynthesis of NaGly is not completely understood, but there are two proposed pathways found in vitro for its biosynthesis: 1) enzymatically regulated conjugation of arachidonic acid and glycine and 2) the oxidative metabolism of the endogenous cannabinoid anandamide.[6][7] In the first pathway, Cytochrome c catalyzes the in vitro synthesis of NaGly from arachidonoyl coenzyme A and glycine in the presence of hydrogen peroxide.[8] In the second pathway, alcohol dehydrogenase catalyzes the oxidation of anandamide into Narachidonoyl glycine.[9]
52.2 Research 52.2.1
Effects on the nervous system
NAGly has been hypothesized to have a neurophysiological function of pain suppression, ed by evidence that it suppresses formalin-induced pain behavior in rats.[10] In particular, peripherally istered NAGly inhibited phase 2 pain behavior, suggesting either a direct suppresion of nociceptive afferents on the nerve or an indirect modulation of the afferents’ interstitial environment.[10] In either case, these findings hold promise for NAGly as a means of mitigating postoperative or chronic pain. NAGly is also effective in acute pain
models, reducing mechanical allodynia and thermal hyperalgesia induced by intraplantar injection of Fruend’s complete adjuvant.[11] Similar mechanical allydonia induced by partial ligation of the sciatic nerve was also reduced by NaGly.[12] Other arachidonic acid-amino acid conjugates did not have the same effects and the actions of NaGly were not affected by cannabinoid receptor agonists in either study, suggesting a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain.[11][12] NaGly was shown to be endogenous ligand for the Gprotein couple receptor GPR92 along with farnesyl pyrophosphate.[13] In the dorsal root ganglia (DRG), where GPR92 was found to be localized NaGly increased intracellular calcium levels in DRG neurons, indicating a role of NaGly in the sensory nervous system through the activation of GPR92.[13]
52.2.2 Effects on the immune system NAGly has been the focus of research on the immune system because of its antinociceptive effects and inhibitory action on components of the immune system. Specifically, it significantly inhibited TNFα and IFNγ production, and it shows potential as a therapeutic treatment for chronic inflammation.[14] Moreover, NAGly has been shown to act as a substrate for cyclooxygenase-2 (COX-2), the enzyme primarily known for producing prostaglandins associated with increases in inflammation and hyperalgesia. In many mammalian tissues that express COX-2, significant levels of NAGly are naturally present, and in these tissues COX-2 selectively metabolizes NAGly prostaglandin (PG) H2 glycine and HETEGly.[15]
52.2.3 Cell migration NAGly has been hypothesized to induce cell migration in BV-2 microglia cells.[4] The same research suggests that this migration occurs through GPR18. This was verified using GPR18 transfected HEK-293 cells. The same migration wasn't witnessed using nontransfected and GPR55 transfected HEK-293.[4] Addi-
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CHAPTER 52. N-ARACHIDONYLGLYCINE
tionally, tetrahydrocannabinol and NaGly are full agonists at the GPR18 receptors and induce migration in human endometrial HEC-1B cells.[16] Understanding functions of NaGly in such structures provides a promising future in helping treat diseases such as endometriosis.
52.2.4
Other targets
Insulin secretion
ligand for orphan G-protein-coupled receptor GPR18.”. Biochemical and biophysical research communications 347 (3): 827–32. PMID 16844083. [6] Bradshaw, Heather B; Rimmerman, Neta; Hu, Sherry; Benton, Valery M; Stuart, Jordyn M; Masuda, Kim; Cravatt, Benjamin F; O'Dell, David K; Walker, J Michael (1 January 2009). “The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways”. BMC Biochemistry 10 (1): 14. doi:10.1186/1471-2091-10-14.
NaGly was identified as a novel insulin secretagogue and was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium channels.[17] Additionally, this action was dependent on extracellular glucose level.[17]
[7] Aneetha, Halikhedkar; O’Dell, David K.; Tan, Bo; Walker, J. Michael; Hurley, Thomas D. (1 January 2009). “Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: Synthesis of N-acyl glycinals”. Bioorganic & Medicinal Chemistry Letters 19 (1): 237–241. doi:10.1016/j.bmcl.2008.10.087.
Additional biochemical interactions
[8] McCue, JM; Driscoll, WJ; Mueller, GP (Jan 11, 2008). “Cytochrome c catalyzes the in vitro synthesis of arachidonoyl glycine.”. Biochemical and biophysical research communications 365 (2): 322–7. PMID 17986381.
NaGly has been shown to inhibit the glycine transporter GLYT2a in a non-competitive fashion with arachidonic acids and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachodnoyl amino acids, especially because other conjugated amino acids had similar effects.[18]
52.3 References [1] Burstein, Sumner; Huang, S.M.; Petros, T.J.; Rossetti, R.G.; Walker, J.M.; Zurier, R.B. (30 April 2002). “Regulation of anandamide tissue levels by N-arachidonylglycine”. Biochemical Pharmacology 64 (7): 1147–1150. doi:10.1016/S0006-2952(02)01301-1. PMID 12234618. [2] Sheskin, Tzviel; Hanus, L.; Slager, J.; Vogel, Z.; Mechoulam, R. (1997). “Structural Requirements for Binding of Anandamide-Type Compounds to the Brain Cannabinoid Receptor”. Journal of Medicinal Chemistry 40 (5): 659–667. doi:10.1021/jm960752x. PMID 9057852. [3] Bradshaw, Heather; Rimmerman, N.; Hu, S.J.; Burstein, S.; Walker, J.M. (2009). “Novel Endogenous N-Acyl Glycines: Identification and Characterization”. Vitamins and Hormones. Vitamins & Hormones 81: 191–205. doi:10.1016/S0083-6729(09)81008-X. ISBN 9780123747822. PMID 19647113. [4] McHugh, Douglas; Hu, Sherry SJ; Rimmerman, Neta; Juknat, Ana; Vogel, Zvi; Walker, J Michael; Bradshaw, Heather B (1 January 2010). “N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor”. BMC Neuroscience 11 (1): 44. doi:10.1186/1471-2202-11-44. [5] Kohno, M; Hasegawa, H; Inoue, A; Muraoka, M; Miyazaki, T; Oka, K; Yasukawa, M (Sep 1, 2006). “Identification of N-arachidonylglycine as the endogenous
[9] Aneetha, H; O'Dell, DK; Tan, B; Walker, JM; Hurley, TD (Jan 1, 2009). “Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: synthesis of N-acyl glycinals.”. Bioorganic & medicinal chemistry letters 19 (1): 237–41. PMID 19013794. [10] Huang, Susan M.; Bisogno, T., Petros, T.J., Chang, S.Y., Zavitsanos, P.A., Zipkin, R.E., Sivakumar, R., Coop, A., Maeda, D.Y., De Petrocellis, L., Burstein, S., Di Marzo, V., Walker, J.M. (November 16, 2001). “Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain”. The Journal of Biological Chemistry 276 (46): 42639–42644. doi:10.1074/jbc.M107351200. PMID 11518719. [11] Succar, Rebecca; Mitchell, Vanessa A; Vaughan, Christopher W (August 2007). “Actions of N-arachidonylglycine in a rat inflammatory pain model”. Molecular Pain 3 (1): 24. doi:10.1186/1744-8069-3-24. [12] Vuong, Leeza A.Q.; Mitchell, Vanessa A.; Vaughan, Christopher W. (1 January 2008). “Actions of N-arachidonyl-glycine in a rat neuropathic pain model”. Neuropharmacology 54 (1): 189–193. doi:10.1016/j.neuropharm.2007.05.004. [13] Oh, D. Y.; Yoon, J. M.; Moon, M. J.; Hwang, J.I.; Choe, H.; Lee, J. Y.; Kim, J. I.; Kim, S.; Rhim, H.; O'Dell, D. K.; Walker, J. M.; Na, H. S.; Lee, M. G.; Kwon, H. B.; Kim, K.; Seong, J. Y. (22 May 2008). “Identification of Farnesyl Pyrophosphate and NArachidonylglycine as Endogenous Ligands for GPR92”. Journal of Biological Chemistry 283 (30): 21054–21064. doi:10.1074/jbc.M708908200. [14] Ferrante, A; Poulos A; Pitt M; Easton C; Sleigh M; Rathjen D; Widmer F. “Methods of Treating Immunopathologies Using Polyunsaturated Fatty Acids”. United States patent publication WO 97/38688.
52.3. REFERENCES
[15] Prusakiewicz, J; Kingsley P; Kozak K; Marnett L (2002). “Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2”. Biochemical and Biophysical Research Communications (296): 612–617. [16] McHugh, Douglas; Page, Jeremy; Dunn, Emily; Bradshaw, Heather B (1 April 2012). "Δ9Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells”. British Journal of Pharmacology 165 (8): 2414–2424. doi:10.1111/j.1476-5381.2011.01497.x. [17] Ikeda, Yukio; Iguchi, Haruhisa; Nakata, Masanori; Ioka, Ryoichi X.; Tanaka, Toshiya; Iwasaki, Satoshi; Magoori, Kenta; Takayasu, Shinobu; Yamamoto, Tokuo T.; Kodama, Tatsuhiko; Yada, Toshihiko; Sakurai, Takeshi; Yanagisawa, Masashi; Sakai, Juro (1 August 2005). “Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin Secretagogues”. Biochemical and Biophysical Research Communications 333 (3): 778–786. doi:10.1016/j.bbrc.2005.06.005. [18] Wiles, Amy L.; Pearlman, Rhonda-Jo; Rosvall, Mari; Aubrey, Karin R.; Vandenberg, Robert J. (1 November 2006). “N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a”. Journal of Neurochemistry 99 (3): 781–786. doi:10.1111/j.1471-4159.2006.04107.x.
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Chapter 53
AZ-11713908 AZ-11713908 is a drug developed by AstraZeneca which is a peripherally selective cannabinoid agonist, acting as a potent agonist at the CB1 receptor and a partial agonist at CB2 . It has poor blood–brain barrier penetration, and so while it is an effective analgesic in animal tests, it produces only peripheral effects at low doses, with much weaker symptoms of central effects compared to other cannabinoid drugs such as WIN 55,212-2.[1] A large number of related benzimidazole derived cannabinoid ligands are known.[2][3][4][5]
53.1 See also • AM-6545 • CB-13
53.2 References [1] Yu XH, Cao CQ, Martino G, Puma C, Morinville A, StOnge S, Lessard E, Perkins MN, Laird JM (November 2010). “A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain”. Pain 151 (2): 337–44. doi:10.1016/j.pain.2010.07.019. PMID 20696525. [2] Verbist BM, De Cleyn MA, Surkyn M, Fraiponts E, Aerssens J, Nijsen MJ, Gijsen HJ (April 2008). “5-Sulfonyl-benzimidazoles as selective CB2 agonists”. Bioorganic & Medicinal Chemistry Letters 18 (8): 2574–9. doi:10.1016/j.bmcl.2008.03.048. PMID 18394887. [3] Pagé D, Balaux E, Boisvert L, Liu Z, Milburn C, Tremblay M, Wei Z, Woo S, Luo X, Cheng YX, Yang H, Srivastava S, Zhou F, Brown W, Tomaszewski M, Walpole C, Hodzic L, St-Onge S, Godbout C, Salois D, Payza K, Payza K (July 2008). “Novel benzimidazole derivatives as selective CB2 agonists”. Bioorganic & Medicinal Chemistry Letters 18 (13): 3695–700. doi:10.1016/j.bmcl.2008.05.073. PMID 18522867. [4] WO patent 2004/108688, LIU Z, PAGÈ D, WALPOLE C, YANG H, “BENZIMIDAZOLE DERIVATIVES, COMPOSITIONS CONTAINING THEM, PREPARATION THEREOF AND USES THEREOF”, granted 16.12.2004
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[5] WO patent 2004/108712, LIU Z, PAGÈ D, WALPOLE C, YANG H, “BENZIMIDAZOLE DERIVATIVES, COMPOSITIONS CONTAINING THEM, PREPARATION THEREOF AND USES THEREOF”, granted 16.12.2004
Chapter 54
BAY 38-7271 Originally synthesized by chemist Wayne E. Kenney, BAY 38-7271 (KN 38-7271) is a drug which is a cannabinoid receptor agonist developed by Bayer AG. It has analgesic and neuroprotective effects and is used in scientific research, with proposed uses in the treatment of traumatic brain injury.[1][2] It is a full agonist with around the same potency as 55,940 in animal studies, and has fairly high affinity for both CB1 and CB2 receptors, with Kᵢ values of 2.91nM at CB1 and 4.24nM at CB2 .[3][4] It has now been licensed to KeyNeurotek Pharmaceuticals for clinical development,[5] and is currently in Phase II trials.[6] But its development appears stopped.
54.1 References [1] Mauler F, Horváth E, De Vry J, Jäger R, Schwarz T, Sandmann S, Weinz C, Heinig R, Böttcher M. BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury. CNS Drug Reviews. 2003 Winter;9(4):343-58. PMID 14647528 [2] Mauler F, Hinz V, Augstein KH, Fassbender M, Horváth E. Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271. Brain Research. 2003 Oct 31;989(1):99-111. PMID 14519516 [3] Mauler F, Mittendorf J, Horváth E, De Vry J. Characterization of the diarylether sulfonylester (-)-(R)−3(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties. Journal of Pharmacology and Experimental Therapeutics. 2002 Jul;302(1):359-68. PMID 12065738 [4] De Vry J, Rüdiger Jentzsch K. Discriminative stimulus effects of BAY 38-7271, a novel cannabinoid receptor agonist. European Journal of Pharmacology. 2002 Dec 20;457(2-3):147-52. PMID 12464360 [5] Pipeline [6] KeyNeurotek Pharmaceuticals AG Reports Positive Phase I Data of Its Cannabinoid Receptor-Agonist
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Chapter 55
BAY 59-3074 BAY 59-3074 is a drug which is a cannabinoid receptor partial agonist developed by Bayer AG. It has analgesic effects and is used in scientific research. It is orally active in animals, and has modest affinity for both CB1 and CB2 receptors, with Kᵢ values of 48.3nM at CB1 and 45.5nM at CB2 .[1][2]
55.1 References [1] De Vry J, Denzer D, Reissmueller E, Eijckenboom M, Heil M, Meier H, Mauler F. 3-[2-cyano-3(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1butanesulfonate (BAY 59-3074): a novel cannabinoid Cb1/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects. Journal of Pharmacology and Experimental Therapeutics. 2004 Aug;310(2):620-32. PMID 15140913 [2] De Vry J, Jentzsch KR. Discriminative stimulus effects of the structurally novel cannabinoid CB1/CB2 receptor partial agonist BAY 59-3074 in the rat. European Journal of Pharmacology. 2004 Nov 28;505(1-3):127-33. PMID 15556145
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Chapter 56
BML-190 BML-190 (Indomethacin morpholinylamide) is a drug used in scientific research that acts as a selective CB2 inverse agonist.[1] BML-190 is structurally derived from the NSAID indomethacin but has a quite different biological activity.[2] The activity produced by this compound is disputed, with some sources referring to it as a CB2 agonist rather than an inverse agonist;[3][4] this may reflect an error in classification, or alternatively it may produce different effects in different tissues, more research is required to resolve this dispute.
56.1 References [1] New, DC; Wong, YH (2003). “BML-190 and AM251 act as inverse agonists at the human cannabinoid CB2 receptor: signalling via cAMP and inositol phosphates”. FEBS Letters 536 (1–3): 157–60. doi:10.1016/S00145793(03)00048-6. PMID 12586356. [2] Klegeris, A; Bissonnette, CJ; McGeer, PL (2003). “Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor”. British Journal of Pharmacology 139 (4): 775– 86. doi:10.1038/sj.bjp.0705304. PMC 1573900. PMID 12813001. [3] Melck, D; De Petrocellis, L; Orlando, P; Bisogno, T; Laezza, C; Bifulco, M; Di Marzo, V (2000). “Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation”. Endocrinology 141 (1): 118–26. doi:10.1210/en.141.1.118. PMID 10614630. [4] Scutt, A; Williamson, EM (2007). “Cannabinoids stimulate fibroblastic colony formation by bone marrow cells indirectly via CB2 receptors”. Calcified tissue international 80 (1): 50–9. doi:10.1007/s00223-006-0171-7. PMID 17205329.
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Chapter 57
(C6)- 47,497 (C6)- 47,497 ( 47,497 dimethylhexyl homologue) is a synthetic cannabinoid, a 47,497 homologue. Its systematic name is 2-[(1R,3S)−3hydroxycyclohexyl]−5-(1,1-dimethylhexyl)phenol.
57.1 See also • Synthetic cannabis • (C7)- 47,497 ( 47,497 itself) • (C8)- 47,497 • (C9)- 47,497
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Chapter 58
(C9)- 47,497 (C9)- 47,497 ( 47,497 dimethylnonyl homologue) is a synthetic cannabinoid, a 47,497 homologue. Its systematic name is 2-[(1R,3S)−3hydroxycyclohexyl]−5-(1,1-dimethylnonyl)phenol.
58.1 See also • Synthetic cannabis • (C6)- 47,497 • (C7)- 47,497 ( 47,497 itself) • (C8)- 47,497
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Chapter 59
Canbisol Canbisol (Nabidrox), is a synthetic cannabinoid derivative that is the dimethylheptyl homologue of 9-nor−9βhydroxyhexahydrocannabinol (HHC). It is a potent agonist at both the CB1 and CB2 receptors, with a binding affinity of 0.1nM at CB1 and 0.2nM at CB2 .[1] It is mainly used in scientific research, in receptor binding studies to determine the structure and function of the cannabinoid receptors,[2][3][4] but has been made illegal in some countries due to its possible abuse potential as a cannabinomimetic drug.[5]
59.1 See also • HU-210 • HU-243 • Nabilone
59.2 References [1] Rhee MH, et al. (September 1997). “Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase”. Journal of Medicinal Chemistry 40 (20): 3228–33. doi:10.1021/jm970126f. PMID 9379442. [2] Rhee MH, et al. (December 2000). “Functional role of tryptophan residues in the fourth transmembrane domain of the CB(2) cannabinoid receptor”. Journal of Neurochemistry 75 (6): 2485–91. PMID 11080201. [3] Rhee MH (September 2002). “Functional role of serine residues of transmembrane dopamin VII in signal transduction of CB2 cannabinoid receptor”. Journal of Veterinary Science 3 (3): 185–91. PMID 12514330. [4] Zhang R, et al. (July 2005). “Cysteine 2.59(89) in the second transmembrane domain of human CB2 receptor is accessible within the ligand binding crevice: evidence for possible CB2 deviation from a rhodopsin template”. Molecular Pharmacology 68 (1): 69–83. doi:10.1124/mol.104.007823. PMID 15840841. [5] The Misuse of Drugs Act 1971 (Amendment) Order 2009
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Chapter 60
Cannabichromene Cannabichromene (abbreviated as CBC) is a cannabinoid found in the cannabis plant. It bears structural similarity to the other natural cannabinoids, including tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol, and cannabinol, among others. Evidence has suggested that it may play a role in the anti-inflammatory and anti-viral effects of cannabis, and may contribute to the overall analgesic effects of medical cannabis. However, more research into the compound may be needed before any definite medical effects can be verified.[1] CBC has two stereoisomers. It is not scheduled by the Convention on Psychotropic Substances. CBC is nonpsychotropic.[2]
60.1 Medical uses A 2011 study in the British Journal of Pharmacology found that CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control.[2] A study in Neurochemistry International suggested that cannabichromene might stimulate the growth of brain cells by stimulating adult neural stem progenitor cells (NSPCs). The study said “our results suggest that CBC raises the viability of NSPCs while inhibiting their differentiation into astroglia, possibly through upregulation of ATP and adenosine signalling.[3]
60.2 References [1] Gaoni, Y.; Mechoulam, R. (1966). “Cannabichromene, a new active principle in hashish”. Chemical Communications 1: 20–1. doi:10.1039/C19660000020. [2] Maione, Sabatino; Piscitelli, Fabiana; Gatta, Luisa; Vita, Daniela; De Petrocellis, Luciano; Palazzo, Enza; De Novellis, Vito; Di Marzo, Vincenzo (2011). “Nonpsychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action”. British Journal of Pharmacology 162 (3): 584–96. doi:10.1111/j.14765381.2010.01063.x. PMID 20942863.
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[3] Shinjyo, Noriko; Di Marzo, Vincenzo (2013). “The effect of cannabichromene on adult neural stem/progenitor cells”. Neurochemistry International 63 (5): 432–7. doi:10.1016/j.neuint.2013.08.002. PMID 23941747.
Chapter 61
Cannabicyclohexanol Cannabicyclohexanol (CCH, 47,497 dimethyloctyl homologue, (C8)- 47,497) is a cannabinoid receptor agonist drug, developed by Pfizer in 1979. On 19 January 2009, the University of Freiburg in announced that an analog of 47,497 was the main active ingredient in the herbal incense product Spice, specifically the 1,1-dimethyloctyl homologue of 47,497, which is now known as cannabicyclohexanol.[2][3][4][5] The 1,1-dimethyloctyl homologue of 47,497 is in fact several times more potent than the parent compound,[6] which is somewhat unexpected as the 1,1-dimethylheptyl is the most potent substituent in classical cannabinoid compounds such as HU-210.[7]
61.1 See also • Synthetic cannabis • (C6)- 47,497 • (C7)- 47,497 ( 47,497 itself) • (C9)- 47,497 • O-1871
61.2 References [1] Cook, Morgan (2011-02-28). “Synthetic marijuana illegal as of Tuesday”. North County Times (San Diego). Retrieved 2011-02-28. [2] Hauptwirkstoff von „Spice“ identifiziert, University of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm. 2009-01-19.19/ [3] Spice - weitere Analyseresultate http://www. basg.at/servlet/sls/Tornado/web/ages/content/ 4E5A4B86295BF5C0C125753E006A5E3C [4] Auwärter V, et al. 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? Journal of Mass Spectrometry. 2 February 2009. PMID 19189348
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[5] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda Y (May 2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1-3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892. [6] Compton DR, Johnson MR, Melvin LS, Martin BR. Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents. Journal of Pharmacology and Experimental Therapeutics. 1992 Jan;260(1):201-9. PMID 1309872 [7] Martin BR, et al. Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacology, Biochemistry and Behavior. 1991 Nov;40(3):471-8. PMID 1666911
Chapter 62
Cannabicyclol Cannabicyclol (CBL) is a non-psychotomimetic cannabinoid found in the Cannabis species. CBL is a degradative product like cannabinol. Light converts cannabichromene to CBL. It has 16 stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
62.1 See also • Cannabinoids • Cannabis • Medical marijuana
62.2 External links • CTD’s Cannabicyclol page from the Comparative Toxicogenomics Database • Erowid Compounds found in Cannabis sativa • http://www.wiley-vch.de/stmdata/pdf/ CompoundList.pdf • http://www.a1b2c3.com/drugs/mj028.htm
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Chapter 63
Cannabidiol Not to be confused with Cannabinol.
63.1.2 Neurological effects
Cannabidiol (CBD) is one of at least 85 active cannabinoids identified in cannabis.[4] It is a major phytocannabinoid, ing for up to 40% of the plant’s extract.[5] CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol (THC).[5] An orally-istered liquid containing CBD has received orphan drug status in the US, for use as a treatment for dravet syndrome, under the brand name Epidiolex.[6]
A 2010 study found that strains of cannabis containing higher concentrations of cannabidiol did not produce short-term memory impairment vs. strains with similar concentrations of THC, but lower concentrations of CBD. The researchers attributed this attenuation of memory effects to CBD’s role as a CB1 antagonist. Transdermal CBD is neuroprotective in animals.[8]
63.1 Clinical applications
63.1.3 Psychotropic effect
The bud of a Cannabis sativa flower coated with trichomes
63.1.1
Antimicrobial actions
Cannabidiol’s strong antioxidant properties have been shown to play a role in the compound’s neuroprotective and anti-ischemic effects.[9]
CBD has anti-psychotic effects and may counteract the potential psychotomimetic effects of THC on individuals with latent schizophrenia;[5] some reports show it to be an alternative treatment for schizophrenia that is safe and well-tolerated.[10] Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA.[10][11] Leweke et al. performed a double blind, 4 week, explorative controlled clinical trial to compare the effects of purified cannabidiol and the atypical antipsychotic amisulpride on improving the symptoms of schizophrenia in 42 patients with acute paranoid schizophrenia. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale. While there was no statistical difference between the two treatment groups, cannabidiol induced significantly fewer side effects (extrapyramidal symptoms, increase in prolactin, weight gain) when compared to amisulpride.[12] Studies have shown cannabidiol decreases activity of the limbic system[13] and decreases social isolation induced by THC.[14] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.[15][16]
CBD absorbed transcutaneously may attenuate the in- Chronic cannabidiol istration in rats was found creased sebum production at the root of acne, according to produce anxiogenic-like effects, indicating that to an untested hypothesis.[7] prolonged treatment with cannabidiol might incite 84
63.4. PHARMACOLOGY
85
anxiogenic effects.[17] Those results have been contested cannabionoid profile consistently around 1% cannabidiol by,[18] and contradict [19] whose experimentation cover (CBD) with THC less than 0.1%.[32] the same duration. Extraction can be done with olive oil, ethanol, or CO2, Cannabidiol has demonstrated antidepressant-like effects and other nonpolar to semipolar solvents. in animal models of depression.[20][21][22] Hemp world production is around 30000 tonnes per year.
63.1.4
Dravet syndrome
See also: Charlotte’s Web (cannabis) Dravet syndrome is a rare form of epilepsy that is difficult to treat. Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and catastrophic form of intractable epilepsy that begins in infancy. Initial seizures are most often prolonged events and in the second year of life other seizure types begin to emerge.[23] While high profile and anecdotal reports of results from high-CBD/low-THC preparations have sparked interest in treatment with cannabinoids,[24] there is insufficient medical evidence to draw conclusions about their safety or efficacy.[24][25]
63.4 Pharmacology 63.4.1 Pharmacodynamics
Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.[9] While one would assume that this would cause cannabidiol to reduce the effects of THC, it may potentiate THC’s effects by increasing CB1 receptor density or through another CB1 -related mechanism.[33] It is also an inverse agonist of CB2 receptors.[9][34] Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[35] Cannabidiol has also been shown to act as a 5-HT₁A receptor agonist,[36] an action which is involved in its antidepressant,[20][37] anxiolytic,[37][38] and neuroprotective[39][40] effects. Cannabidiol is an 63.2 CBD-enhanced cannabis allosteric modulator of μ and δ-opioid receptors.[41] Decades ago, selective breeding by growers in US dra- Cannabidiol’s pharmacological effects have also been atreceptor agonism and intracellular matically lowered the CBD content of cannabis; their cus- tributed to PPAR-γ [5] calcium release. tomers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[26] To meet the demands of medical cannabis patients, growers are cur63.4.2 Pharmacokinetic interactions rently developing more CBD-rich strains.[27] In November 2012, Tikun Olam, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.[28][29] The researchers said the cannabis plant, enriched with CBD, “can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes”. Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, a cannabinoid researcher, said "...Avidekel is thought to be the first CBD-enriched cannabis plant with no THC to have been developed in Israel”.[30] In February 2014, a patent application was filed for a cannabis plant named 'avidekel'.[31]
63.3 Industrial hemp
There is some preclinical evidence to suggest that cannabidiol may reduce THC clearance, modestly increasing THC’s plasma concentrations resulting in a greater amount of THC available to receptors, increasing the effect of THC in a dose-dependent manner.[42][43] Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[44]
63.4.3 Pharmaceutical preparations Nabiximols (USAN, trade name Sativex) is an aerosolized mist for oral istration containing a near 1:1 ratio of CBD and THC. The drug was approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis.[45][46][47]
63.5 Isomerism
Several industrial hemp varieties can be legally cultivated in western Europe. They might seem to contain Based on: Nagaraja, Kodihalli Nanjappa, Synthesis of very small portion of cannabinoid, which is true in one delta-3-cannabidiol and the derived rigid analogs, Arisense. Nevertheless a variety such as “Fedora 17” has a zona University 1987.
86
CHAPTER 63. CANNABIDIOL hemp oil high in cannabidiol, are legal in the United States for this reason. Some cannabidiol oil is derived from marijuana and is therefore high in THC.[61] This type of cannabidiol oil would be considered a Schedule I as a result. However, cannabidiol derived from industrial hemp is legal and unscheduled itself.[61] In other words, cannabidiol’s legal status depends on where it is derived from, as cannabidiol itself is not scheduled.[57]
Cannabidiol numbering
63.8 US patent See also: Tetrahydrocannabinol#Isomerism, Abnormal In October 2003, U.S. patent #6630507 entitled cannabidiol. “Cannabinoids as antioxidants and neuroprotectants” was assigned to “The United States Of America As Represented By The Department Of Health And Human Ser63.6 Chemistry vices.” The patent was filed in April 1999 and listed as the inventors: Aidan J. Hampson, Julius Axelrod, and MaurCannabidiol is insoluble in water but soluble in organic izio Grimaldi, who all held positions at the National Instisolvents, such as pentane. At room temperature it is a tute of Mental Health (NIMH) in Bethesda, MD, which is colorless crystalline solid.[48] In strongly basic medium part of the National Institutes of Health (NIH), an agency and the presence of air it is oxidized to a quinone.[49] Un- of the United States Department of Health and Human der acidic conditions it cyclizes to THC.[50] The synthesis Services (HHS). The patent mentions cannabidiol’s abilof cannabidiol has been accomplished by several research ity as an antiepileptic, to lower intraocular pressure in the groups.[51][52][53] treatment of glaucoma, lack of toxicity or serious side effects in large acute doses, its neuroprotectant properties, its ability to prevent neurotoxicity mediated by NMDA, AMPA, or kainate receptors; its ability to attenuate glu63.6.1 Biosynthesis tamate toxicity, its ability to protect against cellular damCannabis produces CBD-carboxylic acid through the age, its ability to protect brains from ischemic damage, same metabolic pathway as THC, until the last step, its anxiolytic effect, and its superior antioxidant activity where CBDA synthase performs catalysis instead of which can be used in the prophylaxis and treatment of oxidation associated diseases.[62] THCA synthase.[54] On November 17, 2011, the Federal published that the National Institutes of Health of the United States Department of Health and Human Services was “contem63.7 Legal status plating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507” to the Cannabidiol is not scheduled by the Convention on Psy- company KannaLife based in New York, for the develchotropic Substances. opment and sale of cannabinoid and cannabidiol based Cannabidiol is a Schedule II drug in Canada.[55] therapeutics for the treatment of hepatic encephalopathy in humans.[63][64][65] Cannabidiol’s legal status in the United States:
On July 9, 2012 — KannaLife Sciences, Inc. (“KannaLife”) Signed an Exclusive License Agreement With National Institutes of Health – Office of Technology Transfer (“NIH-OTT”) aka the United States Federal Government for the Commercialization of U.S. Patent 6,630,507, “Cannabinoids as Antioxidants and NeuroMarijuana is defined by 21 U.S.C. §802(16), which is part protectants” (the “’507 Patent”). of the Controlled Substances Act. The mature stalks and seeds of the Cannabis sativa L. plant, as well as prod- http://www.kannalife.com/ ucts derived from the mature stalks and seeds are ex- kannalife-sciences-inc-signs-exclusive-license-agreement-with-national-in plicitly exempt from classification as marijuana.[57][58][59] On March 31, 2014 KannaLife Sciences, Inc. Under this exception, what are known as industrial hemp- (“KannaLife”) and Kannaway LLC (“Kannaway”, a finished products are legally imported into the United multi-level marketing program similar to Amway), States each year.[60] Hemp finished products, including have entered into a five year sales, marketing While the DEA Drug Schedule classifies THC (Tetrahydrocannabinols) and marijuana as Schedule I, cannabidiol is not found on the list.[56] Other synthetic cannabinoids such as JWH-019,073,081,122,200,203,250,398 are also listed in Schedule I, but cannabidiol is absent.[56]
63.9. REFERENCES
87
and product development agreement (the “Agree- [10] Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS (April 2006). “Cannabidiol, a Cannabis ment”). - See more at: http://globenewswire.com/ sativa constituent, as an antipsychotic drug”. Braz. J. Med. news-release/2014/03/31/622898/10074649/en/ Biol. Res. (Review) 39 (4): 421–9. doi:10.1590/S0100KannaLife-Sciences-Inc-and-Kannaway-LLC-Sign-Long-Term-Sales-Marketing-and-Product-Development-Agreement. 879X2006000400001. PMID 16612464. html#sthash.pnvD6OXs.dpuf KannaLife-Sciences-Inc-and-Kannaway-LLCSign-Long-Term-Sales-Marketing-and-ProductDevelopment-Agreement
[11] Long, L. E.; Malone, D. T.; Taylor, D. A. (2005). “Cannabidiol Reverses MK-801-Induced Disruption of Prepulse Inhibition in Mice”. Neuropsychopharmacology 31 (4): 795–803. doi:10.1038/sj.npp.1300838. PMID 16052245.
63.9 References
[12] Leweke, FM; Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M and Koethe D. (2012). “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia”. Translational Psychiatry 2 (3): e94–. doi:10.1038/tp.2012.15. PMC 3316151. PMID 22832859.
[1] Mechoulam R, Parker LA, Gallily R (November 2002). “Cannabidiol: an overview of some pharmacological aspects”. J Clin Pharmacol (Review) 42 (11 Suppl): 11S–19S. doi:10.1177/0091270002238789. PMID 12412831. [2] Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G (May 2009). “Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders”. Phytother Res (Review) 23 (5): 597–602. doi:10.1002/ptr.2625. PMID 18844286. [3] Martland JM, Russo EB (2001). “Cannabis and cannabis extracts: greater than the sum of their parts?". Journal of Cannabis Therapeutics 1 (3/4): 103–132. doi:10.1300/J175v01n03_08. [4] Borgelt LM, Franson KL, Nussbaum AM, Wang GS (February 2013). “The pharmacologic and clinical effects of medical cannabis”. Pharmacotherapy (Review) 33 (2): 195–209. doi:10.1002/phar.1187. PMID 23386598. [5] Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (December 2012). “Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders”. Philos. Trans. R. Soc. Lond., B, Biol. Sci. (Review) 367 (1607): 3364– 78. doi:10.1098/rstb.2011.0389. PMC 3481531. PMID 23108553. [6] Wilner, AN (25 March 2014). “Marijuana for Epilepsy: Weighing the Evidence”. Medscape Neurology. WebMD. Retrieved 2 April 2014. [7] Russo EB (August 2011). “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”. Br. J. Pharmacol. (Review) 163 (7): 1344–64. doi:10.1111/j.1476-5381.2011.01238.x. PMC 3165946. PMID 21749363. [8] Liput, D. J.; Hammell, D. C.; Stinchcomb, A. L.; Nixon, K (2013). “Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder”. Pharmacology Biochemistry and Behavior 111: 120–7. doi:10.1016/j.pbb.2013.08.013. PMID 24012796. [9] Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (August 2007). “Cannabidiol--recent advances”. Chem. Biodivers. (Review) 4 (8): 1678–92. doi:10.1002/cbdv.200790147. PMID 17712814.
[13] José Alexandre de Souza Crippa, Antonio Waldo Zuardi, Griselda E J Garrido, Lauro Wichert-Ana, Ricardo Guarnieri, Lucas Ferrari, Paulo M Azevedo-Marques, Jaime Eduardo Cecílio Hallak, Philip K McGuire and Geraldo Filho Busatto (October 2003). “Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow”. Neuropsychopharmacology 29 (2): 417–426. doi:10.1038/sj.npp.1300340. PMID 14583744. [14] Daniel Thomas Malone, Dennis Jongejana and David Alan Taylora (August 2009). “Cannabidiol reverses the reduction in social interaction produced by low dose Δ9-tetrahydrocannabinol in rats”. Pharmacology Biochemistry and Behavior 93 (2): 91–96. doi:10.1016/j.pbb.2009.04.010. PMID 19393686. [15] Mateus M Bergamaschi, Regina Helena Costa Queiroz, Marcos Hortes Nisihara Chagas, Danielle Chaves Gomes de Oliveira, Bruno Spinosa De Martinis, Flávio Kapczinski, João Quevedo, Rafael Roesler, Nadja Schröder, Antonio E Nardi, Rocio Martín-Santos, Jaime Eduardo Cecílio (May 2011). “Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients”. Neuropsychopharmacology 36 (6): 1219–1226. doi:10.1038/npp.2011.6. PMC 3079847. PMID 21307846. [16] Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simões MV, Bhattacharyya S, Fusar-Poli P, Atakan Z, Santos Filho A, Freitas-Ferrari MC, McGuire PK, Zuardi AW, Busatto GF, Hallak JE. (January 2011). “Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report”. J Psychopharmacol. 25 (1): 121–130. doi:10.1177/0269881110379283. PMID 20829306. [17] ElBatsh, MM; Assareh, N; Marsden, CA; Kendall, DA (May 2012). “Anxiogenic-like effects of chronic cannabidiol istration in rats”. Psychopharmacology 221 (2): 239–247. doi:10.1007/s00213-011-2566-z. PMID 22083592. [18] Gururajan, A (2012). “Comment on: “Anxiogenic-like effects of chronic cannabidiol istration in rats” (Elbatsh MM, Assareh N, Marsden CA, Kendall DA, Psychopharmacology 2012)". Psychopharmacology 222 (4):
88
CHAPTER 63. CANNABIDIOL
725–6; author reply 727. doi:10.1007/s00213-012-27803. PMID 22760485. [19] Réus, Gislaine Z. (2011). “istration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala”. Acta Neuropsychiatrica 23 (5): 241–248. doi:10.1111/j.16015215.2011.00579.x. [20] Zanelati, T; Biojone, C; Moreira, F; Guimarães, F; Joca, S (January 2010). “Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors”. British Journal of Pharmacology 159 (1): 122–8. doi:10.1111/j.1476-5381.2009.00521.x. PMC 2823358. PMID 20002102. [21] Réus, GZ; Stringari, RB; Ribeiro, KF; Luft, T; Abelaira, HM; Fries, GR; Aguiar, BW; Kapczinski, F; Hallak, JE; Zuardi, AW; Crippa JA; Quevedo, J (October 2011). “istration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala”. Acta Neuropsychiatrica 23 (5): 241– 248. doi:10.1111/j.1601-5215.2011.00579.x. [22] El-Alfy, AT; Ivey, K; Robinson, K; Ahmed, S; Radwan, M; Slade, D; Khan, I; ElSohly, M; Ross, S (June 2010). “Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”. Pharmacology Biochemistry and Behavior 95 (4): 434– 442. doi:10.1016/j.pbb.2010.03.004. PMC 2866040. PMID 20332000. [23] http://www.dravetfoundation.org/dravet-syndrome/ what-is-dravet-syndrome#sthash.jAC0bZ89.dpuf What is Dravet Syndrome? [24] Melville, Nancy A. (14 Aug 2013), Seizure Disorders Enter Medical Marijuana Debate, Medscape Medical News., retrieved 2014-01-14 [25] Gloss D, Vickrey B (13 June 2012). “Cannabinoids for epilepsy”. Cochrane Database Syst Rev (Review) 6: CD009270. doi:10.1002/14651858.CD009270.pub2. PMID 22696383. [26] Romney, Lee (13 September 2012). “On the frontier of medical pot to treat boy’s epilepsy”. Los Angeles Times. [27] Good, Alastair (26 October 2010). “Growing marijuana that won't get you high”. The Daily Telegraph (London). [28] Sidner, Sara (8 November 2012). “Medical marijuana without the high” (video). CNN. “An Israeli company has cultivated a new type of medical marijuana.” [29] Solon, Olivia (5 July 2012). “Medical Marijuana Without the High”. Wired.com [30] Lubell, Maayan (3 July 2012). “What a drag, Israeli firm grows 'highless’ marijuana”. Reuters. Retrieved 31 Jan 2014. [31] Cohen, Ytzchak (11 September 2014). “Cannabis plant named 'avidekel'". USPTO. Retrieved 7 October 2014.
[32] Fournier, G.; Beherec, O.; Bertucelli, S. (2003). “Intérêt du rapport Δ−9-THC / CBD dans le contrôle des cultures de chanvre industriel”. Annales de Toxicologie Analytique 15 (4): 250. doi:10.1051/ata/2003003. [33] Hayakawa, K.; Mishima, K.; Hazekawa, M.; Sano, K.; Irie, K.; Orito, K.; Egawa, T.; Kitamura, Y.; Uchida, N.; Nishimura, R.; Egashira, N.; Iwasaki, K.; Fujiwara, M. (2008). “Cannabidiol potentiates pharmacological effects of Δ9-tetrahydrocannabinol via CB1 receptordependent mechanism”. Brain Research 1188: 157–164. doi:10.1016/j.brainres.2007.09.090. PMID 18021759. [34] Pertwee, R. G. (2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9tetrahydrocannabivarin”. British Journal of Pharmacology 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291. [35] Ryberg E, Larsson N, Sjögren S, et al. (2007). “The orphan receptor GPR55 is a novel cannabinoid receptor”. British Journal of Pharmacology 152 (7): 1092– 101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302. [36] Russo EB, Burnett A, Hall B, Parker KK (August 2005). “Agonistic properties of cannabidiol at 5-HT1a receptors”. Neurochemical Research 30 (8): 1037–43. doi:10.1007/s11064-005-6978-1. PMID 16258853. [37] Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS (January 2009). “5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats”. British Journal of Pharmacology 156 (1): 181–8. doi:10.1111/j.1476-5381.2008.00046.x. PMC 2697769. PMID 19133999. [38] Campos AC, Guimarães FS (August 2008). “Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats”. Psychopharmacology 199 (2): 223–30. doi:10.1007/s00213-008-1168-x. PMID 18446323. [39] Mishima K, Hayakawa K, Abe K, et al. (May 2005). “Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism”. Stroke; a Journal of Cerebral Circulation 36 (5): 1077–82. doi:10.1161/01.STR.0000163083.59201.34. PMID 15845890. [40] Hayakawa K, Mishima K, Nozako M, et al. (March 2007). “Repeated treatment with cannabidiol but not Delta9tetrahydrocannabinol has a neuroprotective effect without the development of tolerance”. Neuropharmacology 52 (4): 1079–87. doi:10.1016/j.neuropharm.2006.11.005. PMID 17320118. [41] Kathmann, Markus; Flau, Karsten; Redmer, Agnes; Tränkle, Christian; Schlicker, Eberhard (2006). “Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors”. Naunyn-Schmiedeberg’s Archives of Pharmacology 372 (5): 354–361. doi:10.1007/s00210-006-0033-x. PMID 16489449.
63.10. EXTERNAL LINKS
89
[42] Bornheim, LM; Kim, KY; Li, J; Perotti, BY; Benet, LZ (August 1995). “Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain”. Drug Metabolism and Disposition 23 (8): 825– 831. PMID 7493549.
[55] Controlled Drugs and Substances Act - Schedule II
[43] Klein, C; Karanges, E; Spiro, A; Wong, A; Spencer, J; Huynh, T; Gunasekaran, N; Karl, T; Long, LE; Huang, XF; Liu, K; Arnold, JC; McGregor, IS (November 2011). “Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats”. Psychopharmacology 218 (2): 443–457. doi:10.1007/s00213-011-2342-0. PMID 21667074.
[58] Title 21 US Code Controlled Substances Act, text of the CSA.
[44] Hunt, CA; Jones, RT; Herning, RI; Bachman, J (June 1981). “Evidence that Cannabidiol Does Not Significantly Alter the Pharmacokinetics of Tetrahydrocannabinol in Man”. Journal of Pharmacokinetics and Biopharmaceutics 9 (3): 245–260. doi:10.1007/BF01059266. PMID 6270295.
[61] Cannabidiol: The side of marijuana you don't know
[45] United States Adopted Names Council: Statement on a nonproprietary name [46] “Fact Sheet — Sativex”. Health Canada. Retrieved 16 May 2013. [47] GWPharma- Welcome [48] Jones PG, Falvello L, Kennard O, Sheldrick GM Mechoulam R (1977). “Cannabidiol”. Acta Cryst. B33 (10): 3211–3214. doi:10.1107/S0567740877010577. [49] Mechoulam R, Ben-Zvi Z (1968). “Hashish—XIII On the nature of the beam test”. Tetrahedron 24 (16): 5615– 5624. doi:10.1016/0040-4020(68)88159-1. PMID 5732891. [50] Gaoni Y, Mechoulam R (1966). “Hashish—VII The isomerization of cannabidiol to tetrahydrocannabinols”. Tetrahedron 22 (4): 1481–1488. doi:10.1016/S00404020(01)99446-3. [51] Petrzilka T, Haefliger W, Sikemeier C, Ohloff G, Eschenmoser A (1967). “Synthese und Chiralität des ()-Cannabidiols”. Helv. Chim. Acta 50 (2): 719–723. doi:10.1002/hlca.19670500235. PMID 5587099. [52] Gaoni Y, Mechoulam R (1985). “Boron trifluoride etherate on alumuna — a modified Lewis acid reagent. An improved synthesis of cannabidiol”. Tetrahedron Letters 26 (8): 1083–1086. doi:10.1016/S0040-4039(00)98518-6. [53] Kobayashi Y, Takeuchi A, Wang YG (2006). “Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate”. Org. Lett. 8 (13): 2699–2702. doi:10.1021/ol060692h. PMID 16774235. [54] Marks, M.; Tian, L.; Wenger, J.; Omburo, S.; SotoFuentes, W.; He, J.; Gang, D.; Weiblen, G.; Dixon, R. (2009). “Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa”. Journal of Experimental Botany 60 (13): 3715– 3726. doi:10.1093/jxb/erp210. PMC 2736886. PMID 19581347.
[56] CSA Schedule, List of drugs by schedule. [57] Definition of marijuana under the Controlled Substances Act.
[59] Hemp Industries Assn., v. Drug Enforcement ., 9th Circuit Court of Appeals case involving industrial hemp. [60] Hemp, Many definitions of common associated with hemp, including the history of hemp use.
[62] US patent 6630507, Hampson, Aidan J.; Axelrod, Julius; Grimaldi, Maurizio, “Cannabinoids as antioxidants and neuroprotectants”, issued 2003-10-07 [63] “Federal | Prospective Grant of Exclusive License: Development of Cannabinoid(s) and Cannabidiol(s) Based Therapeutics To Treat Hepatic Encephalopathy in Humans”. Federal.gov. November 17, 2011. Retrieved August 13, 2013. [64] “KannaLife Sciences, Inc. Signs Exclusive License Agreement With National Institutes Of Health Office Of Technology Transfer (NIH-OTT)". thestreet.com. Retrieved 2012-07-09. [65] “KannaLife in R&D Collaboration for CannabinoidBased Drugs”. Genengnews.com. Retrieved 2013-04-04.
63.10 External links • Project CBD Non-profit educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol.
Chapter 64
Cannabidivarin Cannabidivarin (CBDV) is a non-psychoactive cannabinoid found in Cannabis. It is a homolog of cannabidiol (CBD), with the side-chain shortened by two methylene bridges (CH2 units). Plants with relatively high levels of CBDV have been reported in feral populations of C. indica ( = C. sativa ssp. indica var. kafiristanica) from northwest India, and in hashish from Nepal.[1][2] Similarly to CBD, it has 7 double bond isomers and 30 stereoisomers (see: Cannabidiol#Double bond isomers and their stereoisomers). It is not scheduled by Convention on Psychotropic Substances.
64.1 See also • Cannabinoids • Cannabis • Medical marijuana
64.2 References [1] Turner, C.E., P. C. Cheng, G.S. Lewis, M.H.Russell and G.K. Sharma. 1979. Constituents of Cannabis sativa XV: Botanical and chemical profile of Indian variants. Planta medica 37(3): 217-225. [2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). American Journal of Botany 91(6): 966975.
64.3 External links • Erowid Compounds found in Cannabis sativa
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Chapter 65
Cannabigerol Cannabigerol (CBG) is a non-psychoactive cannabinoid found in the Cannabis genus of plants. Cannabigerol is found in higher concentrations in hemp rather than in varieties of Cannabis cultivated for high THC content and their corresponding psychoactive properties. Cannabigerol has been found to act as a high affinity α2 -adrenergic receptor agonist, moderate affinity 5HT₁A receptor antagonist, and low affinity CB1 receptor antagonist.[1] It also binds to the CB2 receptor, but whether it acts as an agonist or antagonist at this site is unknown.[1] Cannabigerol has been shown to relieve interocular pressure, which may be of benefit in the treatment of glaucoma.[2][3] It can also be used to treat inflammatory bowel disease. [4] It has two E/Z isomers. It is not scheduled by Convention on Psychotropic Substances.
65.1 See also • Cannabinoid • Medical cannabis
65.2 References [1] Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee R (December 2009). “Evidence that the plant cannabinoid cannabigerol is a highly potent alpha(2)adrenoceptor agonist and moderately potent 5HT receptor antagonist”. British Journal of Pharmacology 159 (1): 129–141. doi:10.1111/j.1476-5381.2009.00515.x. PMC 2823359. PMID 20002104. [2] Colasanti, B. (1990). “A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol”. Journal of ocular pharmacology 6 (4): 259–269. doi:10.1089/jop.1990.6.259. PMID 1965836. [3] Colasanti, B.; Craig, C.; Allara, R. (1984). “Intraocular pressure, ocular toxicity and neurotoxicity after istration of cannabinol or cannabigerol”. Experimental eye research 39 (3): 251–259. doi:10.1016/00144835(84)90013-7. PMID 6499952.
91
[4] http://www.ncbi.nlm.nih.gov/pubmed/23415610
Chapter 66
Cannabinoidergic Cannabinoidergic, or cannabinergic, means related to the endocannabinoid neurotransmitters. As with such as dopaminergic and serotonergic, related proteins and cellular components involved endocannabinoid signaling, such as the cannabinoid (CB1 ) receptor, as well as exogenous compounds, such as phytocannabinoids or other cannabinoids which modulate the activity of endocannabinoid system, can be described as cannabinoidergic.[1]
66.1 See also • Adenosinergic • Cholinergic • GABAergic • Glutamatergic • Glycinergic • Histaminergic • Monoaminergic • Opioidergic
66.2 References [1] Palmer, SL; Thakur GA; Makriyannis A (December 31, 2002). “Cannabinergic ligands”. Chemistry and physics of lipids 121 (1-2): 3–19. doi:10.1016/s00093084(02)00143-3. PMID 12505686.
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Chapter 67
Cannabinol Not to be confused with Cannabidiol. Cannabinol (CBN) is a weak psychoactive cannabinoid found only in trace amounts in Cannabis sativa and Cannabis indica.[5] It is mostly a metabolite of tetrahydrocannabinol (THC).[6] CBN acts as a weak agonist of CB1 receptors but has a higher affinity to CB2 receptors, with lower affinities in comparison to THC.[7][8] Because of its somewhat selective CB2 agonism, it is used experimentally as an immunosuppressant.
[8] Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998). “Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors”. Life Sciences 63 (1): PL1–6. doi:10.1016/S0024-3205(98)00238-0. PMID 9667767.
67.3 External links
In contrast to tetrahydrocannabinol, it has no double bond isomers nor stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
67.1 See also • Cannabinoids
67.2 References [1] Cannabinol in the ChemIDplus database. [2] David R. Lide (2012). CRC Handbook of Chemistry and Physics. CRC Press. pp. 3–90. ISBN 1-43988049-2. [3] Sigma-Aldrich Co., Cannabinol solution, 1.0 mg/mL in methanol, analytical standard, for drug analysis. [4] Biotrend: Cannabinol (PDF: 21 kB) [5] Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE (1975). “Effects of delta9-tetrahydrocannabinol and cannabinol in man”. Pharmacology 13 (6): 502–12. doi:10.1159/000136944. PMID 1221432. [6] McCallum ND, Yagen B, Levy S, Mechoulam R (May 1975). “Cannabinol: a rapidly formed metabolite of delta1- and delta-6-tetrahydrocannabinol”. Experientia 31 (5): 520–1. doi:10.1007/bf01932433. PMID 1140243. [7] Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK (October 2000). “Novel cannabinol probes for CB1 and CB2 cannabinoid receptors”. Journal of Medicinal Chemistry 43 (20): 3778–85. doi:10.1021/jm0001572. PMID 11020293.
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• Erowid Compounds found in Cannabis sativa
Chapter 68
Cannabivarin Cannabivarin, also known as cannabivarol or CBV, is a non-psychoactive cannabinoid found in minor amounts in the hemp plant Cannabis sativa. It is an analog of cannabinol (CBN) with the side chain shortened by two methylene bridges (-CH2 -). CBV is an oxidation product of tetrahydrocannabivarin (THCV, THV).[1] It has no double bond isomers nor stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
68.1 References [1] Keith Bailey, Denise Gagné (October 1975). “Distinction of synthetic cannabidiol, cannabichromene, and cannabivarin by GLC using on-column methylation”. Journal of Pharmaceutical Sciences 64 (10): 1719–1720. doi:10.1002/jps.2600641033.
68.2 See also • Cannabinoids • Cannabis • Medical marijuana
68.3 External links • Erowid Compounds found in Cannabis sativa
94
Chapter 69
Caryophyllene • Black Caraway (Carum nigrum) [7.8%][13]
Caryophyllene /ˌkæri.ɵfɪˈliːn/, or (−)-β-caryophyllene, is a natural bicyclic sesquiterpene that is a constituent of many essential oils, especially clove oil, the oil from the stems and flowers of Syzygium aromaticum (cloves),[1] the essential oil of hemp Cannabis sativa,[2] rosemary Rosmarinus oficinalis,[3] and hops.[4] It is usually found as a mixture with isocaryophyllene (the cis double bond isomer) and α-humulene (obsolete name: α-caryophyllene), a ring-opened isomer. Caryophyllene is notable for having a cyclobutane ring, a rarity in nature.
• Cloves (Syzygium aromaticum)[1] [1.7%−19,5% of clove bud essential oil][14][15] • Hops (Humulus lupulus)[16] [5.1–14.5%][17] • Basil (Ocimum spp.)[18] [5.3–10.5% O. gratissimum; 4.0–19.8% O. micranthum][19] • Oregano (Origanum [4.9%−15.7][21][22]
Caryophyllene is one of the chemical compounds that contributes to the spiciness of black pepper. In a study conducted by Jürg Gertsch et al. from the Swiss Federal Institute of Technology (ETH Zurich), betacaryophyllene was shown to be selective agonist of cannabinoid receptor type-2 (CB2 ) and to exert significant cannabimimetic antiinflammatory effects in mice.[2] Antinociceptive,[5] neuroprotective,[6] anxiolytic and antidepressant [7] and anti-alcoholism [8] activity have been uncovered. Because the widespread plant natural product beta-caryophyllene is an FDA approved food additive and ingested daily with food it is the first dietary cannabinoid. Whether this compound is able to modulate inflammatory processes in humans via the endocannabinoid system is yet unknown. Beta-caryophyllene does not bind to the centrally expressed cannabinoid receptor type-1 (CB1 ) and therefore does not exert psychomimetic effects.
• Black pepper (Piper nigrum) [7.29%][23] • West African Pepper (Piper guineense) [57.59% (black); 51.75% (white)][23] • Lavender (Lavandula angustifolia) [4.62% of lavender oil][24] • Rosemary (Rosmarinus officinalis)[3] [0.1–8.3%][25] • True cinnamon (Cinnamomum zeylanicum) [6.9– 11.1%][26] • Malabathrum (Cinnamomum tamala) [25.3%][27]
The first total synthesis of caryophyllene in 1964 by E.J. Corey was considered one of the classic demonstrations of the possibilities of synthetic organic chemistry at the time.[9] Caryophyllene oxide is the component responsible for cannabis identification by drug-sniffing dogs[10][11]
vulgare)[20]
• Cananga odorata [3.1%−10.7%][28] • Copaiba oil (Copaifera spp.)
[29][30][31][32]
69.2 Compendial status • Food Chemical Codex [33], [34]
69.1 Natural sources The approximate quantity of caryophyllene in the essential oil of each source is given in square brackets ([ ]):
69.3 Notes and references
• Cannabis, hemp, marijuana (Cannabis sativa)[2] [3.8–37.5% of cannabis flower essential oil][12] 95
[1] Ghelardini C, Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A (2001). “Local anaesthetic activity of beta-caryophyllene”. Farmaco 56 (5–7): 387–9. doi:10.1016/S0014-827X(01)01092-8. PMID 11482764.
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[2] Gertsch J, Leonti M, Raduner S, et al. (July 2008). “Beta-caryophyllene is a dietary cannabinoid”. Proceedings of the National Academy of Sciences of the United States of America 105 (26): 9099–104. doi:10.1073/pnas.0803601105. PMC 2449371. PMID 18574142. [3] Ormeño E, Baldy V, Ballini C, Fernandez C (September 2008). “Production and diversity of volatile terpenes from plants on calcareous and siliceous soils: effect of soil nutrients”. J. Chem. Ecol. 34 (9): 1219–29. doi:10.1007/s10886-008-9515-2. PMID 18670820. [4] Glenn Tinseth, “Hop Aroma and Flavor”, January/February 1993, Brewing Techniques.
Accessed July 21, 2010.
CHAPTER 69. CARYOPHYLLENE
[13] Singh G, Marimuthu P, de Heluani CS, Catalan CA (January 2006). “Antioxidant and biocidal activities of Carum nigrum (seed) essential oil, oleoresin, and their selected components”. J. Agric. Food Chem. 54 (1): 174–81. doi:10.1021/jf0518610. PMID 16390196. [14] Alma, M. Hakkı; Ertaş, Murat; Nitz, Siegfrie; Kollmannsberger, Hubert (May 2007). Lucia, Lucian A.; Hubbe, Martin A., eds. “Chemical composition and content of essential oil from the bud of cultivated Turkish clove” (PDF). BioResources (Raleigh, North Carolina, USA: North Carolina State University) 2 (2): 265–269. ISSN 1930-2126. Retrieved September 6, 2010. “The results showed that the essential oils mainly contained about [...] 3.56% β-Caryophyllene” [15] Clove Essential Oil
[5] Katsuyama S., Mizoguchi H., Kuwahata H., et al. (2013). “Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception”. European journal of pain 17 (5): 664–675. doi:10.1002/j.1532-2149.2012.00242.x.
[16] Wang G, Tian L, Aziz N, et al. (November 2008). “Terpene Biosynthesis in Glandular Trichomes of Hop”. Plant Physiol. 148 (3): 1254–66. doi:10.1104/pp.108.125187. PMC 2577278. PMID 18775972.
[6] Guimarães-Santos, Adriano (2012). “Copaiba OilResin Treatment Is Neuroprotective and Reduces Neutrophil Recruitment and Microglia Activation after Motor Cortex Excitotoxic Injury”. Evidence-Based Complementary and Alternative Medicine 2012: 1–9. doi:10.1155/2012/918174. PMC 3291111.
[17] Bernotienë, Genovaitë; Nivinskienë, Ona; Butkienë, Rita; Mockutë, Danutë (2004). “Chemical composition of essential oils of hops (Humulus lupulus L.) growing wild in Auk taitija”. Chemija. 2 (Vilnius, Lithuania: Lithuanian Academy of Sciences) 4: 31–36. ISSN 0235-7216. Retrieved September 6, 2010.
[7] Bahi Amine, Al Mansouri Shamma, Al Memari Elyazia, Al Ameri Mouza, Nurulain Syed M., Ojha Shreesh. (2014). "β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice.”. Physiology & behavior 135: 119– 124. doi:10.1016/j.physbeh.2014.06.003.
[18] Zheljazkov VD, Cantrell CL, Tekwani B, Khan SI (January 2008). “Content, composition, and bioactivity of the essential oils of three basil genotypes as a function of harvesting”. J. Agric. Food Chem. 56 (2): 380–5. doi:10.1021/jf0725629. PMID 18095647.
[8] Al Mansouri Shamma, Ojha Shreesh, Al Maamari Elyazia, Al Ameri Mouza, Nurulain Syed M., Bahi Amine. (2014). “The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice.”. Pharmacology, biochemistry, and behavior. 2014;124C:260-268 124: 260–268. doi:10.1016/j.pbb.2014.06.025. [9] Corey EJ, Mitra RB, Uda H (1964). “Total Synthesis of d,l-Caryophyllene and d,l-Isocaryophyllene”. Journal of the American Chemical Society 86 (3): 485–492. doi:10.1021/ja01057a040. [10] Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects Ethan B Russo. Br J Pharmacol. 2011 August; 163(7): 1344–1364.
[19] Silva, Maria Goretti de Vasconcelos; Matos, Francisco José de Abreu; Lopes, Paulo Roberto Oliveira; Silva, Fábio Oliveira; Holanda, Márcio Tavares (August 2, 2004). Cragg, Gordon M.; Bolzani, Vanderlan S.; Rao, G. S. R. Subba, eds. “Composition of essential oils from three Ocimum species obtained by steam and microwave distillation and supercritical CO2 extraction” (PDF). Arkivoc (ARKAT USA, Inc.) 2004 (vi): 66–71. doi:10.3998/ark.5550190.0005.609. ISSN 1424-6376. Retrieved September 6, 2010. [20] Harvala C, Menounos P, Argyriadou N (February 1987). “Essential Oil from Origanum dictamnus”. Planta Med. 53 (1): 107–9. doi:10.1055/s-2006-962640. PMID 17268981.
[11] Stahl E, Kunde R. Die Leitsubstanzen der HaschischSuchhunde. Kriminalistik: Z Gesamte Kriminal Wiss Prax. 1973;27:385–389.
[21] Calvo-Irabien, L. M.; Yam-Puc, J. A.; Dzib, G.; Escalante-Erosa, F.; Peña-Rodriguez, L. M. (July 2009). “Effect of Postharvest Drying on the Composition of Mexican Oregano (Lippia graveolens) Essential Oil”. Journal of Herbs, Spices & Medicinal Plants (London, UK: Taylor & Francis) 15 (3): 281–287. doi:10.1080/10496470903379001. ISSN 1540-3580.
[12] Mediavilla, Vito; Simon Steinemann. “Essential oil of Cannabis sativa L. strains”. International Hemp Association. Retrieved 11 July 2008.
[22] The essential oil of Origanum vulgare L. ssp. vulgare growing wild in vilnius district (Lithuania) Phytochemistry. 2001 May;57(1):65-9.
69.3. NOTES AND REFERENCES
97
[23] Jirovetz L, Buchbauer G, Ngassoum MB, Geissler M (November 2002). “Aroma compound analysis of Piper nigrum and Piper guineense essential oils from Cameroon using solid-phase microextraction-gas chromatography, solid-phase microextraction-gas chromatography-mass spectrometry and olfactometry”. J Chromatogr A 976 (1–2): 265–75. doi:10.1016/S0021-9673(02)00376-X. PMID 12462618. [24] A. Prashar, I. C. Locke, C. S. Evans (2004). Cytotoxicity of lavender oil and its major components to human skin cells. Cell Proliferation 37 (3), 221–229. [25] Jamshidi, R.; Afzali, Z.; Afzali, D. (February 2009). “Chemical Composition of Hydrodistillation Essential Oil of Rosemary in Different Origins in Iran and Comparison with Other Countries” (PDF). American-Eurasian Journal of Agricultural & Environmental Sciences (Pakistan: IDOSI Publications) 5 (1): 78–81. ISSN 1990-4053. Retrieved September 6, 2010. [26] Kaul PN, Bhattacharya AK, Rao BRR, et al. (2003). “Volatile constituents of essential oils isolated from different parts of cinnamon (Cinnamomum zeylanicum Blume)". Journal of the Science of Food and Agriculture 83 (1): 53–55. doi:10.1002/jsfa.1277. [27] Ahmed A, Choudhary MI, Farooq A, et al. (2000). “Essential oil constituents of the spice Cinnamomum tamala (Ham.) Nees & Eberm.”. Flavour and Fragrance Journal 15 (6): 388–390. doi:10.1002/10991026(200011/12)15:6<388::AID-FFJ928>3.0.CO;2-F. [28] Ylang Ylang Essential Oil [29] . PMID 22466849. Missing or empty |title= (help) [30] . PMID 21095089. Missing or empty |title= (help) [31] http://staff.najah.edu/sites/default/files/Within_plant_ distribution_and_emission_of_sesquiterpenes_from_ Copaifera_officinalis.pdf [32] http://www.rain-tree.com/copaiba.htm [33] The United States Pharmacopeial Convention. “Revisions to FCC, First Supplement”. Retrieved 29 June 2009. [34] Therapeutic Goods istration. stances”. Retrieved 29 June 2009.
“Chemical sub-
Chapter 70
CB-13 CB-13 (SAB-378)[1] is a cannabinoid drug, which acts as a potent agonist at both the CB1 and CB2 receptors, but has poor blood–brain barrier penetration, and so produces only peripheral effects at low doses, with symptoms of central effects such as catalepsy only appearing at much higher dose ranges. It has antihyperalgesic properties in animal studies,[2] and has progressed to preliminary human trials.[3]
70.1 See also • AM-6545 • AZ-11713908
70.2 References [1] Cluny, N. L.; Keenan, C. M.; Duncan, M.; Fox, A.; Lutz, B.; Sharkey, K. A. (2010). “Naphthalen-1-yl(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a Peripherally Restricted Cannabinoid CB1/CB2 Receptor Agonist, Inhibits Gastrointestinal Motility but Has No Effect on Experimental Colitis in Mice”. Journal of Pharmacology and Experimental Therapeutics 334 (3): 973. doi:10.1124/jpet.110.169946. PMID 20571060. [2] Dziadulewicz, E. K.; Bevan, S. J.; Brain, C. T.; Coote, P. R.; Culshaw, A. J.; Davis, A. J.; Edwards, L. J.; Fisher, A. J.; Fox, A. J.; Gentry, C.; Groarke, A.; Hart, T. W.; Huber, W.; James, I. F.; Kesingland, A.; La Vecchia, L.; Loong, Y.; Lyothier, I.; McNair, K.; O'Farrell, C.; Peacock, M.; Portmann, R.; Schopfer, U.; Yaqoob, M.; Zadrobilek, J. (2007). “Naphthalen-1-yl-(4pentyloxynaphthalen-1-yl)methanone: A Potent, Orally Bioavailable Human CB1/CB2Dual Agonist with Antihyperalgesic Properties and Restricted Central Nervous System Penetration”. Journal of Medicinal Chemistry 50 (16): 3851–3856. doi:10.1021/jm070317a. PMID 17630726. [3] Gardin A, Kucher K, Kiese B, Appel-Dingemanse S (April 2009). “Cannabinoid receptor agonist 13, a novel cannabinoid agonist: first in human pharmacokinetics and safety”. Drug Metabolism and Disposition: the Biological Fate of Chemicals 37 (4): 827–33. doi:10.1124/dmd.108.024000. PMID 19144772.
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Chapter 71
CBS-0550 CBS-0550 is a drug developed by Taisho Pharmaceutical, which acts as a potent and selective cannabinoid CB2 receptor agonist, with 1400x selectivity for CB2 over the related CB1 receptor. Unlike most cannabinoid agonists, CBS-0550 has good solubility in water, and in animal studies it was found to produce analgesic and antihyperalgesic effects.[1]
71.1 See also • A-836,339 • SER-601
71.2 References [1] Ohta H, et al. Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic action. Bioorganic and Medicinal Chemistry. 2008 Feb 1;16(3):1111-24. PMID 18006322
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Chapter 72
47,497 47,497 or (C7)- 47,497 is a cannabinoid receptor 72.2 agonist drug, developed by Pfizer in the 1980s.[1] It has analgesic effects and is used in scientific research. It is a 72.2.1 potent CB1 agonist with a K of 2.1nM.[2][3][4]
Legal status
On 22 January 2009, 47,497 was added to the German controlled drug schedules (“Betäubungsmittelgesetz”),[12] along with its dimethylhexyl, dimethyloctyl and dimethylnonyl homologues.[13]
72.1 Homologue On the 19th of January 2009, the University of Freiburg in announced that an analog of 47,497 is the main active ingredient in the herbal “incense” product Spice, specifically the 1,1-dimethyloctyl homologue of 47,497. Both the dimethylheptyl and dimethyloctyl homologues were detected in different batches, with considerable variation in the concentration present in different samples that were analysed. The weaker dimethylhexyl and dimethylnonyl homologues were not found in any batches of smoking blends tested, but have been legally scheduled alongside the others in some jurisdictions, to forestall any potential use for this purpose.[5][6][7] The 1,1-dimethyloctyl homologue of 47,497 is in fact several times more potent than the parent compound,[8] which is somewhat unexpected as the 1,1-dimethylheptyl is the most potent substituent in classical cannabinoid compounds such as HU-210.[9] The unapproved use of these compounds in herbal smoking blends has led to a resurgence in legitimate scientific research into their use,[10] and consequently the C8 homologue of 47,497 has been assigned a proper name, cannabicyclohexanol.[11]
72.2.2 47,497 and its C6, C8, and C9 homologues were made illegal in on 24 February 2009.[14]
72.2.3 Latvia 47,497 and its C6, C8, and C9 homologues were made illegal in Latvia on 28 November 2009.[15]
72.2.4 Lithuania 47,497 and its C6, C8, and C9 homologues were made illegal in Lithuania on 5 June 2009.[16]
72.2.5 Sweden 47,497 and its C6, C7, C8, and C9 homologues were made illegal in Sweden on 15 September 2009.
72.2.6 Romania 47,497 and its C6, C7, C8, and C9 homologues were made illegal in Romania on 15 February 2010.(Illegal Substances in Romania after 15.02.2010
72.2.7 United States Cannabicyclohexanol
As of March 1, 2011, it is a schedule 1 drug.[17][18] 100
72.4. REFERENCES
72.3 See also • (C6)- 47,497 • (C8)- 47,497 • (C9)- 47,497 • 50,556-1 • 55,244 • 55,940 • -945,598 • HHC • O-1871
72.4 References [1] Weissman A, Milne GM, Melvin LS Jr. Cannabimimetic activity from -47,497, a derivative of 3phenylcyclohexanol. Journal of Pharmacology and Experimental Therapeutics. 1982 Nov;223(2):516-23. PMID 6290642 [2] Shim JY, Welsh WJ, Howlett AC. Homology model of the CB1 cannabinoid receptor: sites critical for nonclassical cannabinoid agonist interaction. Biopolymers. 2003;71(2):169-89. PMID 12767117 [3] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168. Springer. ISBN 3-54022565-X [4] Little PJ, et al. Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. Journal of Pharmacology and Experimental Therapeutics 1988; 247:1046–1051. [5] Hauptwirkstoff von „Spice“ identifiziert, University of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm. 2009-01-19.19/ [6] Spice - weitere Analyseresultate http://www. basg.at/servlet/sls/Tornado/web/ages/content/ 4E5A4B86295BF5C0C125753E006A5E3C [7] Auwärter V, et al. 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? Journal of Mass Spectrometry. 2009 Feb 2. PMID 19189348 [8] Compton DR, Johnson MR, Melvin LS, Martin BR. Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents. Journal of Pharmacology and Experimental Therapeutics. 1992 Jan;260(1):201-9. PMID 1309872 [9] Martin BR, et al. Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacology, Biochemistry and Behavior. 1991 Nov;40(3):471-8. PMID 1666911
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[10] Uchiyama N, et al. Effects of synthetic cannabinoids on electroencephalogram power spectra in rats. Forensic Science International. 2011 Jun 1. PMID 21640532 [11] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda Y (May 2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1-3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892. [12] Modedroge “Spice” ist verboten! [13] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19. Januar 2009, S. 49–50. [14] Décrets, arrêtés, circulaires: Arrêté du 24 février 2009 modifiant l’arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants [15] Grozījumi Ministru kabineta 2005.gada 8.novembra noteikumos Nr.847 “Noteikumi par Latvijā kontrolējamajām narkotiskajām vielām, psihotropajām vielām un prekursoriem” [16] http://www3.lrs.lt/pls/inter3/dokpaieska.showdoc_l?p_ id=345197 [17] Cook, Morgan (2011-02-28). “Synthetic marijuana illegal as of Tuesday”. North County Times (San Diego). Retrieved 2011-02-28. [18] https://federal.gov/a/2011-4428
Chapter 73
55,244 55,244 is a compound which is a cannabinoid receptor agonist. It has analgesic effects and is used in scientific research. It is an extremely potent CB1 full agonist with a Kᵢ of 0.21nM, making it more potent than the commonly used full agonist HU-210.[1]
73.1 See also • 47,497
73.2 References [1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649
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Chapter 74
55,940 55,940 is a cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis). 55,940 was created by Pfizer in 1974 but was never marketed. It is currently used to study the endocannabinoid system. Some effects that have been noted are a greatly decreased rates of lever pressing in exposed mice, and a greater reaction to opiates in exposed mice. A study found that 55,940 can upregulate 5-HT2A receptors in mice.[1] 55,940 is 45 times more potent than Δ9 -THC, and fully antagonized by rimonabant (SR141716A).[2] 55,940 is considered a full agonist at both CB1 and CB2 receptors and has Kᵢ values of 0.58nM and 0.68nM respectively, but is an antagonist at GPR55, the putative “CB3 " receptor.[3] 55,940 showed protective effects on rat brain mitochondria upon paraquat exposure.[4] It also showed neuroprotective effects by reducing intracellular calcium release and reducing hippocampal cell death in cultured neurons subjected to high levels of NMDA.[5]
of binding sites for [3 H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain”. Life Sciences 58 (15): 1239–1247. doi:10.1016/00243205(96)00085-9. PMID 8614277. [3] Kapur, A.; Zhao, P.; Sharir, H.; Bai, Y.; Caron, M. G.; Barak, L. S.; Abood, M. E. (2009). “Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands”. The Journal of Biological Chemistry 284 (43): 29817–29827. doi:10.1074/jbc.M109.050187. PMC 2785612. PMID 19723626. [4] Velez-Pardo, C.; Jimenez-Del-Rio, M.; Lores-Arnaiz, S.; Bustamante, J. (2010). “Protective effects of the synthetic cannabinoids 55,940 and JWH-015 on rat brain mitochondria upon paraquat exposure”. Neurochemical Research 35 (9): 1323–1332. doi:10.1007/s11064-0100188-1. PMID 20514518. [5] Zhuang, S. Y.; Bridges, D.; Grigorenko, E.; McCloud, S.; Boon, A.; Hampson, R. E.; Deadwyler, S. A. (2005). “Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodinesensitive stores”. Neuropharmacology 48 (8): 1086– 1096. doi:10.1016/j.neuropharm.2005.01.005. PMID 15910885.
55,940 induced cell death in NG 108-15 Mouse neuroblastoma x Rat glioma hybrid brain cancer (genetically engineered mouse x rat brain cancer) cells.[6][7]
[6] Tomiyama, K.; Funada, M. (2011). “Cytotoxicity of synthetic cannabinoids found in 'Spice' products: The role of cannabinoid receptors and the caspase cascade in the NG 108-15 cell line”. Toxicology Letters 207 (1): 12–17. doi:10.1016/j.toxlet.2011.08.021. PMID 21907772.
74.1 See also
[7] “General Cell Collection: NG108-15”. Public Health England Culture Collections.
• 47,497
74.2 References [1] Franklin, J. M.; Carrasco, G. A. (2013). “Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT₂A) receptor activity via ERK1/2 signaling”. Synapse 67 (3): 145–159. doi:10.1002/syn.21626. PMID 23151877. [2] Rinaldi-Carmona, M.; Pialot, F.; Congy, C.; Redon, E.; Barth, F.; Bachy, A.; Brelière, J. C.; Soubrié, P.; le Fur, G. (1996). “Characterization and distribution
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Chapter 75
Dexanabinol Dexanabinol (HU-211 or ETS2101[1] ) is a synthetic cannabinoid derivative that is the “unnatural” enantiomer of the potent cannabinoid agonist HU-210.[2] Unlike other cannabinoid derivatives, HU-211 does not act as a cannabinoid receptor agonist, but instead has NMDA antagonist effects.[3] It therefore does not produce cannabislike effects, but is anticonvulsant and neuroprotective, and is widely used in scientific research as well as currently being studied for practical applications such as treatment of head injury or stroke or cancer.[4][5][6] It was shown to be safe in clinical trials[7] and is currently undergoing Phase I trials for the treatment of brain cancer.[8]
75.1 References [1] e-therapeutics Clinical Development Pipeline [2] Pop E (September 2000). “Nonpsychotropic synthetic cannabinoids”. Current Pharmaceutical Design 6 (13): 1347–60. doi:10.2174/1381612003399446. PMID 10903397. [3] Feigenbaum JJ, et al. (December 1989). “Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker”. Proceedings of the National Academy of Sciences of the United States of America 86 (23): 9584–7. doi:10.1073/pnas.86.23.9584. PMC 298542. PMID 2556719. [4] Biegon A; Joseph AB (August 1995). “Development of HU-211 as a neuroprotectant for ischemic brain damage”. Neurological Research 17 (4): 275–80. PMID 7477742. [5] Darlington CL (October 2003). “Dexanabinol: a novel cannabinoid with neuroprotective properties”. IDrugs : the Investigational Drugs Journal 6 (10): 976–9. PMID 14534855. [6] Vink R; Nimmo AJ (January 2009). “Multifunctional drugs for head injury”. Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 6 (1): 28–42. doi:10.1016/j.nurt.2008.10.036. PMID 19110197. [7] Maas AI, et al. (January 2006). “Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial”. Lancet Neurol 5 (1): 38–45. doi:10.1016/S14744422(05)70253-2. PMID 16361021.
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[8] University of California, San Diego "Synthetic Cannabinoid May Be Used as Brain Cancer Treatment". (28 September 2012) Laboratory Equipment. Retrieved 28 September 2012.
Chapter 76
Dimethylheptylpyran Dimethylheptylpyran (DMHP, 3-(1,2dimethylheptyl)-Δ6a,10a -THC, 1,2-dimethylheptylΔ3 THC, A-40824, EA-1476) is a synthetic analogue of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9 -THC, the active component of cannabis.[1] DMHP is a pale yellow, viscous oil which is insoluble in water, but dissolves in alcohol or non-polar solvents.
76.1 Effects DMHP is similar in structure to THC, differing only in the position of one double bond, and the replacement of the 3-pentyl chain with a 3-(1,2-dimethylheptyl) chain.[2] It produces similar activity to THC, such as sedative effects, but is considerably more potent,[3] especially having much stronger analgesic and anticonvulsant effects than THC, although comparatively weaker psychological effects. It is thought to act as a CB1 agonist, in a similar manner to other cannabinoid derivatives.[4]
76.2 Investigation as non-lethal incapacitating agent DMHP and its O-acetate ester were extensively investigated by the US military chemical weapons program in the Edgewood Arsenal experiments, as possible nonlethal incapacitating agents.[5] DMHP has three stereocenters and consequently has eight possible stereoisomers, which differ considerably in potency. The racemic mix of all eight isomers of the O-acetyl ester was given the code number EA-2233, with the eight individual isomers numbered EA-2233-1 through EA-2233-8. The most potent isomer was EA2233-2, with an active dose range in humans of 0.5–2.8 μg/kg (i.e. ~35–200 μg for a 70 kg adult). Active doses varied markedly between individuals, but when the dose of EA-2233 was taken up to 1–2 mg, all volunteers were considered to be incapable of performing military duties, with the effects lasting as long as 2–3 days.
ducing the active metabolite 11-hydroxy-DMHP, but the lipophilicity of DMHP is even higher than that of THC itself, giving it a long duration of action and an extended half-life in the body of between 20–39 hours, with the half-life of the 11-hydroxy-DMHP metabolite being longer than 48 hours. Cannabinoids as a class are generally safe compounds with a large safety margin, making potent cannabinoid drugs ideal as potential non-lethal incapacitating agents. DMHP and its esters produce sedation and mild hallucinogenic effects similar to large doses of THC, but in addition to this they also cause pronounced hypotension (low blood pressure) which occurs at doses well below the hallucinogenic dose, and can lead to severe dizziness, fainting, ataxia and muscle weakness, sufficient to make it difficult to stand upright or carry out any kind of vigorous physical activity (an effect known colloquially as “couch lock”). The acute toxicity of DMHP was found to be low in both human and animal studies, with the ratio of ED50 to LD50 (Therapeutic Index) in animals being around 2000x, with death ultimately resulting from a combination of hypotension and hypothermia and preventable with ive treatment. The combination of strong incapacitating effects and a favourable safety margin led the Edgewood Arsenal team to conclude that DMHP and its derivatives, especially the O-acetyl ester of the most active isomer, EA-2233-2, were among the more promising non-lethal incapacitating agents to come out of their research program. However they were disadvantaged by producing severe hypotension at incapacitating doses, and were not as effective as the more widely publicised anticholinergic agents such as 3-Quinuclidinyl benzilate which had also already been weaponised.[6] Funding for continued development was ultimately not approved, and the cannabinoid research program was indefinitely suspended along with the rest of the Edgewood Arsenal experiments in the late 1970s, in accordance with the US commitment to cease research into chemical weapons under disarmament treaties.
DMHP is metabolised in a similar manner to THC, pro105
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Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
76.3 Isomerism Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6Hbenzo[c]chromen-1-ol. See also: Tetrahydrocannabinol § Isomerism
76.4 References [1] Adams R, Harfenist M, Loewe S (1949). Journal of the American Chemical Society 71 (5): 1624. doi:10.1021/ja01173a023. [2] Razdan RK (1980). “The Total Synthesis of Cannabinoids”. Total Synthesis of Natural Products, Volume 4. Wiley-Interscience. doi:10.1002/9780470129678.ch2. ISBN 9780471054603. [3] Wilkison, DM; Pontzer, N; Hosko, MJ (1982). “Slowing of cortical somatosensory evoked activity by delta 9tetrahydrocannabinol and dimethylheptylpyran in alphachloralose-anesthetized cats”. Neuropharmacology 21 (7): 705–9. doi:10.1016/0028-3908(82)90014-4. PMID 6289158. [4] Parker, LA; Mechoulam, R (2003). “Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats”. Integrative physiological and behavioral science : the official journal of the Pavlovian Society 38 (2): 133–45. doi:10.1007/BF02688831. PMID 14527182. [5] Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents. Vol. 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Commission on Life Sciences. The National Academies Press. 1984. pp. 79–99. [6] Ketchum, James S. (2006) Chemical Warfare Secrets Almost Forgotten. ChemBooks Inc. ISBN 978-1-42430080-8
CHAPTER 76. DIMETHYLHEPTYLPYRAN
Chapter 77
Docosatetraenoylethanolamide Docosatetraenoylethanolamide (DEA) is an endogenous ethanolamide that has been shown to act on the cannabinoid (CB1 ) receptor.[1] DEA is similar in structure to anandamide (AEA, a recognized endogenous ligand for the CB1 receptor), containing docosatetraenoic acid in place of arachidonic acid. While DEA has been shown to bind to the CB1 receptor with similar potency and efficacy as AEA, its role as a cannabinergic neurotransmitter is not well understood.
77.1 References [1] Hanus, L., Gopher, A., Almog, S., et al. (1993). “Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor”. J Med Chem 36 (20): 3032–3034. doi:10.1021/jm00072a026. PMID 8411021.
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Chapter 78
Drinabant Drinabant (INN; AVE-1625) is a drug that acts as a selective CB1 receptor antagonist, which was under investigation varyingly by Sanofi-Aventis as a treatment for obesity, schizophrenia, Alzheimer’s disease, Parkinson’s disease, and nicotine dependence.[1][2][3] Though initially studied as a potential treatment for a variety of different medical conditions, Sanofi-Aventis eventually narrowed down the therapeutic indications of the compound to just appetite suppression. Drinabant reached phase IIb clinical trials for this purpose in the treatment of obesity but was shortly thereafter discontinued,[4] likely due to the observation of severe psychiatric side effects including anxiety, depression, and thoughts of suicide in patients treated with the now-withdrawn rimonabant, another CB1 antagonist that was also under development by Sanofi-Aventis.[5]
78.1 See also • Cannabinoid receptor antagonist
78.2 References [1] Lange JH, Kruse CG (2008). “Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives”. Chemical Record (New York, N.Y.) 8 (3): 156–68. doi:10.1002/tcr.20147. PMID 18563799. [2] Kwon MO, Herrling P (2005). “List of drugs in development for neurodegenerative diseases. Update September 2005”. Neuro-degenerative Diseases 2 (2): 61–108. doi:10.1159/000089285. PMID 16909049. [3] Gerald Litwack (14 August 2009). Anandamide. Academic Press. p. 172. ISBN 978-0-12-374782-2. Retrieved 13 May 2012. [4] Reggio, Patricia H. (2009). “Toward the design of cannabinoid CB1 receptor inverse agonists and neutral antagonists”. Drug Development Research 70 (8). doi:10.1002/ddr.20337. ISSN 0272-4391. [5] Lee HK, Choi EB, Pak CS (2009). “The current status and future perspectives of studies of cannabinoid
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receptor 1 antagonists as anti-obesity agents”. Current Topics in Medicinal Chemistry 9 (6): 482–503. doi:10.2174/156802609788897844. PMID 19689362.
Chapter 79
EAM-2201 EAM-2201 (4'-ethyl-AM-2201, 5"-fluoro-JWH-210) is a drug that presumably acts as a potent agonist for the cannabinoid receptors. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in Japan in July 2012 as an ingredient in synthetic cannabis smoking blends.[1] Like the closely related MAM-2201 which had been first reported around a year earlier, EAM-2201 thus appears to be another novel compound invented by designer drug suppliers specifically for recreational use. Structurally, EAM2201 is a hybrid of two known cannabinoid compounds JWH-210 and AM-2201, both of which had previously been used as active ingredients in synthetic cannabis blends before being banned in many countries.
79.4 References
79.1 Pharmacology Nothing has been published on the pharmacology of EAM-2201, though it presumably has similar properties to the closely related AM-2201 and JWH-210, which are both full agonists and unselectively bind to CB1 and CB2 cannabinoid receptors with low nanomolar affinity.
79.2 Legal status EAM-2201 was banned in New Zealand as a temporary class drug from 6 December 2012, after reports of addiction and psychosis associated with use of products containing EAM-2201 as an active ingredient, however this has been protested by some s who claim to have found medical benefits in the treatment of conditions such as phantom limb pain, since medicinal marijuana is not available in New Zealand and synthetic cannabis products are used as a legal alternative.[2][3]
79.3 Detection A forensic standard of EAM-2201 is available and commonly used in mass spectrometry, and the compound has been cited on the Forendex website of potential drugs of abuse.[4][5] 109
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [2] I was possessed by a demon, says ex-legal high . New Zealand Herald, Monday 1 Oct 2012 [3] Amputee: K2 'takes away my pain'. New Zealand Herald, Wednesday 28 Nov 2012 [4] https://www.caymanchem.com/app/template/Product. vm/catalog/ISO00127 [5] Peter Rösner, G. Fritschi, Southern Association of Forensic Scientists, http://forendex.southernforensic. org/s/references/Molecular_Index_Of_ _Cannabimimetics_(2).pdf
Chapter 80
Endocannabinoid reuptake inhibitor Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit or completely stop the reabsorption of endocannabinoid neurotransmitters into their corresponding pre-synaptic neurons.
80.1 Etymology There are several parts to the phrase endocannabinoid reuptake inhibitor. First, a reuptake inhibitor is a substance that prevents its respective neurotransmitters from being reabsorbed into the pre-sypnatic neurones, which makes them continually recycle themselves, thus creating a large increase in neurotransmission. Next, a cannabinoid is simply a class of closely related substances such as Tetrahydrocannabinol and Cannabidiol. 'Endo' is a prefix used to describe a cannabinoid that is naturally found within an animal. In retrospect, an endocannabinoid reuptake inhibitor is a substance that when ingested by an animal prevents reuptake of its endogenous cannabinoids. Endocannabinoid uptake inhibitors that bind to fatty acid binding protons (FABPs) have been described.
docannabinoid system using VDM-11 and AA-5-HT reduced the ultimate size of the tumors in the treated rats. These findings suggest that the use of cannabinoids and/or eCBR inhibitors could be used to effectively treat tumors and/or cancer, which only adds to the controversy around cannabinoids and the cannabis plant as medicine. As one might expect, combining a cannabinoid receptor antagonist with an eCBRI reverses the effects of the reuptake inhibitor, and therefore could hinder treatment. Cannabinoid receptor antagonists aren't something common, so normally this isn't something to worry about. But if smoked cannabis or cannabis extract is to be used as a treatment, it would be necessary to cultivate varieties with little to no amounts of these compounds, as they are found in low concentrations in most varieties. One example of these antagonist compounds which is found in the cannabis plant is THCV (tetrahydrocannabivarin).
80.4 Examples of eCBRIs • AM404 • O-2093
80.2 Pharmacology
• OMDM-2
The inhibition of endocannabinoid reuptake raises the amount of those neurotransmitters available in the synaptic cleft and therefore increases neurotransmission. Following the increase of neurotransmission in the endocannabinoid system is the stimulation of its functions which, in humans, include: suppression of pain perception (analgesia), increased appetite, mood elevation and inhibition of short-term memory.
• UCM-707 • VDM-11 • URB597
80.5 See also • Endocannabinoid system
80.3 Use in medicine Other than toxicity research and recreational use, eCBRIs could have some potential in fighting tumors and possibly cancer. A study done in 2004 on rats with thyroid tumors showed that reuptake inhibition of the en110
• Reuptake inhibitor • Cannabinoid receptor antagonist • Endocannabinoid transporters
80.6. REFERENCES
80.6 References 1. http://www.fasebj.org/cgi/content/full/18/13/1606 2. http://www.ncbi.nlm.nih.gov/pubmed/16770320 3. PLOS ONE
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Chapter 81
Endocannabinoid system The endocannabinoid system is a group of neuromodulatory lipids and their receptors in the brain that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory; it mediates the psychoactive effects of cannabis and, broadly speaking, includes:
that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement.[10] In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps • The endogenous arachidonate-based lipids, explain why cannabinoids possess a greater efficacy in alanandamide (N-arachidonoylethanolamide, AEA) tering rodent motor movements than they do in humans. and 2-arachidonoylglycerol (2-AG); these are A recent analysis of cannabinoid binding in CB1 and known as "endocannabinoids" and are physio- CB2 receptor knockout-mice found cannabinoid responlogical ligands for the cannabinoid receptors. siveness even when these receptors were not being exEndocannabinoids are all eicosanoids.[1] pressed, indicating that an additional binding receptor may be present in the brain.[10] Binding has been demon• The enzymes that synthesize and degrade the endo- strated by 2-arachidonoylglycerol (2-AG) on the TRPV1 cannabinoids, such as fatty acid amide hydrolase or receptor suggesting that this receptor may be a candidate monoacylglycerol lipase. for the established response.[11] • The cannabinoid receptors CB1 and CB2 , two G protein-coupled receptors that are located in the 81.1.2 central and peripheral nervous systems.
The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators[2][3][4] for a variety of physiological processes, including motor learning,[5] synaptic plasticity,[6] appetite,[7] and pain sensation.[8]
81.1 Basic overview 81.1.1
Expression of receptors
For a more thorough description on receptor localization, see Cannabinoid receptor type 1 (CB1 ) and Cannabinoid receptor type 2 (CB2 ).
Endocannabinoid synthesis, lease, and degradation
re-
During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades. Based on the cell, these effects may result in the onsite synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.[9] Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized. This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the stria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered the synthesis of anandamide.[11]
Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain Evidence suggests that the depolarization-induced influx and immune system respectively.[9] Density of expression of calcium into the post-synaptic neuron causes the acvaries based on species and correlates with the efficacy tivation of an enzyme called transacylase. This enzyme 112
81.1. BASIC OVERVIEW is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acylphosphatidylethanolamine (NAPE). Experiments have shown that phospholipase D cleaves NAPE to yield anandamide.[12][13] In NAPE-phospholipase D (NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis.[14] The synthesis of 2-AG is less established and warrants further research.
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but also the PI3/PKB and MEK/ERK pathway (GalveRoperh et al., 2002; Davis et al., 2005; Jones et al., 2005; Graham et al., 2006). Results from rat hippocampal gene chip data after acute istration of tetrahydrocannabinol (THC) showed an increase in the expression of transcripts encoding myelin basic protein, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin and ribosomal RNAs (Kittler et al., 2000). In addition, CB1 activation has been demonstrated to increase the activity of tranOnce released into the extracellular space by a puta- scription factors like c-Fos and Krox-24 (Graham et al., 2006). tive endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves 81.1.4 Binding and neuronal excitability anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL), and 2-AG into arachi- The molecular mechanisms of CB1 -mediated changes donic acid and glycerol.[15] While arachidonic acid is a to the membrane voltage have also been studied in desubstrate for leukotriene and prostaglandin synthesis, it tail. CB1 agonists reduce calcium influx by blocking N-, P/Q- and L-type is unclear whether this degradative byproduct has novel the activity of voltage-dependent [19][20] [16][17] calcium channels. In addition to acting on calfunctions in the central nervous system. Emerging cium channels, activation of Gi/o and Gs, the two most data in the field also points to FAAH being expressed commonly coupled G-proteins to cannabinoid receptors, in postsynaptic neurons complementary to presynaptic has been shown to modulate potassium channel activity. neurons expressing cannabinoid receptors, ing the Recent studies have found that CB activation specif1 conclusion that it is major contributor to the clearance ically facilitates GIRK, a potassium channel belonging and inactivation of anandamide and 2-AG after endo[20] Both Guo & Ikeda and Binzen et cannabinoid reuptake.[10] A neuropharmacological study to the Kir3 family. al. performed a series of immunohistochemistry experdemonstrated that an inhibitor of FAAH (URB597) seiments that demonstrated CB1 co-localized with GIRK lectively increases anandamide levels in the brain of roand Kv1.4 potassium channels, suggesting that these two dents and primates. Such approaches could lead to the [21] may interact in physiological contexts. development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompa- In the central nervous system, CB1 receptors influence nied by overt signs of abuse liability.[18] neuronal excitability, reducing the incoming synaptic [22] This mechanism, known as presynaptic inhiNotably, a series of recent studies have found that the input. bition, occurs when a postsynaptic neuron releases enexpression of endocannabinoids does not correlate with docannabinoids in retrograde transmission, which then the distribution of cannabinoid receptors in the brain, bind to cannabinoid receptors on the presynaptic termisuggesting that these molecules may also be interactnal. CB receptors then reduce the amount of neurotrans1 ing with other receptors or be involved with other cell [10] mitter released, so that subsequent excitation in the presyprocesses. naptic neuron results in diminished effects on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, 81.1.3 Binding and intracellular effects although recent evidence has shown that CB1 receptors Cannabinoid receptors are G-protein coupled receptors can also regulate neurotransmitter release by a non-ion located on the pre-synaptic membrane. While there have channel mechanism, i.e. through Gi/o-mediated inhibibeen some papers that have linked concurrent stimula- tion of adenylyl cyclase and Protein Kinase A.[23] Still, tion of dopamine and CB1 receptors to an acute rise in direct effects of CB1 receptors on membrane excitabilcyclic adenosine monophosphate (cAMP) production, it ity have been reported, and strongly impact the firing of is generally accepted that CB1 activation via cannabi- cortical neurons[24] In a series of behavioral experiments, noids causes a decrease in cAMP concentration by inhi- Palazzo et al. demonstrated that NMDA, an ionotropic bition of adenylyl cyclase and a rise in the concentration glutamate receptor, and the metabotropic glutamate reof mitogen-activated protein kinase (MAP kinase).[1][10] ceptors (mGluRs) work in concert with CB1 to induce The relative potency of different cannabinoids in inhi- analgesia in mice, although the mechanism underlying bition of adenylyl cyclase correlates with their varying this effect is unclear. Together, these findings suggest that efficacy in behavioral assays. This inhibition of cAMP CB1 influences neuronal excitability by a variety of mechis followed by phosphorylation and subsequent activa- anisms, and these effects are relevant to perception and tion of not only a suite of MAP kinases (p38/p42/p44), behavior.
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CHAPTER 81. ENDOCANNABINOID SYSTEM
81.2 Functions of the endocannabinoid system
ilar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB1 receptors.[11] These findings provide the brain a direct mechanism to selectively inhibit neuronal excitabil81.2.1 Memory ity over variable time scales. By selectively internalizing different receptors, the brain may limit the production of Mice treated with tetrahydrocannabinol (THC) show sup- specific endocannabinoids to favor a time scale in accorpression of long-term potentiation in the hippocampus, a dance with its needs. process that is essential for the formation and storage of long-term memory.[25] These results concur with anecdotal evidence suggesting that smoking Cannabis impairs short-term memory.[26] Consistent with this finding, mice without the CB1 receptor show enhanced memory and 81.2.2 Appetite long-term potentiation indicating that the endocannabinoid system may play a pivotal role in the extinction of old Evidence for the role of the endocannabinoid system in memories. In contrast, a recent study found that the high- food-seeking behavior comes from a variety of cannabidose treatment of rats with the synthetic cannabinoid HU- noid studies. Emerging data suggests that THC acts via 210 over several weeks resulted in stimulation of neural CB1 receptors in the hypothalamic nuclei to directly ingrowth in the rats’ hippocampus region, a part of the lim- crease appetite.[30] It is thought that hypothalamic neubic system playing a part in the formation of declarative rons tonically produce endocannabinoids that work to and spatial memories.[27] Taken together, these findings tightly regulate hunger. The amount of endocannabisuggest that the effects of endocannabinoids on memory noids produced is inversely correlated with the amount of are dependent on what type of neurons are being targeted leptin in the blood.[31] For example, mice without leptin (excitatory vs. inhibitory) and the location of these net- not only become massively obese but express abnormally works in the brain. high levels of hypothalamic endocannabinoids as a comRole in hippocampal neurogenesis In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells.[27][28] In the subgranular zone of the dentate gyrus, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region.[29] NPs in the hippocampus have been shown to possess fatty acid amide hydrolase (FAAH) and express CB1 and utilize 2-AG.[28] Intriguingly, CB1 activation by endogenous or exogenous cannabinoids promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.[27][28]
pensatory mechanism.[7] Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as rimonabant, food intake was reduced.[7] When the CB1 receptor is knocked-out in mice, these animals tend to be leaner and less hungry than wild-type mice. A related study examined the effect of THC on the hedonic (pleasure) value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after istration of a sucrose solution.[32] A related study found that endocannabinoids affect taste perception in taste cells[33] In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.[30]
Induction of synaptic depression The inhibitory effects of cannabinoid receptor stimulation on neurotransmitter release have caused this system to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated. 2AG was found to act on presynaptic CB1 receptors to mediate retrograde short-term depression (STD) following activation of L-type calcium currents, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced long-term depression (LTD). Sim-
81.2.3 Energy balance & metabolism The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. It has also been implied in modulating insulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesity, diabetes, and atherosclerosis, which may also give it a cardiovascular role.[34]
81.2. FUNCTIONS OF THE ENDOCANNABINOID SYSTEM
81.2.4
Stress response
While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis (HPA axis) to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB1 antagonist AM251, ing the conclusion that these effects were cannabinoid-receptor dependent.[35] These findings show that anandamide and 2-AG divergently regulate the HPA axis response to stress: while habituation of the stress-induced HPA axis via 2-AG prevents excessive secretion of glucocorticoids to non-threatening stimuli, the increase of basal corticosterone secretion resulting from decreased anandamide allows for a facilitated response of the HPA axis to novel stimuli.
Exploration, social behavior, and anxiety Prolonged, systemic exposure to cannabinoids has often been associated with anti-social effects. To investigate this theory, a cannabinoid receptor-knockout mouse study examined the effect that these receptors play on exploratory behavior. Researchers selectively targeted glutamatergic and GABAergic cortical interneurons and studied results in open field, novel object, and sociability tests. Eliminating glutamaterigic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement.[36] These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: excessive excitation produces anxiety that limited the mice from exploring both animate and inanimate objects. In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism’s overall sense of arousal during novel situations.
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81.2.5 Immune function Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.[1] Functionally, the activation of cannabinoid receptors has been demonstrated to play a role in the activation of GTPases in macrophages, neutrophils, and BM cells. These receptors have also been implicated in the proper migration of B cells into the marginal zone (MZ) and the regulation of healthy IgM levels.[37] Interestingly, some disorders seem to trigger an upregulation of cannabinoid receptors selectively in cells or tissues related to symptom relief and inhibition of disease progression, such as in that rodent neuropathic pain model, where receptors are increased in the spinal cord microglia, dorsal root ganglion, and thalmic neurons.[9]
Multiple sclerosis Historical records from ancient China and Greece suggest that preparations of Cannabis Indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity. It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans.[38][39] Due to increasing use of medical Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief.[26] In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum.[40] Serial sections of cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease.[40] Other studies suggest that CB1 agonists promote the survival of oligodendrocytes in vitro in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; MollnaHolgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002). 2-AG stimulates proliferation of a microglial cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.[41]
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81.2.6
CHAPTER 81. ENDOCANNABINOID SYSTEM
Female reproduction
See also: Cannabis in pregnancy The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low.[42] These results suggest that intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.[43][44]
81.2.7
Autonomic nervous system
Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.[10]
names Normast and PeaPure as nutraceuticals. Endocannabinoids are involved in placebo induced analgesia responses.[46]
81.2.9 Thermoregulation Anandamide and N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation.[47] TRPV1 is activated by the exogenous ligand capsaicin, the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel with an EC50 of approximately of 50 nM. The high potency makes it the putative endogenous TRPV1 agonist.[48] Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation.[10] TRPV1 may also be activated by methanandamide and arachidonyl-2'chloroethylamide (ACEA).[1]
81.2.10 Sleep
Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects. Intercerebroventricular istration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep.[49] istration of anandamide into the basal forebrain of rats has also been shown to increase levels of adenosine, which plays a role in promoting sleep and suppressing arousal.[50] REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system.[51] Furthermore, anandamide levels possess a 81.2.8 Analgesia circadian rhythm in the rat, with levels being higher in At the spinal cord, cannabinoids suppress noxious- the light phase of the day, which is when rats are usually stimulus-evoked responses of neurons in the dorsal horn, asleep or less active, since they are nocturnal.[52] possibly by modulating descending noradrenaline input from the brainstem.[10] As many of these fibers are primarily GABAergic, cannabinoid stimulation in the spinal 81.3 Experimental use of CB1 -/column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuliphenotype processing in the periphery and dorsal root ganglion. The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor, the TRPV receptor and the GRP55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications[45] and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethanolamide is available under the brand
Neuroscientists often utilize transgenic CB1 knock-out mice to discern novel roles for the endocannabinoid system. While CB1 knock-out mice are healthy and live into adulthood, there are significant differences between CB1 knock-out and wild-type mice. When subjected to a high-fat diet, CB1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype.[53] Compared to wildtype, CB1 knockout mice exhibit severe deficits in motor learning, memory retrieval, and increased difficulty in completing the Morris water maze.[5][54][55] There is also evidence indicating that these knockout animals have an increased incidence and severity of stroke and seizure.[56][57]
81.4. REFERENCES
81.4 References [1] Pertwee RG (April 2006). “The pharmacology of cannabinoid receptors and their ligands: an overview”. Int J Obes (Lond) 30 (Suppl 1): S13–8. doi:10.1038/sj.ijo.0803272. PMID 16570099. [2] Fortin DA, Levine ES (2007). “Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons”. Cereb. Cortex 17 (1): 163– 74. doi:10.1093/cercor/bhj133. PMID 16467564. [3] Good CH (2007). “Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells”. J. Neurosci. 27 (1): 1–3. doi:10.1523/JNEUROSCI.4842-06.2007. PMID 17205618. [4] Hashimotodani Y, Ohno-Shosaku T, Kano M (2007). “Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus”. J. Neurosci. 27 (5): 1211–9. doi:10.1523/JNEUROSCI.415906.2007. PMID 17267577. [5] Kishimoto Y, Kano M (2006). “Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning”. J. Neurosci. 26 (34): 8829–37. doi:10.1523/JNEUROSCI.1236-06.2006. PMID 16928872. [6] Brenowitz SD, Regehr WG (2005). “Associative short-term synaptic plasticity mediated by endocannabinoids”. Neuron 45 (3): 419–31. doi:10.1016/j.neuron.2004.12.045. PMID 15694328. [7] Di Marzo V, Goparaju SK, Wang L, et al. (April 2001). “Leptin-regulated endocannabinoids are involved in maintaining food intake”. Nature 410 (6830): 822–5. doi:10.1038/35071088. PMID 11298451. [8] Cravatt BF, Demarest K, Patricelli MP, et al. (July 2001). “Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase”. Proc. Natl. Acad. Sci. U.S.A. 98 (16): 9371–6. Bibcode:2001PNAS...98.9371C. doi:10.1073/pnas.161191698. JSTOR 3056353. PMC 55427. PMID 11470906. [9] Pertwee RG (January 2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin”. Br. J. Pharmacol. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291. [10] Elphick MR, Egertová M (March 2001). “The neurobiology and evolution of cannabinoid signalling”. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486. [11] Puente N, Cui Y, Lassalle O, et al. (December 2011). “Polymodal activation of the endocannabinoid system in the extended amygdala”. Nat. Neurosci. 14 (12): 1542– 7. doi:10.1038/nn.2974. PMID 22057189.
117
[12] Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (February 2004). “Molecular characterization of a phospholipase D generating anandamide and its congeners”. J. Biol. Chem. 279 (7): 5298–305. doi:10.1074/jbc.M306642200. PMID 14634025. [13] Liu J, Wang L, Harvey-White J, et al. (September 2006). “A biosynthetic pathway for anandamide”. Proc. Natl. Acad. Sci. U.S.A. 103 Bibcode:2006PNAS..10313345L. (36): 13345–50. doi:10.1073/pnas.0601832103. PMC 1557387. PMID 16938887. [14] Leung D, Saghatelian A, Simon GM, Cravatt BF (April 2006). “Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids”. Biochemistry 45 (15): 4720–6. doi:10.1021/bi060163l. PMC 1538545. PMID 16605240. [15] Pazos MR, Núñez E, Benito C, Tolón RM, Romero J (June 2005). “Functional neuroanatomy of the endocannabinoid system”. Pharmacol. Biochem. Behav. 81 (2): 239–47. doi:10.1016/j.pbb.2005.01.030. PMID 15936805. [16] Yamaguchi T, Shoyama Y, Watanabe S, Yamamoto T (January 2001). “Behavioral suppression induced by cannabinoids is due to activation of the arachidonic acid cascade in rats”. Brain Res. 889 (1–2): 149–54. doi:10.1016/S0006-8993(00)03127-9. PMID 11166698. [17] Brock TG (December 2005). “Regulating leukotriene synthesis: the role of nuclear 5-lipoxygenase”. J. Cell. Biochem. 96 (6): 1203–11. doi:10.1002/jcb.20662. PMID 16215982. [18] Clapper JR, Mangieri RA, Piomelli D (2009). “The endocannabinoid system as a target for the treatment of cannabis dependence”. Neuropharmacology 56 (Suppl 1): 235–43. doi:10.1016/j.neuropharm.2008.07.018. PMC 2647947. PMID 18691603. [19] Twitchell W, Brown S, Mackie K (1997). “Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons”. J. Neurophysiol. 78 (1): 43–50. PMID 9242259. [20] Guo J, Ikeda SR (2004). “Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons”. Mol. Pharmacol. 65 (3): 665–74. doi:10.1124/mol.65.3.665. PMID 14978245. [21] Binzen U, Greffrath W, Hennessy S, Bausen M, SaalerReinhardt S, Treede RD (2006). “Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons”. Neuroscience 142 (2): 527– 39. doi:10.1016/j.neuroscience.2006.06.020. PMID 16889902. [22] Freund TF, Katona I, Piomelli D (2003). “Role of endogenous cannabinoids in synaptic signaling”. Physiol.
118
CHAPTER 81. ENDOCANNABINOID SYSTEM
Rev. 83 (3): 1017–66. doi:10.1152/physrev.00004.2003 (inactive 2010-07-25). PMID 12843414. [23] Chevaleyre V, Heifets BD, Kaeser PS, Südhof TC, Purpura DP, Castillo PE (2007). “ENDOCANNABINOIDMEDIATED LONG-TERM PLASTICITY REQUIRES cAMP/PKA SIGNALING AND RIM1α". Neuron 54 (5): 801–12. doi:10.1016/j.neuron.2007.05.020. PMC 2001295. PMID 17553427. [24] Bacci A, Huguenard JR, Prince DA (2004). “Longlasting self-inhibition of neocortical interneurons mediated by endocannabinoids”. Nature 431 (7006): 312–6. Bibcode:2004Natur.431..312B. doi:10.1038/nature02913. PMID 15372034. [25] Hampson RE, Deadwyler SA (1999). “Cannabinoids, hippocampal function and memory”. Life Sci. 65 (6–7): 715–23. doi:10.1016/S0024-3205(99)00294-5. PMID 10462072. [26] Pertwee RG (2001). “Cannabinoid receptors and pain”. Prog. Neurobiol. 63 (5): 569–611. doi:10.1016/S03010082(00)00031-9. PMID 11164622. [27] Jiang W, Zhang Y, Xiao L et al. (2005). “Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects”. J. Clin. Invest. 115 (11): 3104– 16. doi:10.1172/JCI25509. PMC 1253627. PMID 16224541. [28] Aguado T, Monory K, Palazuelos J et al. (2005). “The endocannabinoid system drives neural progenitor proliferation”. FASEB J. 19 (12): 1704–6. doi:10.1096/fj.053995fje. PMID 16037095. [29] Christie BR, Cameron HA (2006). “Neurogenesis in the adult hippocampus”. Hippocampus 16 (3): 199–207. doi:10.1002/hipo.20151. PMID 16411231. [30] Kirkham TC, Tucci SA (2006). “Endocannabinoids in appetite control and the treatment of obesity”. CNS Neurol Disord Drug Targets 5 (3): 272–92. doi:10.2174/187152706777452272. PMID 16787229.
[34] Bellocchio L, Cervino C, Pasquali R, Pagotto U (June 2008). “The endocannabinoid system and energy metabolism”. J. Neuroendocrinol. 20 (6): 850– 7. doi:10.1111/j.1365-2826.2008.01728.x. PMID 18601709. [35] Hill MN, McLaughlin RJ, Bingham B, et al. (May 2010). “Endogenous cannabinoid signaling is essential for stress adaptation”. Proc. Natl. Acad. Sci. U.S.A. 107 (20): 9406–11. Bibcode:2010PNAS..107.9406H. doi:10.1073/pnas.0914661107. PMC 2889099. PMID 20439721. [36] Häring M, Kaiser N, Monory K, Lutz B (2011). “Circuit specific funcBurgess, Harold A, ed. tions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration”. PLoS ONE Bibcode:2011PLoSO...626617H. 6 (11): e26617. doi:10.1371/journal.pone.0026617. PMC 3206034. PMID 22069458. [37] Basu S, Ray A, Dittel BN (December 2011). “Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses”. J. Immunol. 187 (11): 5720–32. doi:10.4049/jimmunol.1102195. PMC 3226756. PMID 22048769. [38] Baker D, Pryce G, Croxford JL et al. (2000). “Cannabinoids control spasticity and tremor in a multiple sclerosis model”. Nature 404 (6773): 84–7. doi:10.1038/35003583. PMID 10716447. [39] Baker D, Pryce G, Croxford JL et al. (2001). “Endocannabinoids control spasticity in a multiple sclerosis model”. FASEB J. 15 (2): 300–2. doi:10.1096/fj.000399fje. PMID 11156943. [40] Cabranes A, Pryce G, Baker D, Fernández-Ruiz J (August 2006). “Changes in CB1 receptors in motor-related brain structures of chronic relapsing experimental allergic encephalomyelitis mice”. Brain Res. 1107 (1): 199–205. doi:10.1016/j.brainres.2006.06.001. PMID 16822488.
[31] Di Marzo V, Sepe N, De Petrocellis L, et al. (December 1998). “Trick or treat from food endocannabinoids?". Nature 396 (6712): 636–7. Bibcode:1998Natur.396..636D. doi:10.1038/25267. PMID 9872309.
[41] Carrier EJ, Kearn CS, Barkmeier AJ, et al. (April 2004). “Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism”. Mol. Pharmacol. 65 (4): 999–1007. doi:10.1124/mol.65.4.999. PMID 15044630.
[32] De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G (July 2012). “Cannabinoid facilitation of behavioral and biochemical hedonic taste responses”. Neuropharmacology 63 (1): 161–8. doi:10.1016/j.neuropharm.2011.10.018. PMC 3705914. PMID 22063718.
[42] Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A (2000). “Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage”. Lancet 355 (9212): 1326–9. doi:10.1016/S0140-6736(00)02115-2. PMID 10776746.
[33] Yoshida R, Ohkuri T, Jyotaki M, et al. (January 2010). “Endocannabinoids selectively enhance sweet taste”. Proc. Natl. Acad. Sci. U.S.A. 107 (2): 935–9. Bibcode:2010PNAS..107..935Y. doi:10.1073/pnas.0912048107. JSTOR 40535875. PMC 2818929. PMID 20080779.
[43] Das SK, Paria BC, Chakraborty I, Dey SK (1995). “Cannabinoid ligand-receptor signaling in the mouse uterus”. Proc. Natl. Acad. Sci. U.S.A. 92 (10): 4332–6. Bibcode:1995PNAS...92.4332D. doi:10.1073/pnas.92.10.4332. PMC 41938. PMID 7753807.
81.5. FURTHER READING
[44] Paria BC, Das SK, Dey SK (1995). “The preimplantation mouse embryo is a target for cannabinoid ligandreceptor signaling”. Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9460–4. Bibcode:1995PNAS...92.9460P. doi:10.1073/pnas.92.21.9460. PMC 40821. PMID 7568154. [45] Keppel Hesselink, J.M. (2002). “New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide”. The Open Pain Journal () 5: 12–23. doi:10.2174/1876386301205010012. Retrieved 2014-01-15. [46] Colloca, Luana (2013-08-28). Placebo and Pain: From Bench to Bedside (1st ed.). Elsevier Science. pp. 11–12. ISBN 9780123979315. [47] Ross RA (November 2003). “Anandamide and vanilloid TRPV1 receptors”. Br. J. Pharmacol. 140 (5): 790– 801. doi:10.1038/sj.bjp.0705467. PMC 1574087. PMID 14517174.
119
[55] Niyuhire F, Varvel SA, Martin BR, Lichtman AH (2007). “Exposure to marijuana smoke impairs memory retrieval in mice”. J. Pharmacol. Exp. Ther. 322 (3): 1067–75. doi:10.1124/jpet.107.119594. PMID 17586723. [56] Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS (September 2002). “Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control”. J. Neurosci. 22 (17): 7695–711. PMID 12196593. [57] Marsicano G, Goodenough S, Monory K, et al. (October 2003). “CB1 cannabinoid receptors and on-demand defense against excitotoxicity”. Science Bibcode:2003Sci...302...84M. 302 (5642): 84–8. doi:10.1126/science.1088208. PMID 14526074.
81.5 Further reading
[48] Huang SM, Bisogno T, Trevisani M, et al. (June 2002). “An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors”. Proc. Natl. Acad. Sci. U.S.A. 99 (12): 8400–5. Bibcode:2002PNAS...99.8400H. doi:10.1073/pnas.122196999. PMC 123079. PMID 12060783.
• Neumeister A, Normandin MD, Pietrzak RH, et al. (2013). “Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study”. Molecular Psychiatry. doi:10.1038/mp.2013.61. Lay summary – ScienceDaily (May 14, 2013).
[49] Murillo-Rodríguez E, Sánchez-Alavez M, Navarro L, Martínez-González D, Drucker-Colín R, Prospéro-García O (November 1998). “Anandamide modulates sleep and memory in rats”. Brain Res. 812 (1–2): 270–4. doi:10.1016/S0006-8993(98)00969-X. PMID 9813364.
• Földy C, Malenka RC, Südhof TC (May 2013). “Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling”. Neuron 78 (3): 498–509. doi:10.1016/j.neuron.2013.02.036. PMC 3663050. PMID 23583622. Lay summary – ScienceDaily (April 11, 2013).
[50] Santucci V, Storme JJ, Soubrié P, Le Fur G (1996). “Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis”. Life Sci. 58 (6): PL103–10. doi:10.1016/00243205(95)02319-4. PMID 8569415. [51] Wang L, Yang T, Qian W, Hou X (January 2011). “The role of endocannabinoids in visceral hyposensitivity induced by rapid eye movement sleep deprivation in rats: regional differences”. Int. J. Mol. Med. 27 (1): 119–26. doi:10.3892/ijmm.2010.547. PMID 21057766. [52] Murillo-Rodriguez E, Désarnaud F, Prospéro-García O (May 2006). “Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat”. Life Sci. 79 (1): 30–7. doi:10.1016/j.lfs.2005.12.028. PMID 16434061. [53] Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrié P (2004). “CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity”. Int. J. Obes. Relat. Metab. Disord. 28 (4): 640–8. doi:10.1038/sj.ijo.0802583. PMID 14770190. [54] Varvel SA, Lichtman AH (2002). “Evaluation of CB1 receptor knockout mice in the Morris water maze”. J. Pharmacol. Exp. Ther. 301 (3): 915–24. doi:10.1124/jpet.301.3.915. PMID 12023519.
• Puighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A (September 2009). “Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling”. Nat. Neurosci. 12 (9): 1152–8. doi:10.1038/nn.2369. PMID 19648913. Lay summary – ScienceDaily (August 4, 2009). • Niehaus JL, Liu Y, Wallis KT, et al. (December 2007). “CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a”. Mol. Pharmacol. 72 (6): 1557– 66. doi:10.1124/mol.107.039263. PMC 2644445. PMID 17895407. Lay summary – ScienceDaily (November 30, 2007).
81.6 External links • Homepage of the ICRS - The International Cannabinoid Research Society • Homepage of the ECSN - The Endocannabinoid System Network
Chapter 82
Endocannabinoid transporters Most neurotransmitters are water-soluble and require transmembrane proteins to transport them across the cell membrane. The endocannabinoids (anandamide, AEA, and 2-arachidonoylglycerol, 2-AG) on the other hand, are non-charged lipids that readily cross lipid membranes.[1][2][3][4][5] However, since the endocannabinoids are water immiscible, protein transporters have been described that act as carriers to solubilize and transport the endocannabinoids through the aqueous cytoplasm. These include the heat shock proteins (Hsp70s) and fatty acid binding proteins for anandamide (FABPs).[6][7] FABP inhibitors attenuate the breakdown of anandamide by the enzyme fatty acid amide hydrolase (FAAH) in cell culture.[6] One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds (named the “truxilloids’) that act as a anti-nociceptive agent with mild anti-inflammatory activity in mice.[8] These truxillic acids and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice[9] and are active components of a Chinese herbal medicine ((-)-Incarvillateine Incarvillea sinensis) used to treat rheumatism and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their antinociceptive effects.
82.1 References [1] Kaczocha, Martin; Lin, Qingqing; Nelson, Lindsay D.; McKinney, Michelle K.; Cravatt, Benjamin F.; London, Erwin; Deutsch, Deutsch (2012). “Anandamide Externally Added to Lipid Vesicles Containing-Trapped Fatty Acid Amide Hydrolase (FAAH) Is Readily Hydrolyzed in a Sterol-Modulated Fashion”. ACS Chemical Neuroscience 3 (5): 364–368. doi:10.1021/cn300001w. PMID 22860204. [2] Bojesen, Inge N.; Hansen, Harald S. (2005). “Membrane transport of anandamide through resealed human red blood cell membranes”. The Journal of Lipid Research. 46 no. (8): 1652–1659. doi:10.1194/jlr.M400498JLR200. [3] Kaczocha, Martin; Hermann, Anita; Glaser, Sherrye T.; Bojesen, Inge N.; Deutsch, Dale G. (2006). “Anandamide
120
Uptake Is Consistent with Rate-limited Diffusion and Is Regulated by the Degree of Its Hydrolysis by Fatty Acid Amide Hydrolase”. The Journal of Biological Chemistry 281 (14): 9066–9075. doi:10.1074/jbc.M509721200. PMID 16461355. [4] Sandberg, A.; Fowler, C.J. (2005). “Measurement of saturable and non-saturable components of anandamide uptake into P19 embryonic carcinoma cells in the presence of fatty acid-free bovine serum albumin.”. Chemistry and Physics of Lipids 134 (2): 131– 139. doi:10.1016/j.chemphyslip.2004.12.010. PMID 15784231. [5] Di Pasquale, E.; Chahinian, H.; Sanchez, P.; Fantini, J. (2009). “The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both CholesterolDependent” [Translated title]. PLoS ONE 4 (3): e4989. doi:10.1371/journal.pone.0004989. PMID 19330032. [6] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). “Identification of intracellular carriers for the endocannabinoid anandamide”. Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565. [7] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgro, A.; Maccarrone, M. (2009). “Molecular identification of albumin and Hsp70 as cytosolic anandamidebinding proteins”. Chemistry & Biology 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. [8] Berger, W.T.; Ralph, B.P.; Kaczocha, M.; Sun, J.; Balius, T.E.; Rizzo, R.C.; Haj-Dahmane, S.; Ojima, I.; Deutsch, D.G. (2012). “Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs”. PLoS ONE 12 (7): e50968. doi:10.1371/journal.pone.0050968. [9] Nakamura, M.; Chi, Y.M.; Yan, W.M.; Nakasugi, Y.; Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nahara, T.; Sakurada, S. (1999). “Strong antinociceptive effect of incarvillateine, a novel monoterpene alkaloid from Incarvillea sinensis”. Journal of Natural Products 62 (9): 1293–1294. doi:10.1021/np990041c. PMID 10514316.
Chapter 83
GW-405,833 GW-405,833 (L-768,242) is a drug that acts as a potent and selective partial agonist for the cannabinoid receptor subtype CB2 , with an EC50 of 0.65nM and selectivity of around 1200x for CB2 over CB1 receptors.[1][2] Animal studies have shown it to possess antiinflammatory and anti-hyperalgesic effects at low doses, followed by ataxia and analgesic effects when the dose is increased.[3][4] Selective CB2 agonist drugs such as GW-405,833 are hoped to be particularly useful in the treatment of allodynia and neuropathic pain for which current treatment options are often inadequate.[5][6]
83.1 References [1] Huffman JW. The search for selective ligands for the CB2 receptor. Current Pharmaceutical Design. 2000 Sep;6(13):1323-37. doi:10.2174/1381612003399347 PMID 10903395 [2] Marriott KS, Huffman JW. Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. Current Topics in Medicinal Chemistry. 2008;8(3):187-204. doi:10.2174/156802608783498014 PMID 18289088 [3] Clayton N, Marshall FH, Bountra C, O'Shaughnessy CT. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain. 2002 Apr;96(3):253-60. PMID 11972997 [4] Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL, Mark L, Pearson MS, Miller W, Shan S, Rabadi L, Rotshteyn Y, Chaffer SM, Turchin PI, Elsemore DA, Toth M, Koetzner L, Whiteside GT. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology. 2005 Apr;48(5):658-72. PMID 15814101 [5] Beltramo M, Bernardini N, Bertorelli R, Camla M, Nicolussi E, Fredduzzi S, Reggiani A. CB2 receptormediated antihyperalgesia: possible direct involvement of neural mechanisms. European Journal of Neuroscience. 2006 Mar;23(6):1530-8. doi:10.1111/j.14609568.2006.04684.x PMID 16553616
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[6] Leichsenring A, Andriske M, Bäcker I, Stichel CC, Lübbert H. Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain. Naunyn Schmiedebergs Archives of Pharmacology. 2009 Jan 18. PMID 19152053
Chapter 84
GW-842,166X GW-842,166X is a drug which acts as a potent and selective cannabinoid CB2 receptor agonist, with a novel chemical structure based on a pyrimidine core. It has potent analgesic, anti-inflammatory and anti-hyperalgesic actions in animal models, but without cannabis-like behavioural effects due to its extremely low affinity for the CB1 receptor.[1][2][3]
84.1 References [1] Giblin GM, O'Shaughnessy CT, Naylor A, Mitchell WL, Eatherton AJ, Slingsby BP, Rawlings DA, Goldsmith P, Brown AJ, Haslam , Clayton NM, Wilson AW, Chessell IP, Wittington AR, Green R (May 2007). “Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro2H-pyran-4-yl)methyl]−4-(trifluoromethyl)5pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain”. Journal of Medicinal Chemistry 50 (11): 2597–600. doi:10.1021/jm061195+. PMID 17477516. [2] Giblin GM, Billinton A, Briggs M, Brown AJ, Chessell IP, Clayton NM, Eatherton AJ, Goldsmith P, Haslam C, Johnson MR, Mitchell WL, Naylor A, Perboni A, Slingsby BP, Wilson AW (October 2009). “Discovery of 1-[4-(3-chlorophenylamino)−1methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]−1-morpholin4-ylmethanone (GSK554418A), a brain penetrant 5-azaindole CB2 agonist for the treatment of chronic pain”. Journal of Medicinal Chemistry 52 (19): 5785–8. doi:10.1021/jm9009857. PMID 19743867. [3] Han, S.; Thatte, J.; Jones, R. M. (2009). “Chapter 11: Recent Advances in the Discovery of CB2 Selective Agonists”. Annual Reports in Medicinal Chemistry 44: 227. doi:10.1016/S0065-7743(09)04411-X.
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Chapter 85
Hemopressin Hemopressin (Hp) is an alpha hemoglobin fragment with the sequence PVNFKFLSH, originally identified in extracts of rat brain using an enzyme capture technique.[1] It binds cannabinoid receptors, acting as an inverse agonist at CB1 receptors.[2] Longer forms of hemopressin containing 2-3 additional amino acids on the N-terminus have been identified in extracts of mouse brain. These longer hemopressin peptides, named RVD-Hpα and VDHpα, bind to CB1 receptors and are agonists.[3] In addition to the Hp peptides from alpha hemoglobin, a related peptide from beta hemoglobin has been found in mouse brain extracts; this peptide, named VD-Hpβ, is also an agonist at CB1 cannabinoid receptors.[3]
85.3 References
The original Hp peptide reduces sensitivity to painful stimuli in an experimental model of hyperalgesia.[4] Hp also reduces food intake in mice.[5] However, it remains to be shown if Hp is an endogenous brain peptide. The original purification used boiling acid to extract the peptide from rat brain, and hot acid can specifically cleave D-P bonds. The N-terminally-extended forms RVDHpα and VD-Hpα may represent the true endogenous forms.[6]
[1] Rioli V, Gozzo FC, Heimann AS, et al. (March 2003). “Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme”. J. Biol. Chem. 278 (10): 8547–55. doi:10.1074/jbc.M212030200. PMID 12500972. [2] Heimann AS, Gomes I, Dale CS, et al. (December 2007). “Hemopressin is an inverse agonist of CB1 cannabinoid receptors”. Proc. Natl. Acad. Sci. U.S.A. 104 (51): 20588–93. Bibcode:2007PNAS..10420588H. doi:10.1073/pnas.0706980105. PMC 2154475. PMID 18077343. [3] Gomes I, Grushko JS, Golebiewska U, et al. (September 2009). “Novel endogenous peptide agonists of cannabinoid receptors”. FASEB J. 23 (9): 3020– 9. doi:10.1096/fj.09-132142. PMC 2735371. PMID 19380512. [4] Dale CS, Pagano Rde L, Rioli V, et al. (March 2005). “Antinociceptive action of hemopressin in experimental hyperalgesia”. Peptides 26 (3): 431–6. doi:10.1016/j.peptides.2004.10.026. PMID 15652650. [5] Dodd GT, Mancini G, Lutz B, et al. (May 2010). “The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice”. J Neurosci. 30 (21): 7369–76. doi:10.1523/JNEUROSCI.545509.2010. PMID 20505104.
85.1 Role in diet Scientists at the University of Manchester have discovered that hemopressin could be used as an appetite suppressant without having the side effects of many other drugs that are used for this purpose. In laboratory tests hemopressin was istrated to mice and rats, which significantly reduced food intake. Hemopressin works by affecting the reward centres of the brain which make us feel happy when we eat too much. A further research should be carried out in order to confirm these effects and the safety on people.[7]
85.2 See also • RVD-Hpα 123
[6] Gelman JS, Sironi J, Castro LM, et al. (May 2010). “Hemopressins and other hemoglobin-derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in efat/fat mice”. J Neurochem. 113 (4): 871–80. doi:10.1111/j.14714159.2010.06653.x. PMC 2867603. PMID 20202081. [7] http://uk.health.lifestyle.yahoo.net/ hemopressin-naturally-supresses-appetite.htm
Chapter 86
HU-210 HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from (1R,5S)-myrtenol[3] by a group led by Professor Raphael Mechoulam at the Hebrew University.[4][5][6] HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action.[7] HU-210 is the (–)−1,1-dimethylheptyl analog of 11-hydroxy- Δ8 - tetrahydrocannabinol; in some references it is called 1,1-dimethylheptyl- 11hydroxytetrahydrocannabinol. The abbreviation “HU” stands for Hebrew University.
86.2 Legal status 86.2.1 United States HU-210 is a schedule I controlled substance under the Controlled Substances Act. [14] To view national schedule, see: List of Schedule I drugs (US),
The (+) enantiomer of HU-210 has almost all of the cannabinoid activity, with the (−) enantiomer HU-211 86.2.2 New Zealand being inactive as a cannabinoid but instead acting as an Banned in New Zealand as of 8 May 2014. NMDA antagonist having neuroprotective effects.[8][9] HU-210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal neural stem and progenitor cells likely via a sequential activation of CB1 receptors, Gᵢ/ₒ proteins, and ERK signaling. It was also indicated by this increased neural growth to entail antianxiety and antidepressant effects.[10]
86.3 Other HU Cannabinoids • HU-211
HU-210, alongside other synthetic cannabinoids like WIN 55,212-2 and JWH-133, is implicated in preventing the inflammation caused by amyloid beta proteins involved in Alzheimer’s disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through the activation of cannabinoid receptors, which prevents microglial activation that elicits the inflammation. In addition, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.[11]
• HU-239
HU-210 is a potent analgesic with many of the same effects as natural THC.
• HU-336
• HU-243 • HU-308 • HU-320 • HU-331
• HU-345
86.1 Recreational use
[15]
86.4 See also
According to the U.S. Customs and Border Protection, HU-210 was discovered in Spice Gold incense products seized at the US border in January 2009. Over 100 pounds of Spice products were seized based on this finding.[12] HU-210 was also detected in three Spice products in the UK, as reported in June 2009.[13] 124
• Spice (drug) • 47,497 • JWH-018
86.6. EXTERNAL LINKS
86.5 References [1] http://www.deadiversion.usdoj.gov/drugs_concern/ spice/spice_hu210.htm [2] http://www.deadiversion.usdoj.gov/schedules/ orangebook/c_cs_alpha.pdf [3] Mechoulam, R., Lander, N., Breuer, A., Zahalka, J. Synthesis of the Individual, Pharmacologically Distinct, Enantiomers of a Tetrahydrocannabinol Derivative. Tetrahedron: Asymmetry. 1990. Vol 1, No 5. pp 315318. [4] Mechoulam, R., et al. (1988). “Enantiomeric cannabinoids: stereospecificity of psychotropic activity”. Experientia 44 (9): 762–764. doi:10.1007/BF01959156. PMID 3416993. [5] Little PJ, Compton DR, Mechoulam R, Martin BR. Stereochemical effects of 11-OH-Δ8-THC-dimethylheptyl in mice and dogs. Pharmacology, Biochemistry, and Behavior. 1989 Mar;32(3):661-666. [6] Järbe, T.; Hiltunen, A.; Mechoulam, R. (1989). “Stereospecificity of the discriminative stimulus functions of the dimethylheptyl homologs of 11-hydroxy-delta 8tetrahydrocannabinol in rats and pigeons”. The Journal of Pharmacology and Experimental Therapeutics 250 (3): 1000–1005. PMID 2550611. [7] Devane, W. A., et al. (1992). “A novel probe for the cannabinoid receptor”. Journal of Medical Chemistry 35 (11): 2065–2069. doi:10.1021/jm00089a018. PMID 1317925. [8] Howlett, A.; Champion, T.; Wilken, G.; Mechoulam, R. (1990). “Stereochemical effects of 11-OH-Δ8tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor”. Neuropharmacology 29 (2): 161. doi:10.1016/00283908(90)90056-W. PMID 2158635. [9] Darlington CL (October 2003). “Dexanabinol: a novel cannabinoid with neuroprotective properties”. IDrugs : the Investigational Drugs Journal 6 (10): 976–9. PMID 14534855. [10] Jiang, W., et al. (2005). “Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects”. The Journal of Clinical Investigation 115 (11): 3104– 3116. doi:10.1172/JCI25509. PMC 1253627. PMID 16224541. [11] Ramírez Bg, E. A. ; Blázquez, C.; Gómez Del Pulgar, T.; Guzmán, M.; De Ceballos, M. L. (2005). “Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation”. Journal of Neuroscience 25 (8): 1904–1913. doi:10.1523/JNEUROSCI.4540-04.2005. PMID 15728830. [12] “Lab Results Confirm CBP in Ohio Discover Synthetic Narcotics in Incense Packets - CBP.gov”.
125
[13] “EMCDDA Action on new drugs briefing paper: Understanding the ‘Spice’ phenomenon”. [14] “Spice Cannabinoid - HU-210”. [15] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are
86.6 External links • Comment in Nature on the article about neurogenesis.
Chapter 87
HU-243 HU-243 (AM-4056) is a synthetic cannabinoid drug that is a single enantiomer of the hydrogenated derivative of the commonly used reference agonist HU-210. It is a potent agonist at both the CB1 and CB2 receptors, with a binding affinity of 0.041nM at the CB1 receptor, making it marginally more potent than HU-210, which had an affinity of 0.061nM in the same assay.[1]
87.1 See also • AM-2389 • Nabidrox • Nabilone
87.2 References [1] Stern, E.; Lambert, D. M. (2007). “Medicinal Chemistry Endeavors around the Phytocannabinoids”. Chemistry & Biodiversity 4 (8): 1707–1728. doi:10.1002/cbdv.200790149. PMID 17712816.
126
Chapter 88
HU-308 HU-308 is a drug that acts as a cannabinoid agonist. It is highly selective for the CB2 receptor subtype, with a selectivity of over 5000x for CB2 vs CB1 .[1] The synthesis and characterization took place in the laboratory of Prof. Mechoulam at the Hebrew University of Jerusalem in the late 1990s. It has analgesic effects,[2] promotes proliferation of neural stem cells,[3] and protects both liver and blood vessel tissues against oxidative stress via inhibition of TNF-α.[4][5]
88.1 See also • HU-210 • HU-320
88.2 References [1] Hanus, L., et al. (1999). “HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor”. Proceedings of the National Academy of Sciences of the United States of America 96 (25): 14228–14233. Bibcode:1999PNAS...9614228H. doi:10.1073/pnas.96.25.14228. PMC 24419. PMID 10588688. [2] Labuda, C.; Koblish, M.; Little, P. (2005). “Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain”. European Journal of Pharmacology 527 (1–3): 172–174. doi:10.1016/j.ejphar.2005.10.020. PMID 16316653. [3] Palazuelos, J., et al. (2006). “Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 (13): 2405–2407. doi:10.1096/fj.06-6164fje. PMID 17015409. [4] Rajesh, M.; Pan, H.; Mukhopadhyay, P.; Batkai, S.; OseiHyiaman, D.; Hasko, G.; Liaudet, L.; Gao, B.; Pacher, P. (2007). “Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis”. Journal of leukocyte biology 82 (6): 1382–1389. doi:10.1189/jlb.0307180. PMC 2225476. PMID 17652447.
127
[5] Rajesh, M., et al. (2007). “CB2-receptor stimulation attenuates TNF-α-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion”. American journal of physiology. Heart and circulatory physiology 293 (4): H2210–H2218. doi:10.1152/ajpheart.00688.2007. PMC 2229632. PMID 17660390.
Chapter 89
HU-331 HU-331 is a quinone anticarcinogenic drug synthesized from cannabidiol, a cannabinoid in the Cannabis sativa plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible effect on the action of DNA topoisomerase I. The cannabinoid quinone HU331 is a very specific inhibitor of topoisomerase II, compared with most known anticancer quinones.[1] One of the main objectives of these studies is the development of a new quinone derived compound that produces antineoplastic activity while maintaining low toxicity at therapeutic doses.
89.1 Mechanism of action Inhibitors of topoisomerases can act at two different levels. First inhibiting topoisomerase, which stabilize the topoisomerase-DNA complex and thus introduce DNA breaks in the wires that lead to apoptosis, then inhibiting the catalytic activity of topoisomerase, which hinders the activity of these enzymes without introducing breaks into the DNA chains. HU-331 seems to be a catalytic inhibitor of topoisomerase II, probably by enzymatic ligation to the protein. This molecule does not cause damage to DNA, but protects cells from damage, natural, or induced by other inhibitors of topoisomerase II that act as inhibitors of topoisomerase. Even when 60% of the target cells are killed by treatment with HU-331, other cells’ nucleic content remains unharmed, with less breakage of DNA chains that control important cellular functions.[2] Doxorubicin, like other anticancer quinones, was used for chemotherapy in human cancers for many years. The mechanism of action of these drugs has been the subject of considerable controversy since chemotherapeutic drugs exert their cytotoxic effect on target cells by nonspecific mechanisms. The doxorubicin damages DNA by intercalation, the generation of reactive oxygen species and inhibition of DNA topoisomerase I and II. This leads to breaking the chains of DNA single and double strands. The protein associated with these ruptures are the topoisomerase II and DNA damage is catalyzed
by this enzyme.[2] Thus, while doxorubicin and other anthraquinones act through many mechanisms such as apoptosis, abrogation of the cell cycle cell, activation of caspases, generation of ROS, inhibition of both topoisomerases, activation of intracellular secondary messengers, etc. Hu-331 is more active and less toxic, since it generates reactive oxygen species in the heart and has a specific activity that gives great potential to develop as a new anticancer drug, according to Kogan et al.[2] Cannabinoids can act as anticancer compounds killing several oncogenic cells followed by direct interaction with cannabinoid receptors. The growth of glioma is inhibited by a selective activation of the CB2 cannabinoid receptor and endogenous cannabinoids such as anandamide inhibit the proliferation of cells involved in lung cancer. The reason behind the antitumor effect of HU-331 appears unknown as cannabinoid receptor antagonists do not inhibit HU-331, despite being mediated by a cannabinoid receptor. The HU-331 exerts an antiangiogenic effect accompanied by apoptosis of endothelial cells. Although in some studies. HU-331 has not caused the death of cells by oncogenic apoptosis. The conclusion that would lead cells to apoptosis based on treatment with the drug did not increase the proportion of cells containing DNA Lues in the sub-G1 phase and have not found the expression of caspase-3 in cancer cells.[2]
89.2 See also • HU-210 • HU-320 • HU-336
89.3 References
128
[1] Kogan N.M. et al. (2007). “HU-331, a novel cannabinoidbased anticancer topoisomerase II inhibitor”. Mol. Cancer Ther. 6 (1): 173–183. doi:10.1158/1535-7163.MCT06-0039. PMID 17237277. [2] Kogan N.M. et al. (2007). “A Cannabinoid Anticancer Quinone, HU-331, Is More Potent and Less Car-
89.3. REFERENCES
diotoxic Than Doxorubicin: A Comparative in Vivo Study”. J. Pharmacol. Exp. Ther. 322 (2): 646–653. doi:10.1124/jpet.107.120865. PMID 17478614.
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Chapter 90
11-Hydroxy-THC 11-Hydroxy-Δ9 -tetrahydrocannabinol, abbreviated as 11-OH-THC, is the main active metabolite of THC which is formed in the body after cannabis consumption.[1] 11-Hydroxy-THC has been shown to be active in its own right,[2] but the effects produced are not necessarily identical to those of THC.[3] This might partially explain the biphasic effects of cannabis, whereby some effects such as increased appetite tend to be delayed rather than occurring immediately when the drug is consumed.[4] 11-Hydroxy-THC is subsequently metabolised further to 11-nor-9-carboxy-THC, which is not psychoactive but might still play a role in the analgesic and antiinflammatory effects of cannabis.
90.1 References [1] Johnson JR, Jennison TA, Peat MA, Foltz RL (1984). “Stability of delta 9-tetrahydrocannabinol (THC), 11hydroxy-THC, and 11-nor-9-carboxy-THC in blood and plasma”. Journal of analytical toxicology 8 (5): 202–4. doi:10.1093/jat/8.5.202. PMID 6094914. [2] Turkanis SA, Karler R (1988). “Changes in neurotransmitter release at a neuromuscular junction of the lobster caused by cannabinoids”. Neuropharmacology 27 (7): 737–42. doi:10.1016/0028-3908(88)90083-4. PMID 2901683. [3] Hollister LE, Gillespie HK (1975). “Action of delta-9tetrahydrocannabinol. An approach to the active metabolite hypothesis”. Clin. Pharmacol. Ther. 18 (6): 714–9. PMID 1204277. [4] Lemberger, L; Martz, R; Rodda, B; Forney, R; Rowe, H (1973). “Comparative Pharmacology of Δ9Tetrahydrocannabinol and its Metabolite, 11-OH-Δ9Tetrahydrocannabinol”. The Journal of Clinical Investigation 52 (10): 2411–7. doi:10.1172/JCI107431. PMC 302499. PMID 4729039.
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Chapter 91
9-nor-9β-Hydroxyhexahydrocannabinol 9-nor−9β-Hydroxyhexahydrocannabinol (HHC), is a synthetic cannabinoid derivative which resulted from early modifications to the structure of THC, in a search for the simplest compound that could still fulfil the binding requirements to produce cannabis-like activity.[1][2] HHC is active in its own right with similar potency to THC, but further simplification and variation of this parent structure lead to more potent, yet structurally simpler derivatives such as 47,497 and 55,940,[3][4][5] which after several steps of modification have become quite structurally distinct from THC, while HHC on the other hand is still substantially similar in structure to THC. The discovery of this simplified class of cannabinoid derivatives was highly significant in of the widespread use of 55,940 for early scientific research into the cannabinoid receptors,[6] as well as later work using more complex compounds such as 55,244 to map the CB1 binding site in more detail, but aside from these specific applications, these compounds attracted little attention and no compounds from this series were developed for medical use despite favourable safety profiles in animal studies. Unexpectedly, some 25 years later, these compounds came back into prominence when an obscure derivative (C8)- 47,497 was found to have been sold as the active ingredient in the “herbal” cannabis substitute product Spice,[7] which ironically has led to a resurgence of interest into laboratory-conducted scientific research of this family of drugs.
91.1 See also • AM-2389 • HU-243
91.2 References [1] Johnson MR, et al. Potent Analgetics Derived From 9Nor-9β-Hydroxyhexahydrocannabinol. NIDA Research Monograph 34; 1980. pp 68-74.
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[2] Melvin LS, Johnson MR. Structure-Activity Relationships of Tricyclic and Nonclassical Bicyclic Cannabinoids. NIDA Research Monograph 79; 1987. pp 31-47. [3] Weissman, A; Milne, GM; Melvin Jr, LS (1982). “Cannabimimetic activity from -47,497, a derivative of 3-phenylcyclohexanol”. The Journal of Pharmacology and Experimental Therapeutics 223 (2): 516–23. PMID 6290642. [4] Melvin, LS, et al. (1984). “A cannabinoid derived prototypical analgesic”. Journal of Medical Chemistry 27 (1): 67–71. doi:10.1021/jm00367a013. PMID 6690685. [5] Compton, DR; Johnson, MR; Melvin, LS; Martin, BR (1992). “Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents”. The Journal of Pharmacology and Experimental Therapeutics 260 (1): 201–9. PMID 1309872. [6] Devane, WA, et al. (1988). “Determination and characterization of a cannabinoid receptor in rat brain”. Molecular Pharmacology 34 (5): 605–13. PMID 2848184. [7] Auwärter, V, et al. (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–7. doi:10.1002/jms.1558. PMID 19189348.
Chapter 92
Ibipinabant Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB1 antagonist.[1] It has potent anorectic effects in animals,[2] and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists.[3][4][5]
92.1 See also • Cannabinoid receptor antagonist
92.2 References [1] Lange, JH; Coolen, HK; Van Stuivenberg, HH; Dijksman, JA; Herremans, AH; Ronken, E; Keizer, HG; Tipker, K et al. (2004). “Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists”. Journal of Medical Chemistry 47 (3): 627–43. doi:10.1021/jm031019q. PMID 14736243. [2] Need, AB; Davis, RJ; Alexander-Chacko, JT; Eastwood, B; Chernet, E; Phebus, LA; Sindelar, DK; Nomikos, GG (2006). “The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats”. Psychopharmacology 184 (1): 26–35. doi:10.1007/s00213005-0234-x. PMID 16328376. [3] Lange, JH; Van Stuivenberg, HH; Veerman, W; Wals, HC; Stork, B; Coolen, HK; McCreary, AC; Adolfs, TJ; Kruse, CG (2005). “Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity”. Bioorganic & Medicinal Chemistry Letters 15 (21): 4794–8. doi:10.1016/j.bmcl.2005.07.054. PMID 16140010. [4] Srivastava, BK; Joharapurkar, A; Raval, S; Patel, JZ; Soni, R; Raval, P; Gite, A; Goswami, A et al. (2007). “Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: synthesis, biological evaluation, and molecular
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modeling in the homology model”. Journal of Medical Chemistry 50 (24): 5951–66. doi:10.1021/jm061490u. PMID 17979261. [5] Srivastava, BK; Soni, R; Joharapurkar, A; Sairam, KV; Patel, JZ; Goswami, A; Shedage, SA; Kar, SS et al. (2008). “Bioisosteric replacement of dihydropyrazole of 4S-(-)−3-(4-chlorophenyl)-N-methyl-N'(4-chlorophenyl)-sulfonyl-4-phenyl-4,5-dihydro-1Hpyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole”. Bioorganic & Medicinal Chemistry Letters 18 (3): 963–8. doi:10.1016/j.bmcl.2007.12.036. PMID 18207393.
Chapter 93
IDFP IDFP is an organophosphorus compound related to the nerve agent sarin. Like sarin, IDFP is an irreversible inhibitor for a number of different enzymes that normally serve to break down neurotransmitters, however the long alkyl chain of IDFP makes it dramatically weaker as an inhibitor of acetylcholinesterase (AChE), with an IC50 of only 6300nM, while it is a potent inhibitor of two enzymes monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG), and fatty acid amide hydrolase (FAAH), the primary enzyme that degrades the other main endocannabinoid anandamide. The IC50 of IDFP is 0.8nM at MAGL, and 3.0nM at FAAH. Inhibition of these two enzymes causes markedly increased levels of both anandamide and 2-AG in the brain, resulting in increased cannabinoid signalling and typical cannabinoid behavioral effects in animal studies, while its lack of potency at AChE means that no cholinergic symptoms are produced.[1][2][3][4] Despite its similar chemical structure to the banned nerve agents, the long alkyl chain of IDFP causes it to fall outside the definition of “toxic chemicals” under the Chemical Weapons Convention,[5] and since it also does not exhibit the potent AChE inhibition of related organophosphorus compounds, IDFP is not subject to the same stringent legal controls.
93.1 See also • Methoxy arachidonyl fluorophosphonate • 4-Nonylphenylboronic acid
93.2 References [1] Nomura, D. K.; Blankman, J. L.; Simon, G. M.; Fujioka, K.; Issa, R. S.; Ward, A. M.; Cravatt, B. F.; Casida, J. E. (2008). “Activation of the endocannabinoid system by organophosphorus nerve agents”. Nature Chemical Biology 4 (6): 373–378. doi:10.1038/nchembio.86. PMC 2597283. PMID 18438404. [2] Casida, J. E.; Nomura, D. K.; Vose, S. C.; Fujioka, K. (2008). “Organophosphate-sensitive lipases modulate
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brain lysophospholipids, ether lipids and endocannabinoids”. Chemico-Biological Interactions 175 (1–3): 355– 364. doi:10.1016/j.cbi.2008.04.008. PMC 2582404. PMID 18495101. [3] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.; Mangravite, L. M.; Chiu, S.; Casida, J. E.; Krauss, R. M. (2008). “Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins”. Proceedings of the National Academy of Sciences 105 (38): 14561–14566. doi:10.1073/pnas.0807232105. PMC 2567196. PMID 18794527. [4] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.; Barber, A.; Casida, J. E.; Krauss, R. M. (2011). Bartolomucci, Alessandro, ed. “Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes”. PLoS ONE 6 (11): e26415. doi:10.1371/journal.pone.0026415. PMC 3208546. PMID 22073164. [5] CWC Schedule 1 Part A. Toxic Chemicals
Chapter 94
2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4nonylphenyl)cyclohex-1-ene 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4nonylphenyl)cyclohex-1-ene is an analgesic compound which is a cannabinoid agonist. It is a ring-opened cannabinoid derivative, an analogue of cannabidiol. However, unlike cannabidiol, this compound produces potent cannabis-like effects in animals, suggesting it acts as a CB1 agonist.[1] It can be synthesized by Birch reduction from the nonylanalog of cannabidiol.[2]
94.1 References [1] Razdan, K. (1981). “The Total Synthesis of Cannabinoids”. In John Apsimon. The Total Synthesis of Natural Products. Wiley Interscience. p. 245. ISBN 978-0-47105460-3. OCLC 19487018. [2] Razdan RK, Pars HG, Thompson WR, Granchelli FE (1974). “Lithium-ammonia reduction of tetrahydrocannabinols”. Tetrahedron Letters 15 (49–50): 4315. doi:10.1016/S0040-4039(01)92152-5.
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Chapter 95
JTE 7-31 JTE 7-31 is a selective cannabinoid receptor agonist invented by Japan Tobacco.[1][2] It is a reasonably highly selective CB2 agonist, but still retains appreciable affinity at CB1 , with a Kᵢ of 0.088nM at CB2 vs 11nM at CB1 .
95.1 See also • A-834,735 • JTE-907 • MDA-19 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • S-444,823
95.2 References [1] WO patent 1997/029079, Inaba T, Kaya T, Iwamura H, “Novel compounds and pharmaceutical use thereof”, granted 1997-14-08 [2] US patent 6017919, Inaba T, Kaya T, Iwamura H, “Compounds and pharmaceutical use thereof”, granted 200001-25
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Chapter 96
JTE-907 JTE-907 is a drug used in scientific research that acts as a selective CB2 inverse agonist.[1][2] It has antiinflammatory effects in animal studies,[3] thought to be mediated by an interaction between the CB2 receptor and IgE.[4]
96.1 See also • JTE 7-31
96.2 References [1] Iwamura, H, et al. (2001). “In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor”. The Journal of Pharmacology and Experimental Therapeutics 296 (2): 420–5. PMID 11160626. [2] Raitio, KH, et al. (2006). “Synthesis and SAR studies of 2-oxoquinoline derivatives as CB2 receptor inverse agonists”. Journal of Medical Chemistry 49 (6): 2022–7. doi:10.1021/jm050879z. PMID 16539390. [3] Ueda, Y, et al. (2005). “Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE907, in cutaneous inflammation in mice”. European Journal of Pharmacology 520 (1–3): 164–71. doi:10.1016/j.ejphar.2005.08.013. PMID 16153638. [4] Ueda, Y; Miyagawa, N; Wakitani, K (2007). “Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice”. Life Sciences 80 (5): 414–9. doi:10.1016/j.lfs.2006.09.026. PMID 17055000.
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Chapter 97
JWH-015 JWH-015 is a chemical from the naphthoylindole family that acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8 nM, while its affinity for CB1 is 383 nM, meaning that it binds almost 28x more strongly to CB2 than CB1 [1] However it still displays some CB1 activity, and in some model systems can be very potent and efficacious at activating CB1 receptors,[2] and therefore it is not as selective as newer drugs such as JWH-133.[3] It has been shown to possess immunomodulatory effects,[4][5] and CB2 agonists may be useful in the treatment of pain and inflammation.[6][7] It was discovered and named after Dr. John W. Huffman.
[3] Marriott KS, Huffman JW (2008). “Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor”. Curr Top Med Chem 8 (3): 187–204. doi:10.2174/156802608783498014. PMID 18289088. [4] Ghosh S, Preet A, Groopman JE, Ganju RK (July 2006). “Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes”. Mol. Immunol. 43 (14): 2169–79. doi:10.1016/j.molimm.2006.01.005. PMID 16503355. [5] Montecucco F, Burger F, Mach F, Steffens S (March 2008). “CB2 cannabinoid receptor agonist JWH015 modulates human monocyte migration through defined intracellular signaling pathways”. Am. J. Physiol. Heart Circ. Physiol. 294 (3): H1145–55. doi:10.1152/ajpheart.01328.2007. PMID 18178718.
97.1 Metabolism
[6] Balter MB, Uhlenhuth EH (1992). “Prescribing and use of benzodiazepines: an epidemiologic perspective”. J Psychoactive Drugs 24 (1): 63–4. doi:10.1186/17422094-2-29. PMID 1352348.
JWH-015 has been shown in vitro to be metabolised primarily by hydroxylation and N-dealkylation, and also by epoxidation of the naphthalene ring,[8] similar to the metabolic pathways seen for other aminoalkylindole cannabinoids such as WIN 55,212-2.[9] Epoxidation of polycyclic aromatic hydrocarbons (see for example benzo(a)pyrene toxicity) can produce carcinogenic metabolites, although there is no evidence to show that JWH-015 or other aminoalkylindole cannabinoids are actually carcinogenic in vivo. A study published in the British Journal of Cancer shows that JWH-015 may signal certain cancers to shrink through a process called apoptosis.[10]
[7] Romero-Sandoval A, Eisenach JC (April 2007). “Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision”. Anesthesiology 106 (4): 787–94. doi:10.1097/01.anes.0000264765.33673.6c. PMID 17413917. [8] Zhang Q, Ma P, Cole RB, Wang G. Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS. Analytical and Bioanalytical Chemistry. 2006 Nov;386(5):1345-55. PMID 16955257
97.2 References [1] Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (August 2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 )receptor binding”. Drug Alcohol Depend 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [2] Murataeva N, Mackie K, Straiker A (November 2012). “The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons”. Pharmacol. Res. 66 (5): 437–42. doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID 22921769.
[9] Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang G (October 2002). “In vitro metabolism of R(+)[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist”. Drug Metab. Dispos. 30 (10): 1077–86. doi:10.1124/dmd.30.10.1077. PMID 12228183. [10] N Olea-Herrero, D Vara, S Malagarie-Cazenave, Díaz“Inhibition of human Laviada (18 August 2009). tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2”. British Journal of Cancer: 101, 940–950. doi:10.1038/sj.bjc.6605248. Retrieved 10 July 2014.
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Chapter 98
JWH-051 JWH-051 is an analgesic drug which is a cannabinoid agonist. Its chemical structure is closely related to that of the potent cannabinoid agonist HU-210, with the only difference being the removal of the hydroxyl group at position 1 of the aromatic ring. It was discovered and named after Dr. John W. Huffman. JWH-051 retains high affinity for the CB1 receptor, but is a much stronger agonist for CB2 , with a Ki value of 14nM at CB2 vs 19nM at CB1 .[1] It was one of the first CB2 -selective ligands developed, although its selectivity for CB2 is modest compared to newer compounds such as HU-308. It has similar effects to other cannabinoid agonists such as sedation and analgesia, but with a relatively strong antiinflammatory effect due to its strong activity at CB2 .[2][3][4]
98.1 References [1] Huffman, JW, Yu, S, Showalter, V, Abood, ME, Wiley, JL, Compton, DR, Martin, BR, Bramblett, RD, Reggio, PH (1996). “Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor”. Journal of Medical Chemistry 39 (20): 3875–7. doi:10.1021/jm960394y. PMID 8831752. [2] Huffman, JW (2000). “The search for selective ligands for the CB2 receptor”. Current pharmaceutical design 6 (13): 1323–37. doi:10.2174/1381612003399347. PMID 10903395. [3] Klein, TW, Newton, C, Friedman, H (1998). “Cannabinoid receptors and the cytokine network”. Advances in experimental medicine and biology. Advances in Experimental Medicine and Biology 437: 215–22. doi:10.1007/978-1-4615-5347-2_24. ISBN 978-0-30645838-5. PMID 9666274. [4] Griffin, G, Fernando, SR, Ross, RA, McKay, NG, Ashford, ML, Shire, D, Huffman, JW, Yu, S et al. (1997). “Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals”. European Journal of Pharmacology 339 (1): 53–61. doi:10.1016/S00142999(97)01336-8. PMID 9450616.
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Chapter 99
JWH-057 JWH-057, also known as deoxy-Δ8-THC-DMH, is a selective cannabinoid ligand, with a binding affinity of Kᵢ = 2.9 ± 1.6 nM for the CB2 subtype, and Kᵢ = 23 ± 7 nM for CB1 .[1]
99.1 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073
99.2 References [1] Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH (1996). “Synthesis and Pharmacology of a Very Potent Cannabinoid Lacking a Phenolic Hydroxyl with High Affinity for the CB2 Receptor”. J. Med. Chem. 39 (20): 3875–3877. doi:10.1021/JM960394Y.
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Chapter 100
JWH-120 JWH-120 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is the N-propyl analog of JWH-122. It is a potent and selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 6.1 ± 0.7 nM at this subtype, and 173 times selectivity over the CB1 subtype.[1]
100.1 See also • JWH-122 • JWH-193 • JWH-210 • JWH-398
100.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 101
JWH-122 JWH-122 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is a methylated analogue of JWH-018. It has a Kᵢ of 0.69 nM at CB1 and 1.2 nM at CB2 .[1]
101.1 See also • JWH-193 • JWH-210 • JWH-398
101.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 102
JWH-133 JWH-133 is a potent selective CB2 receptor agonist, with a Ki of 3.4nM and selectivity of around 200x for CB2 over CB1 receptors. It was discovered by, and named after, John W. Huffman.
102.3 External links
JWH-133, alongside WIN 55,212-2 and HU-210, is implicated in preventing the inflammation caused by Amyloid beta proteins involved in Alzheimer’s Disease, in addition to preventing cognitive impairment and loss of neuronal markers. This antiinflamatory action is induced through agonist action at cannabinoid receptors, which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
• JNeurosci.org Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation Also has been shown to block grown of tumors. More clinical studies and trials are needed.
It may be linked with anti-cancer properties, according to pre-trial data from a 2010 study in Madrid. [1]
102.1 Legal Status The substance commonly referred to as “JWH-133” is not a scheduled substance in the U.S., although its young age prevents it from having received the level of government attention as with the older, more widely used and well known chemicals. Low abuse potential makes it less likely for regulation a priori relative to its sister drugs such as JWH-018, as JWH-133 (chemical name (6aR,10aR)−3-(1,1-Dimethylbutyl)−6a,7,10,10atetrahydro −6,6,9-trimethyl-6H-dibenzo[b,d]pyran) is selective for the non-psychoactive CB2 receptor and hence devoid of any psychoactive side effects or abuse potential.[2]
102.2 References [1] http://www.enewspf.com/index. php/latest-news/health-and-fitness/ 18029-marijuana-compound-halts-breast-cancer-tumor-growth-
[2] http://www.usdoj.gov/dea/pubs/scheduling.html
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Chapter 103
JWH-148 JWH-148 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is the indole 2-methyl analog of JWH-120. It is a moderately selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 14.0 ± 1.0 nM at this subtype, and more than 8 times selectivity over the CB1 subtype.[1]
103.1 See also • JWH-120 • JWH-122 • JWH-193 • JWH-210 • JWH-398
103.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 104
JWH-149 JWH-149 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is the N-pentyl analog of JWH-148. It is a potent but only moderately selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 0.73 ± 0.03 nM at this subtype, and more than 6 times selectivity over the CB1 subtype.[1]
104.1 See also • JWH-120 • JWH-122 • JWH-148 • JWH-193 • JWH-210 • JWH-398
104.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 105
JWH-161 JWH-161 is a cannabinoid derivative that was designed by Dr John W. Huffman's team as a hybrid between the dibenzopyran “classical” cannabinoid drugs and the novel indole derivatives, in an attempt to unravel the differences in their binding modes to the CB1 receptor. While retaining structural elements from both families, JWH-161 has a CB1 Kᵢ of 19.0nM, although it was found to be slightly weaker than THC in animal tests.[1]
105.1 References [1] Huffman JW, Padgett LW (2005). “Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes”. Current Medicinal Chemistry 12 (12): 1395–411. doi:10.2174/0929867054020864. PMID 15974991.
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Chapter 106
JWH-176 JWH-176 is an analgesic drug which acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is only 26.0nM, making it more potent than THC itself,[1] however JWH-176 is particularly notable in that it is a hydrocarbon containing no heteroatoms. This demonstrates that reasonably high-affinity cannabinoid binding and agonist effects can be produced by compounds with no hydrogen bonding capacity at all, relying merely on Van der Waals interactions to bind to the receptor.[2] It was discovered by, and named after, Dr. John W. Huffman.
106.1 See also • JWH-175
106.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. [2] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X
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Chapter 107
JWH-359 JWH-359 is a dibenzopyran “classical” cannabinoid drug, which is a potent and selective CB2 receptor agonist, with a Kᵢ of 13.0nM and selectivity of around 220x for CB2 over CB1 receptors. It is related to other dibenzopyran CB2 agonists such as JWH-133 and L-759,656 but with a chiral side chain which has made it useful in mapping the shape of the CB2 binding site.[1][2] It was discovered by, and named after, Dr. John W. Huffman.
107.1 References [1] Huffman, J.; Bushell, S.; Joshi, S.; Wiley, J.; Martin, B. (2006). “Enantioselective synthesis of 1-methoxyand 1-deoxy-2'-methyl-delta8-tetrahydrocannabinols: new selective ligands for the CB2 receptor”. Bioorganic & Medicinal Chemistry 14 (1): 247–262. doi:10.1016/j.bmc.2005.08.013. PMID 16165365. [2] “Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor”. Curr Top Med Chem 8 (3): 187–204. 2008. doi:10.2174/156802608783498014. PMID 18289088.
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Chapter 108
JZL184 JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG).[1] It displays high selectivity for MAGL over other brain serine hydrolases, including the anandamidedegrading enzyme fatty acid amide hydrolase (FAAH), thereby making it a useful tool for studying the effects of endogenous 2-AG signaling, in vivo. istration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects.
108.1 See also • JZL195
108.2 References [1] Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF (November 2008). “Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects”. Nat. Chem. Biol. 5 (1): 37–44. doi:10.1038/nchembio.129. PMC 2605181. PMID 19029917.
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Chapter 109
JZL195 JZL195 is a potent inhibitor of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary enzymes responsible for degrading the endocannabinoids anandamide (AEA) and 2arachidonoylglycerol (2-AG), respectively.[1]
109.1 See also • JZL184
109.2 References [1] Long, J. Z.; Nomura, D. K.; Vann, R. E.; Walentiny, D. M.; Booker, L.; Jin, X.; Burston, J. J.; Sim-Selley, L. J.; Lichtman, A. H.; Wiley, J. L.; Cravatt, B. F. (2009). “Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo”. Proceedings of the National Academy of Sciences 106 (48): 20270. doi:10.1073/pnas.0909411106.
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Chapter 110
KM-233 KM-233 is a drug which is an analogue of Δ8tetrahydrocannabinol (THC), the less active but more stable isomer of the active component of Cannabis. km-233 differs from Δ8-THC by the pentyl side chain being replaced by a 1,1-dimethylbenzyl group. It has high binding affinity in vitro for both the CB1 and CB2 receptors, with a CB2 affinity of 0.91nM and 13x selectivity over the CB1 receptor.[1] In animal studies it has been found to be effective for the treatment of glioma, a form of brain tumor.[2] A large number of related analogues are known where the 1,1-dimethylbenzyl group is substituted or replaced by other groups, with a fairly well established structure-activity relationship.[3][4][5][6][7]
110.1 See also • AM-411 • AMG-36
110.2 References [1] Krishnamurthy M, Ferreira AM, Moore BM 2nd. Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids. Bioorganic and Medicinal Chemistry Letters. 2003 Oct 20;13(20):3487-90. PMID 14505654 [2] Duntsch C, et al. Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma. Journal of Neuro-oncology. 2006 Apr;77(2):143-52. PMID 16314952 [3] Nadipuram AK, et al. Synthesis and testing of novel classical cannabinoids: exploring the side chain ligand binding pocket of the CB1 and CB2 receptors. Bioorganic and Medicinal Chemistry. 2003 Jul 17;11(14):3121-32. PMID 12818675 [4] Durdagi S, et al. The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2. Journal of Medicinal Chemistry. 2007 Jun 14;50(12):2875-85. PMID 17521177
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[5] Krishnamurthy M, Gurley S, Moore BM 2nd. Exploring the substituent effects on a novel series of C1'-dimethylaryl Delta8-tetrahydrocannabinol analogs. Bioorganic and Medicinal Chemistry. 2008 Jul 1;16(13):6489-500. PMID 18524604 [6] Ferreira AM, et al. Quantitative structure-activity relationship (QSAR) for a series of novel cannabinoid derivatives using descriptors derived from semi-empirical quantum-chemical calculations. Bioorganic and Medicinal Chemistry. 2009 Mar 15;17(6):2598-606. PMID 19250829 [7] Brogi S, et al. Three-dimensional quantitative structureselectivity relationships analysis guided rational design of a highly selective ligand for the cannabinoid receptor 2. European Journal of Medicinal Chemistry. 2011 Feb;46(2):547-55. PMID 21183257
Chapter 111
L-759,633 L-759,633 is an analgesic drug that is a cannabinoid agonist. It is a fairly selective agonist for the CB2 receptor, with selectivity of 163x for CB2 over CB1 .[1] It produces some similar effects to other cannabinoid agonists such as analgesia, but with little or no sedative or psychoactive effects due to its weak CB1 activity, and a relatively strong antiinflammatory effect due to its strong activity at CB2 .[2][3]
111.1 See also • L-759,656 • L-768,242
111.2 References [1] Ross, RA, Brockie, HC, Stevenson, LA, Murphy, VL, Templeton, F, Makriyannis, A, Pertwee, RG (1999). “Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630”. British Journal of Pharmacology 126 (3): 665– 72. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID 10188977. [2] Huffman, JW (2000). “The search for selective ligands for the CB2 receptor”. Current pharmaceutical design 6 (13): 1323–37. doi:10.2174/1381612003399347. PMID 10903395. [3] Huffman, JW (2005). “CB2 receptor ligands”. Mini reviews in medicinal chemistry 5 (7): 641–9. doi:10.2174/1389557054368844. PMID 16026310.
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Chapter 112
L-759,656 L-759,656 is an analgesic drug that is a cannabinoid agonist. It is a highly selective agonist for the CB2 receptor, with selectivity of 414x for CB2 over CB1 ,[1] although it is still not as selective as newer agents such as HU-308. It produces some similar effects to other cannabinoid agonists such as analgesia, but with little or no sedative or psychoactive effects due to its weak CB1 activity, and a relatively strong antiinflammatory effect due to its strong activity at CB2 .[2][3]
112.1 See also • L-759,633 • L-768,242
112.2 References [1] Ross, R.; Brockie, H.; Stevenson, L.; Murphy, V.; Templeton, F.; Makriyannis, A.; Pertwee, R. (1999). “Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630”. British Journal of Pharmacology 126 (3): 665– 672. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID 10188977. [2] Huffman, J. W. (2000). “The search for selective ligands for the CB2 receptor”. Current pharmaceutical design 6 (13): 1323–1337. doi:10.2174/1381612003399347. PMID 10903395. [3] Huffman, J. W. (2005). “CB2 receptor ligands”. Mini reviews in medicinal chemistry 5 (7): 641–649. doi:10.2174/1389557054368844. PMID 16026310.
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Chapter 113
LASSBio-881 LASSBio-881 is a drug which acts as both a non-selective partial agonist of the CB1 and CB2 cannabinoid receptors, and also as an antagonist of the TRPV1 receptor, as well as having antioxidant effects. It has potent anti-inflammatory and anti-hyperalgesic effects in animal studies.[1][2][3]
113.1 References [1] Duarte CD, Tributino JL, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda AL, Barreiro EJ, Fraga CA. Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenylN-acylhydrazone derivatives: Discovery of LASSBio881, a new ligand of cannabinoid receptors. Bioorganic and Medicinal Chemistry. 2007 Mar 15;15(6):2421-33. PMID 17275312 [2] Tributino JL, Santos ML, Mesquita CM, Lima CK, Silva LL, Maia RC, Duarte CD, Barreiro EJ, Fraga CA, Castro NG, Miranda AL, Guimaraes MZ. LASSBio-881: an Nacylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation. British Journal of Pharmacology. 2010 Apr;159(8):171623. PMID 20401963 [3] Santana P et al. NEUROACTIVE PROPERTIES OF THE MULTIFUNCTIONAL PROTOTYPE LASSBio881: FOCUS ON THE CANNABINOID SYSTEM
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Chapter 114
LBP-1 (drug) LBP-1 is a drug originally developed by Organon for the treatment of neuropathic pain,[1][2] and subsequently further developed by Merck after they acquired Organon’s patents following their merger with Schering-Plough.[3][4][5] It acts as a potent and selective cannabinoid receptor agonist, with high potency at both the CB1 and CB2 receptors, but low penetration of the blood–brain barrier. This makes LBP-1 peripherally selective, and while it was effective in animal models of neuropathic pain and allodynia, it did not produce cannabinoid-appropriate responding suggestive of central effects, at any dose tested.[6]
114.1 See also • Org 28312 • Org 28611
114.2 References [1] Julia Adam. Indole Derivatives. Patent WO 2008/101995 [2] Paul David Ratcliffe, Julia Adam-Worrall, Angus John Morrison, Stuart John Francis, Takao Kiyoi. Indole Derivatives. Patent US 7763732 [3] Morrison AJ, Adam JM, Baker JA, Campbell RA, Clark JK, Cottney JE, Deehan M, Easson AM, Fields R, Francis S, Jeremiah F, Keddie N, Kiyoi T, McArthur DR, Meyer K, Ratcliffe PD, Schulz J, Wishart G, Yoshiizumi K. Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor. Bioorganic and Medicinal Chemistry Letters. 2011 Jan 1;21(1):506-9. PMID 21075630 [4] Kiyoi T, Adam JM, Clark JK, Davies K, Easson AM, Edwards D, Feilden H, Fields R, Francis S, Jeremiah F, McArthur D, Morrison AJ, Prosser A, Ratcliffe PD, Schulz J, Wishart G, Baker J, Campbell R, Cottney JE, Deehan M, Epemolu O, Evans L. Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists. Bioorganic and Medicinal Chemistry Letters. 2011 Mar 15;21(6):1748-53. PMID 21316962
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[5] Ratcliffe P, Adam JM, Baker J, Bursi R, Campbell R, Clark JK, Cottney JE, Deehan M, Easson AM, Ecker D, Edwards D, Epemolu O, Evans L, Fields R, Francis S, Harradine P, Jeremiah F, Kiyoi T, McArthur D, Morrison A, ier P, Pick J, Schnabel PG, Schulz J, Steinbrede H, Walker G, Westwood P, Wishart G, de Haes JU. Design, synthesis and structure-activity relationships of (indo-3yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate. Bioorganic and Medicinal Chemistry Letters. 2011 Apr 15;21(8):2541-6. PMID 21411321 [6] Adam JM, Clark JK, Davies K, Everett K, Fields R, Francis S, Jeremiah F, Kiyoi T, Maidment M, Morrison A, Ratcliffe P, Prosser A, Schulz J, Wishart G, Baker J, Boyce S, Campbell R, Cottney JE, Deehan M, Martin I. Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain. Bioorganic and Medicinal Chemistry Letters. 2012 Apr 15;22(8):2932-7. PMID 22421020
Chapter 115
Leelamine Leelamine is a diterpene amine that has weak affinity for the cannabinoid receptors CB1 and CB2 , as well as being an inhibitor of pyruvate dehydrogenase kinase.[1] Optically active leelamine is also used as a chiral resolving agent for carboxylic acids.[2][3]
115.1 See also • THC • Resin acid
115.2 References [1] “Leelamine - Dehydroabietylamine - Cayman Chemical”. Retrieved May 20, 2013. [2] US patent 3454626 [3] US patent 4559178
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Chapter 116
Levonantradol Levonantradol ( 50,556-1) is a synthetic cannabinoid analog of dronabinol (Marinol) developed by Pfizer in the 1980s. It is around 30x more potent than THC, and exhibits antiemetic and analgesic effects via activation of CB1 and CB2 cannabinoid receptors.[1] Levonantradol is not currently used in medicine as dronabinol or nabilone are felt to be more useful for most conditions, however it is widely used in research into the potential therapeutic applications of cannabinoids.[2][3][4]
drug must be dissolved in 5% ethanol, 5% emulphur, and 90% sterile saline. Synthetic cannabinoids like Levonantradol readily cross the blood-brain barrier because they are highly lipophilic and have low molecular weights. Levonantradol’s bioavailability is variable due to the first metabolism.
116.1 Pharmacodynamics
Levonantradol has been clinically tested in cancer patients for its pain relief and antiemetic benefits. Cancer patients that endure chemotherapy often develop intense nausea, and Levonantradol has been tested to reduce these emetic symptoms. It is often used instead of THC because it has a higher efficacy. Levonantradol also acts on pain pathways in the central nervous system, which enables the drug to alleviate pain. Studies have shown an absence of emetic side effects within the half-life of the Levonantradol istered. Other studies suggest that cannabinoid agonists can synergize opioid anti-nociception. Cannabinoid receptors are located in nociceptive pathways, and CBs can promote signal transduction in TRP channels. Although Levonantradol relieves nociceptive and postoperative pain, decreases nausea, and improves spasticity in addition to being more effective than placebos, it has yet to be approved as legal medicine. Researchers have concluded that Levonantradol is no more effective than Codeine, which is why they do not recommend expansion into clinical practice.
Levonantradol is a full CB1 receptor agonist. Cannabinoid receptors belong to the superfamily of G-protein coupled receptors (GPCRs), and endogenous cannabinoids naturally activate GPCRs. GPCRs modulate the inhibition of adenylyl cyclase and accumulation of the second messenger, cyclic adenosine monophosphate (cAMP). The CB1 receptor is the most common GPCR in the central nervous system. The activation of CB1 Rs decrease calcium conductance and increase potassium conductance in the brain. CB signaling naturally modulates synaptic transmission and mediates psychoactivity, and synthetic cannabinoids mimic these same actions. Although the efficacy of Levonantradol is dependent on the level of GR activity, Full agonists like Levonantradol have the ability to activate GPCRs and convert Gα into a high affinity state for GTP or low affinity state for GDP. Previous studies suggest that Levonantradol has a higher binding affinity and efficacy than other similar synthetic cannabinoids (e.g. Δ9 -THC).
116.3 Treatment
116.4 Side effects 116.2 Pharmacokinetics Although Levonantradol has been extensively tested on animals including cats, rodents, and non-human primates. It has also been tested among cancer patient populations in clinical trials. Levonantradol is most commonly istered intramuscularly (I.M.), however it can also be istered orally. The dosage can range from 0.25 mg3.0 mg every 2–4 hours, and the half-life is 1–2 hours. In order to ister Levonantradol intramuscularly, the
The side effects for Levonantradol include ptosis, sedation, and ataxia in non-human primates. In rodents, the symptoms include dysphoria, memory impairment, motor incoordination, reduced concentration, and disorientation. Levonantradol also decreases startle response. In humans, side effects include dry mouth, drowsiness, dizziness, altered perception, mild sedation, and lack of concentration. It can cause an increase in heart rate and decrease in blood pressure. Euphoric symptoms rarely occurred in subjects.
156
116.7. REFERENCES
116.5 See also • 47,497
116.6 Notes [1] Little PJ, et al. Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. Journal of Pharmacology and Experimental Therapeutics 1988; 247:1046–1051. [2] Tramer MR, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. British Medical Journal 2001 Jul 7;323(7303):16-21. [3] Campbell FA, et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. British Medical Journal. 2001 Jul 7;323(7303):13-6. [4] Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. Journal of Ethnopharmacology. 2006 Apr 21;105(1-2):1-25.
116.7 References • Childers, SR (Mar 10, 2006). “Activation of Gproteins in brain by endogenous and exogenous cannabinoids.”. The AAPS journal 8 (1): E112–7. doi:10.1208/aapsj080113. PMC 2751429. PMID 16584117. • Hosking, R.D.; Zajicek, J.P. (2008). “Therapeutic potential of cannabis in pain medicine”. British Journal of Anaesthesia 101 (1): 59–68. doi:10.1093/bja/aen119. • McCarthy, LE; Borison, HL (Aug–Sep 1981). “Antiemetic activity of N-methyllevonantradol and nabilone in cisplatin-treated cats.”. Journal of clinical pharmacology 21 (8–9 Suppl): 30S–37S. doi:10.1002/j.1552-4604.1981.tb02570.x. PMID 6271834. • Milewich, L; Gant, NF; Schwarz, BE; Chen, GT; MacDonald, PC (Mar 15, 1979). “5 alphaReductase activity in human placenta.”. American journal of obstetrics and gynecology 133 (6): 611– 7. PMID 34324.
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Chapter 117
List of AM cannabinoids Alexandros Makriyannis is a professor in the Department of Medicinal Chemistry at Northeastern University, where his research group has synthesized many new compounds with cannabinoid activity. Some of those are: • AM-087 — an analgesic CB1 agonist derived from Δ8 THC substituted with a side chain on the 3position, it has a Kᵢ of 0.43nM making it roughly 100x as potent as THC. • AM-251 — an inverse agonist at the CB1 cannabinoid receptor that is structurally related to SR141716A (rimonabant), but has a higher binding affinity with a Kᵢ value of 7.5nM.[1] • AM-281 — N-(morpholin-4-yl)−1-(2,4dichlorophenyl)−5-(4-iodophenyl)−4-methyl1H-pyrazole-3-carboxamide[1] • AM-356 — a synthetically created stable chiral analog of anandamide, it acts on the cannabinoid receptors with a Kᵢ of 17.9nM at CB1 and 868nM at CB2 .[2] • AM-374 — palmitylsulfonyl fluoride[3] • AM-381 — stearylsulfonyl fluoride • AM-404 — an active metabolite of paracetamol (acetaminophen) and a likely inhibitor of fatty acid amide hydrolase (FAAH) • AM-411 — an adamantyl-substituted derivative of Δ8 THC, it is a potent and fairly selective CB1 full agonist with a Kᵢ of 6.80nM. It is also a moderately potent CB2 agonist with a Kᵢ of 52.0nM. • AM-630 — a potent and selective inverse agonist for the cannabinoid receptor CB2 , with a Kᵢ of 32.1nM at CB2 and 165x selectivity over CB1 , at which it acts as a weak partial agonist. • AM-661 — 1-(N-methyl-2-piperidine)methyl-2methyl-3-(2-iodo)benzoylindole[4] • AM-678 — another name for JWH-018, it is a full agonist at both cannabinoid receptors with some selectivity for CB2 . 158
• AM-679 — an iodobenzoylindole which acts as a moderately potent agonist for the cannabinoid receptors, with a Kᵢ of 13.5nM at CB1 and 49.5nM at CB2 . • AM-694 — an iodobenzoylindole which acts as a potent and selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 0.08nM at CB1 and 18x selectivity over the related CB2 receptor (1.44nM).[5] • AM-735 — 3-bornyl-Δ8-THC, a mixed CB1 / CB2 agonist with Kᵢ of 8.9nM at CB1 and 7.4nM at CB2 .[6] • AM-855 — an analgesic derivative of Δ8 tetrahydrocannabinol, it is an agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 22.3nM at CB1 and 58.6nM at CB2 . • AM-881 — a chlorine-substituted stereoisomer of anandamide whose Kᵢ = 5.3nM at CB1 and 95nM at CB2 .[2] • AM-883 — an allyl-substituted stereoisomer of anandamide whose Kᵢ = 9.9nM at CB1 and 226nM at CB2 .[2] • AM-905 — a potent and reasonably selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 1.2nM at CB1 and 5.3nM at CB2 . • AM-906 — a potent and dodecally selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 0.8nM at CB1 and 9.5nM at CB2 . • AM-919 — a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 2.2nM at CB1 and 3.4nM at CB2 . It is a derivative of HU-210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-926 — a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 2.2nM at CB1 and 4.3nM at CB2 . It is a derivative of HU-210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-938 — a potent agonist at both CB1 and CB2 with quadruple selectivity for CB2 , with a Kᵢ of
117.1. SEE ALSO 1.2nM at CB1 and 0.3nM at CB2 . It is a derivative of HU-210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-1116 — a dimethylated stereoisomer of anandamide whose Kᵢ = 7.4nM at CB1 .[2] • AM-1172 — an endocannabinoid analog specifically designed to be a potent and selective inhibitor of AEA uptake that is resistant to FAAH hydrolysis. • AM-1220 — a potent and selective analgesic CB1 agonist (as racemate) with a Kᵢ of 3.88nM at CB1 and 73.4nM at CB2 , giving it 19x selectivity for CB1 . (R) enantiomer has around 1000x higher affinity for CB1 than (S) enantiomer.[7][8] • AM-1221 — a potent and selective CB2 agonist with a Kᵢ of 0.28nM at CB2 and 52.3nM at CB1 , giving it a selectivity of almost 187x. • AM-1235 — a moderately CB1 selective agonist, with a Kᵢ of 1.5nM at CB1 and 20.4nM at CB2 , giving it a selectivity of around 13x.[9] • AM-1241 — a potent and selective analgesic CB2 agonist with a Kᵢ of 3.4nM at CB2 and 80x selectivity over CB1 .[10] • AM-1248 — a moderately potent agonist with some selectivity for CB1 , containing an unusual 3(adamant-1-oyl) substitution on the indole ring.
159 • AM-3102 — an analog of oleoylethanolamide, the endogenous agonist for proliferator-activated receptor α (PPARα). It also acts as a weak cannabinoid agonist with Kᵢ values of 33µM at CB1 and 26µM at CB2 . • AM-4030 — a potent agonist at both CB1 and CB2 , it is dodecally selective for CB1 , with a Kᵢ of 0.7nM at CB1 and 8.6nM at CB2 . It is a derivative of HU210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-4054 — a potent but slow-onset agonist with CB1 affinity of 2.2nM and a 40x selectivity for CB1 over CB2 .[18][19] • AM-4113 — a CB1 selective neutral antagonist.[20] • AM-6545 — a peripherally selective silent antagonist of CB1 receptors.
117.1 See also • List of JWH cannabinoids • List of HU cannabinoids • List of cannabinoids
117.2 Further reading
• AM-1710 — a CB2 selective cannabilactone with A more complete list can be found here 54x selectivity over CB1 .[11] • AM-1714 — a CB2 selective cannabilactone with 490x selectivity over CB1 .[11] • AM-2201 — a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 1.0nM at CB1 and 2.6nM at CB2 . • AM-2212 — a potent agonist at both CB1 and CB2 with dodecal selectivity for CB1 , with a Kᵢ of 1.4nM at CB1 and 18.9nM at CB2 .[4] • AM-2213 — a potent agonist at both CB1 and CB2 with 10x selectivity for CB1 , with a Kᵢ of 3.0M at CB1 and 30nM at CB2 .[4] • AM-2232 — a potent agonist at both CB1 and CB2 , with a Kᵢ of 0.28nM at CB1 and 1.48nM at CB2 .[9]
117.3 References [1] Lan, Ruoxi; Lu, Qian; Fan, Pusheng; Gatley, John; Volkow, Nora D.; Fernando, Susanthi R.; Pertwee, Roger; Makriyannis, Alexandros (1999). “Design and synthesis of the CB1 selective cannabinoid antagonist AM281: A potential human SPECT ligand”. AAPS PharmSci 1 (2): 39–45. doi:10.1208/ps010204. [2] Selwood, D. (2009). “The Cannabinoid Receptors. Edited by Patricia H. Reggio”. ChemMedChem 4: 1949. doi:10.1002/cmdc.200900286. [3] Pacher, P.; Bátkai, S; Kunos, G (2006). “The Endocannabinoid System as an Emerging Target of Pharmacotherapy”. Pharmacological Reviews 58 (3): 389– 462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
• AM-2233 — (R) enantiomer is potent and selective CB1 agonist used in 131 I radiolabelled form to map distribution of CB1 receptors in brain.[12][13][14][15][16][17]
[4] Hongfeng Deng. Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs. PhD Dissertation, University of Connecticut, 2000.
• AM-2389 — classical cannabinoid derivative with 26x selectivity for CB1 .
[5] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607
160
[6] Lu D, Guo J, Duclos RI Jr, Bowman AL, Makriyannis A. Bornyl- and isobornyl-Delta8-tetrahydrocannabinols: a novel class of cannabinergic ligands. Journal of Medicinal Chemistry. 2008 Oct 23;51(20):6393-9. PMID 18826296 [7] D'ambra, T. (1996). “C-Attached aminoalkylindoles: potent cannabinoid mimetics”. Bioorganic & Medicinal Chemistry Letters 6: 17–14. doi:10.1016/0960894X(95)00560-G. [8] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D. B.; Mukhin, A. G.; Horti, A. G. (2005). “Synthesis and Structure−Activity Relationship of a Novel Series of Aminoalkylindoles with Potential for Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography”. Journal of Medicinal Chemistry 48 (18): 5813. doi:10.1021/jm0502743. PMID 16134948. [9] US patent 7241799, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200707-10 [10] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473. [11] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur GA, Malan TP Jr, Porreca F, Veerappan V, Tian X, George C, Parrish DA, Papahatjis DP, Makriyannis A. Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. Journal of Medicinal Chemistry. 2007 Dec 27;50(26):6493-500. PMID 18038967 [12] Deng H, Gifford AN, Zvonok AM, Cui G, Li X, Fan P, Deschamps JR, Flippen-Anderson JL, Gatley SJ, Makriyannis A (October 2005). “Potent cannabinergic indole analogues as radioiodinatable brain imaging agents for the CB1 cannabinoid receptor”. Journal of Medicinal Chemistry 48 (20): 6386–92. doi:10.1021/jm050135l. PMID 16190764. [13] Hanuš, L. R. O.; Mechoulam, R. (2005). “Cannabinoid chemistry: an overview”. “Cannabinoids as Therapeutics”. Milestones in Drug Therapy MDT. p. 23. doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6. [14] Shen , Xiao JC, Armstrong H, Hagmann W, Fong TM (February 2006). “F200A substitution in the third transmembrane helix of human cannabinoid CB1 receptor converts AM2233 from receptor agonist to inverse agonist”. European Journal of Pharmacology 531 (1–3): 41– 6. doi:10.1016/j.ejphar.2005.12.026. PMID 16438957. [15] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.; Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gifford, A. N. (2006). “Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233”. Synapse 60 (2): 93–101. doi:10.1002/syn.20277. PMID 16715483.
CHAPTER 117. LIST OF AM CANNABINOIDS
[16] Leung K (Dec 12, 2006). “R-2-[131I]Iodophenyl(1-(1-methylpiperidin-2-ylmethyl)−1H-indol-3yl)methanone”. Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. PMID 20641836. [17] Pei, Y., et al. (2008). “Ligand-Binding Architecture of Human CB2 Cannabinoid Receptor: Evidence for Receptor Subtype-Specific Binding Motif and Modeling GPCR Activation”. Chemistry & Biology 15: 1207. doi:10.1016/j.chembiol.2008.10.011. [18] [Paronis CA, Thakur GA, Vemuri K, Makriyannis A, Bergman J. Effects of a Selective Cannabinoid Agonist and Antagonist on Body Temperature in Rats. The FASEB Journal. April 2007 21 (Meeting Abstract Supplement) A409. http://www.fasebj.org/cgi/content/ meeting_abstract/21/5/A409] [19] Paronis, C. A.; Thakur, G. A.; Bajaj, S.; Nikas, S. P.; Vemuri, V. K.; Makriyannis, A.; Bergman, J. (2012). “Diuretic effects of cannabinoids”. Journal of Pharmacology and Experimental Therapeutics 344 (1): 8–14. doi:10.1124/jpet.112.199331. PMID 23019138. [20] Seely KA, Prather PL, James LP, Moran JH. Marijuanabased drugs: innovative therapeutics or designer drugs of abuse? Molecular Interventions. 2011 Feb;11(1):36-51. PMID 21441120
Chapter 118
List of JWH cannabinoids The John W. Huffman research group at Clemson University synthesized over 450 cannabinoids. Some of those are:
• JWH-057 — a 1-deoxy analog of Δ8-THC that has very high affinity for the CB2 receptor, but also has high affinity for the CB1 receptor.[2]
• JWH-007 — an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 receptor and CB2 receptors, with some selectivity for CB2 with a Kᵢ of 2.9nM ± 2.6 and 9.5nM ± 4.5 at CB1 .[1]
• JWH-073 — an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB1 subtype with a Kᵢ of 8.9nM. It is found in some forms of synthetic cannabis.
• JWH-015 — a chemical from the naphthoylindole family, which acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8nM, while its affinity for CB1 is 383nM, meaning that it binds almost 28x more strongly to CB2 than CB1 .[1] • JWH-018 — an analgesic chemical from the naphthoylindole family, which acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2 with a Kᵢ of 2.9nM ± 2.6 and 9nM ± 5 at CB1 .[1] It is found in some forms of synthetic cannabis. • JWH-019 — an agonist at both CB1 and CB2 receptors, it has 1.77x selectivity for CB2 with a Kᵢ of 5.55nM ± 2 and 9.8nM ± 2 at CB1 . • JWH-030 — an analgesic chemical from the naphthoylpyrrole family, it is a partial agonist at CB1 receptors, with a Kᵢ of 87nM, making it roughly half the potency of THC. • JWH-047 — a potent and selective agonist for the CB2 receptor with a Kᵢ of 0.9 nM, and a Kᵢ of 59 ± 3 nM at CB1 , it has a 65x selectivity for CB2 .[1] • JWH-048 — a potent and selective agonist for the CB2 receptor with a Kᵢ of 0.49 nM ± 0.1, and a Kᵢ of 10.7 nM ± 1.0 at CB1 , it has a 22x selectivity for CB2 .[1] • JWH-051 — an analgesic, it has high affinity for the CB1 receptor, but is a much stronger agonist for CB2 , with a Kᵢ value of 0.03nM at CB2 vs 1.20nM at CB1 . It was one of the first CB2 -selective ligands developed, although its selectivity for CB2 is modest compared to newer compounds such as HU-308. 161
• JWH-081 — an analgesic chemical from the naphthoylindole family, which acts as an agonist at both the cannabinoid receptors with a Kᵢ of 1.2nM ± 0.03 at CB1 [3] and 12.4nM ± 2.2 at the CB2 receptors. It is fairly selective for the CB1 subtype with approximately 10x the affinity for CB2 . It is found in some forms of synthetic cannabis. • JWH-098 — a potent and fairly selective CB2 agonist with a Kᵢ of 1.9nM ± 0.3 at CB2 and 4.5nM ± 0.1 at CB1 ,[3] giving it about 2.4x selectivity for CB2 . • JWH-116 — a CB1 ligand with a Kᵢ of 52 ± 5 nM[3] • JWH-120 — a potent and 173-fold selective CB2 agonist with a Kᵢ of 6.1nM ± 0.7, it is the N-propyl homolog of JWH-122.[2] • JWH-122 — a potent and fairly selective CB1 agonist with a Kᵢ of 0.69nM ± 0.5 at CB1 and 1.2nM ± 1.2 at CB2 . It is found in some forms of synthetic cannabis. • JWH-133 — a potent and highly selective CB2 receptor agonist with a Kᵢ of 3.4nM and selectivity of around 200x for CB2 over CB1 receptors.[1] • JWH-139 — 3-(1,1-dimethylpropyl)−6,6,9trimethyl-6a,7,10,10a-tetrahydro-6Hbenzo[c]chromene[4] • JWH-147 — an analgesic drug from the naphthoylpyrrole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Kᵢ of 11.0nM at CB1 vs 7.1nM at CB2 .
162 • JWH-148 — a moderately selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 14.0 ± 1.0 nM at this subtype, and more than 8 times selectivity over the CB1 subtype.[5] • JWH-149 — a potent and fairly selective CB2 agonist with a Kᵢ of 0.73nM ± 0.03 and 5.0nM ± 2.1 at CB1 ,[3] giving it about 6.8x selectivity for CB2 . • JWH-161 — a CB1 ligand with Kᵢ of 19.0nM • JWH-164 — a potent cannabinoid agonist with a Kᵢ of 6.6nM ± 0.7 at CB1 and 6.9nM ± 0.2 at CB2 . • JWH-166 — a potent and highly selective CB2 agonist with a Kᵢ of 1.9nM ± 0.08 at CB2 and 44nM ± 10 at CB1 giving it 23x selectivity for CB2 .[1] • JWH-167 — a weak cannabinoid agonist from the phenylacetylindole family with 1.77x selectivity for CB1 with a Kᵢ of 90nM ± 17 at CB1 and 159nM ± 14 at CB2 .[6] • JWH-171 — an analgesic drug which acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is only 51nM, making it slightly less potent than THC itself. • JWH-175 — (1-pentylindol-3-yl)naphthalen-1ylmethane, 22nM at CB1 [3] • JWH-176 — 1-([(1E)−3-pentylinden-1ylidine]methyl)naphthalene, 26nM at CB1 [3] • JWH-181 — a potent cannabinoid agonist with 2.1x selectivity for CB2 with a Kᵢ of 0.62nM ± 0.04 and 1.3nM ± 0.1 at CB1 . • JWH-182 — a potent cannabinoid agonist with some selectivity for CB1 with a Kᵢ of 0.65nM ± 0.03 and 1.1nM ± 0.1 at CB2 . • JWH-184 — 1-pentyl-1H-indol-3-yl-(4-methyl-1naphthyl)methane, 23nM at CB1 [3] • JWH-185 — 1-pentyl-1H-indol-3-yl-(4-methoxy1-naphthyl)methane, 17nM at CB1 [3] • JWH-192 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methylnaphthalen-1-ylmethane, 41nM at CB1 [3] • JWH-193 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methylnaphthalen-1-ylmethanone, 6nM at CB1 [3] • JWH-194 — 2-methyl-1-pentyl-1H-indol-3-yl-(4methyl-1-naphthyl)methane, 127nM at CB1 [3] • JWH-195 — (1-(2-morpholin-4-ylethyl)indol-3yl)-naphthalen-1-ylmethane, 113nM at CB1 [3] • JWH-196 — 2-methyl-3-(1naphthalenylmethyl)−1-pentyl-1H-Indole, 151nM ± 18 at CB1
CHAPTER 118. LIST OF JWH CANNABINOIDS • JWH-197 — 2-methyl-1-pentyl-1H-indol-3-yl-(4methoxy-1-naphthyl)methane, 323nM at CB1 [3] • JWH-198 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methoxynaphthalen-1-ylmethanone, 10nM at CB1 [3] • JWH-199 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methoxynaphthalen-1-ylmethane, 20nM at CB1 [3] • JWH-200 — an analgesic chemical from the aminoalkylindole family, which acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is 42nM, around the same as that of THC, but interestingly, its analgesic potency in vivo was higher than that of other analogues with stronger CB1 binding affinity in vitro, around 3 times that of THC but with less sedative effect, most likely reflecting favorable pharmacokinetic characteristics. It is found in some forms of synthetic cannabis. • JWH-203 — an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist with approximately equal affinity at both the CB1 and CB2 receptors, having a Kᵢ of 8.0nM at CB1 and 7.0nM at CB2 . Similar to the related 2'-methoxy compound JWH-250, JWH203 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds, and is the most potent compound found in the phenylacetyl group.[6] It is found in some forms of synthetic cannabis. • JWH-205 — 1-(2-methyl-1-pentylindol-3-yl)−2phenylethanone, CB1 : 124nM ± 23 CB2 : 180nM ± 9 CB2 selectivity: 1.45x[6] • JWH-210 — an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both the CB1 and CB2 receptors, with Kᵢ values of 0.46nM at CB1 and 0.69nM at CB2 . It is one of the most potent 4-substituted naphthoyl derivatives in the naphthoylindole series, having a higher binding affinity (i.e. lower Kᵢ) at CB1 than both its 4-methyl and 4-n-propyl homologues (JWH-122 and JWH-182 respectively), and than the 4-methoxy compound JWH-081.[1] It is found in some forms of synthetic cannabis. • JWH-213 — a potent and fairly selective CB2 agonist with a Kᵢ of 0.42nM ± 0.05 at CB2 and 1.5nM ± 0.2 at CB1 giving it 3.6x selectivity over CB1 .[1] • JWH-220 — 19nM at CB1 • JWH-229 — 1-methoxy-3-(1',1'-dimethylhexyl)Δ8 -THC, a dibenzopyran “classical” cannabinoid drug with a Kᵢ of 4.6nM ± 2.0, it is a potent CB2 agonist.
118.1. SEE ALSO • JWH-234 — a cannabinoid agonist that has 2.2x selectivity for CB2 with a Kᵢ value of 8.4nM ± 1.8 at CB2 and 3.8nM ± 0.6 at CB1 . • JWH-249 — CB1 : 8.4nM ± 1.8 CB2 : 20nM ± 2 selectivity for CB1 : 2.38x[6] • JWH-250 — an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors, with a Kᵢ of 11nM at CB1 and 33nM at CB2 .[6] It is found in some forms of synthetic cannabis. • JWH-251 — (1-pentyl-3-(229nM ± 3 methylphenylacetyl)indole) CB1 : CB2 : 146nM ± 36 selectivity for CB1 : 5x[6] • JWH-253 — • JWH-258 — a potent and mildly selective CB1 agonist with a Kᵢ of 4.6nM ± 0.6 and 10.5nM ± 1.3 at CB2 .[1] • JWH-300 — CB1 : 116nM CB2 : 5.3nM[2] • JWH-302 — (1-pentyl-3-(3methoxyphenylacetyl)indole) CB1 : 17nM ± 2 CB2 : 89nM ± 15 selectivity for CB1 : 5.26x[6] • JWH-307 — an analgesic drug from the naphthoylpyrrole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Kᵢ of 7.7nM at CB1 vs 3.3nM at CB2 . • JWH-336 — CB1 : ~1.2nM CB2 : 36nM[2]
163
118.1 See also • List of AM cannabinoids • List of HU cannabinoids • List of cannabinoids • List of miscellaneous designer cannabinoids
118.2 References [1] Huffman, JW, Zengin, G, Wu, MJ, Lu, J, Hynd, G, Bushell, K, Tartal, C, Hurst, DP, Reggio, PH, Selley, DE, Cassidy, MP, Wiley, JL, Martin, BR (2005). “Structureactivity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists”. Bioorganic & Medicinal Chemistry Letters 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455. [2] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473. [3] Huffman, JW, Mabon, R, Wu, MJ, Lu, J, Hart, R, Hurst, DP, Reggio, PH, Wiley, JL, Martin, BR (2003). “3Indolyl-1-naphthylmethanes: New Cannabimimetic Indoles Provide Evidence for Aromatic Stacking Interactions with the CB1 Cannabinoid Receptor”. Bioorganic & Medicinal Chemistry Letters 11 (4): 539–549. doi:10.1016/S0968-0896(02)00451-0. PMID 12538019.
• JWH-350 — a 11-nor-1-methoxy-3-(1',1'dimethylheptyl)−9α-hydroxyhexahydrocannabinol with 33-fold selectivity for the CB2 receptor and high CB2 receptor affinity (Kᵢ=12nM ± 1) has the desirable combination of excellent CB2 affinity combined with little affinity for the CB1 receptor.[2]
[4] Howlett, A. C.; Barth, F; Bonner, TI; Cabral, G; Casellas, P; Devane, WA; Felder, CC; Herkenham, M; MacKie, K (2002). “International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors”. Pharmacological Reviews 54 (2): 161–202. doi:10.1124/pr.54.2.161. PMID 12037135.
• JWH-359 — a dibenzopyran “classical” cannabinoid drug with a Kᵢ of 13.0nM and selectivity of around 220x for CB2 , it is a potent and selective CB2 receptor agonist.
[5] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
• JWH-387 — 1-pentyl-3-(4-bromo-1naphthoyl)indole, an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both receptors with a Kᵢ of 1.2nM at CB1 and 1.1nM at CB2 . • JWH-398 — an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both receptors with a Kᵢ of 2.3nM at CB1 and 2.8nM at CB2 .[7] • JWH-424 — a potent and moderately selective CB2 agonist with a Kᵢ of 5.44nM at CB2 and 20.9nM at CB1 .
[6] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [7] “The Cannabinoid Receptors”. doi:10.1007/978-159745-503-9. Retrieved 28 August 2013.
Chapter 119
LY-2183240 LY-2183240 is a drug which acts both as a potent inhibitor of the reuptake of the endocannabinoid anandamide and as an inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading anandamide. This leads to markedly elevated anandamide levels in the brain, and LY-2183240 has been shown to produce both analgesic and anxiolytic effects in animal models.[1][2][3][4]
Simmons RM, Li D, Iyengar S, Felder CC. Identification of a high-affinity binding site involved in the transport of endocannabinoids. 2005 Dec; 102(49):17852-7. PMID 16314570
2.Jump up ^ Dickason-Chesterfield AK, Kidd SR, Moore SA, Schaus JM, Liu B, Nomikos GG, Felder CC. Pharmacological characterization of endocannabinoid transport and fatty acid amide hydrolase inhibitors. Cellular and Molecular Neurobiology. 2006 Jul-Aug;26(46):407-23. PMID 16736384 3.Jump up ^ Alexander 119.1 See also JP, Cravatt BF. The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and • PF-04457845 several other brain serine hydrolases. Journal of the American Chemical Society. 2006 Aug 2;128(30):9699• URB-597 704. PMID 16866524 4.Jump up ^ Maione S, Morera E, Marabese I, Ligresti A, Luongo L, Ortar G, Di Marzo V. Antinociceptive effects of tetrazole inhibitors 119.2 References of endocannabinoid inactivation: cannabinoid and noncannabinoid receptor-mediated mechanisms. British [1] Dickason-Chesterfield AK, Kidd SR, Moore SA, Schaus Journal of Pharmacology. 2008 Nov;155(5):775-82. JM, Liu B, Nomikos GG, Felder CC. Pharmacological PMID 18660824 5.Jump up ^ Powers MS, Barrenha GD, characterization of endocannabinoid transport and fatty Mlinac NS, Barker EL, Chester JA. Effects of the novel acid amide hydrolase inhibitors. Cellular and Molecu- endocannabinoid uptake inhibitor, LY2183240, on fearlar Neurobiology. 2006 Jul-Aug;26(4-6):407-23. PMID potentiated startle and alcohol-seeking behaviors in mice 16736384 selectively bred for high alcohol preference. Psychophar[2] Alexander JP, Cravatt BF. The putative endocannabi- macology (Berlin). 2010 Dec;212(4):571-83. PMID noid transport blocker LY2183240 is a potent inhibitor 20838777 of FAAH and several other brain serine hydrolases. Journal of the American Chemical Society. 2006 Aug 2;128(30):9699-704. PMID 16866524 [3] Maione S, Morera E, Marabese I, Ligresti A, Luongo L, Ortar G, Di Marzo V. Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: cannabinoid and non-cannabinoid receptormediated mechanisms. British Journal of Pharmacology. 2008 Nov;155(5):775-82. PMID 18660824 [4] Powers MS, Barrenha GD, Mlinac NS, Barker EL, Chester JA. Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference. Psychopharmacology (Berlin). 2010 Dec;212(4):571-83. PMID 20838777
1. Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L, 164
Chapter 120
LY-320,135 LY-320,135 is a drug used in scientific research which acts as a selective antagonist of the cannabinoid receptor CB1 . It was developed by Eli Lilly and Company in the 1990s. LY-320,135 displays fairly good selectivity, with a binding affinity for CB1 around 70x stronger than for CB2 ,[1] but both its potency and selectivity are modest compared to newer agents, and at higher doses it also binds to a range of non-cannabinoid receptors. However LY-320,135 is still fairly widely used in research, particularly for elucidating the mechanisms by which many CB1 antagonists act as inverse agonists at higher doses.[2]
120.1 References [1] Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ, Cullinan GJ, Hunden DC, Johnson DW, Chaney MO, Koppel GA, Brownstein M. LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. Journal of Pharmacology and Experimental Therapeutics. 1998 Jan;284(1):291-7. PMID 9435190 [2] Pertwee RG. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sciences. 2005 Feb 4;76(12):1307-24. PMID 15670612
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Chapter 121
MAM-2201 MAM-2201 (4'-methyl-AM-2201, 5"-fluoro-JWH122) is a drug that presumably acts as a potent agonist for the cannabinoid receptors. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in the Netherlands and in June 2011 as an ingredient in synthetic cannabis smoking blends.[1][2][3] Like RCS-4 and AB001, MAM-2201 thus appears to be a novel compound invented by "research chemical" suppliers specifically for grey-market recreational use. Structurally, MAM-2201 is a hybrid of two known cannabinoid compounds JWH122 and AM-2201, both of which had previously been used as active ingredients in synthetic cannabis blends before being banned in many countries. MAM-2201 has been banned by being added to the temporary class drug schedule in New Zealand, effective from 13 July 2012.[4]
121.2 References
[2] Moosmann, B., et al. (2012). “Separation and structural characterization of the synthetic cannabinoids JWH-412 and 1-(5-fluoropentyl)−1H-indol-3yl]-(4methylnaphthalen-1-yl)methanone using GC–MS, NMR analysis and a flash chromatography system”. Forensic Science International 220 (1–3): e17–e22. doi:10.1016/j.forsciint.2011.12.010. PMID 22264627. [3] Simolka, K., et al. (2012). “Analysis of synthetic cannabinoids in “spice-like” herbal highs: Snapshot of the German market in summer 2011”. Analytical and Bioanalytical Chemistry 404 (1): 157–171. doi:10.1007/s00216012-6122-4. PMID 22710567. [4] Temporary Class Drug Notice, 5 July 2012. NZ Department of Internal Affairs.
121.1 Pharmacology Nothing has been published on the pharmacology of MAM-2201, though it presumably has similar properties to the closely related AM-2201 and JWH-122, which are both full agonists and unselectively bind to CB1 and CB2 cannabinoid receptors with low nanomolar affinity.
121.1.1
[1] EMCDDA–Europol 2011 Annual Report on the implementation of Council Decision 2005/387/JHA
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 is generally applicable to MAM-2201. The pharmacokinetics of MAM-2201 has not been studied, but its metabolism likely differs only slightly from that of JWH-018, with the main metabolic pathway being hydroxylation at various positions, followed by glucuronidation of the hydroxylated metabolites. Ndealkylation is also likely to occur, producing fluoroalkyl metabolites and ultimately 3-fluoropropanoic acid, though the odd-numbered alkyl chain of MAM2201 would not be expected to produce fluoroacetate as a metabolite. Also metabolism of the related compound AM-694 has shown hydrolytic defluorination of the alkyl chain, meaning any fluoroalkyl metabolites formed are likely to be further metabolised themselves.[5] 166
[5] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012). “The detection of the urinary metabolites of 1-(5fluoropentyl)−1H-indol-3-yl]-(2-iodophenyl)methanone (AM-694), a high affinity cannabimimetic, by gas chromatography - mass spectrometry”. Drug Testing and Analysis 5 (2): 110–5. doi:10.1002/dta.1336. PMID 22522907.
Chapter 122
MDA-19 MDA-19 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2 , with reasonable selectivity over the psychoactive CB1 receptor, though with some variation between species. In animal studies it was effective for the treatment of neuropathic pain, but failed to produce cannabis-like behavioural effects.[1][2]
122.1 See also • AM-1221 • JTE 7-31 • JWH-019 • JWH-133 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
122.2 References [1] Diaz P, et al. Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of neuropathic pain. Journal of Medicinal Chemistry. 2008 Aug 28;51(16):4932-47. PMID 18666769 [2] Xu JJ, et al. Pharmacological characterization of a novel cannabinoid ligand, MDA19, for treatment of neuropathic pain. Anesthesia and Analgesia. 2010 Jul;111(1):99-109. PMID 20522703
167
Chapter 123
Menabitan Menabitan (INN; SP-204), or menabitan hydrochloride (USAN), is a synthetic drug which acts as a potent cannabinoid receptor agonist.[1][2] It is closely related to natural cannabinoids of the tetrahydrocannabinol (THC) group, differing mainly by its longer and branched side chain, and the replacement of the 9-position carbon with a nitrogen.[1] It was studied as an analgesic in the 1970s and was found to possess antinociceptive effects in both humans and animals but was never marketed.[1][3][4]
123.1 See also • A-40174 (SP-1) • Dimethylheptylpyran
123.2 References [1] Green K, Kim K (February 1977). “Acute dose response of intraocular pressure to topical and oral cannabinoids”. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 154 (2): 228–31. doi:10.3181/00379727-154-39643. PMID 402656. [2] David J. Triggle (1996). Dictionary of Pharmacological Agents. Boca Raton: Chapman & Hall/CRC. p. 1271. ISBN 978-0-412-46630-4. [3] Reggio PH (1987). “Molecular determinants for cannabinoid activity: refinement of a molecular reactivity template”. NIDA Research Monograph 79: 82–95. PMID 2830539. [4] Gabriel G. Nahas (5 April 1999). Marihuana and Medicine. Humana Press. p. 46. ISBN 978-0-89603593-5. Retrieved 9 May 2012.
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Chapter 124
Methanandamide Methanandamide (AM-356) is a synthetically created stable chiral analog of anandamide.[1] Its effects have been observed to act on the cannabinoid receptors (specifically on CB1 receptors, which are part of the central nervous system) found in different organisms such as mammals, fish, and certain invertebrates (e.g. Hydra).
124.1 References [1] Abadji, V, et al. (1994). "(R)-methanandamide: A chiral novel anandamide possessing higher potency and metabolic stability”. Journal of Medical Chemistry 37 (12): 1889–93. doi:10.1021/jm00038a020. PMID 8021930.
169
Chapter 125
MK-9470 MK-9470 is a synthetic compound, which binds to the CB1 cannabinoid receptor and functions as an inverse agonist.[1]
125.1 References [1] Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ (2007). "[18 F]MK9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid1 receptor”. Proc. Natl. Acad. Sci. U.S.A. 104 (23): 9800–5. Bibcode:2007PNAS..104.9800B. doi:10.1073/pnas.0703472104. PMC 1877985. PMID 17535893.
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Chapter 126
N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide 7-methoxy-1-(2-morpholinoethyl)-N-((1S,4R)−1,3,3trimethylbicyclo[2.2.1]heptan-2-yl)−1H-indole-3carboxamide (N-[(S)-fenchyl]−1-[2-(morpholin-4yl)ethyl]−7-methoxyindole-3-carboxamide, UR-12, MN-25) is a drug invented by Bristol-Myers Squibb,[1] that acts as a reasonably selective agonist of peripheral cannabinoid receptors.[2] It has moderate affinity for CB2 receptors with a Kᵢ of 11nM, but 22x lower affinity for the psychoactive CB1 receptors with a Kᵢ of 245nM. The indole 2-methyl derivative has the ratio of affinities reversed however, with a Kᵢ of 8nM at CB1 and 29nM at CB2 ,[3][4] which contrasts with the usual trend of 2-methyl derivatives having increased selectivity for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).[5][6] Chemically, it is closely related to another indole-3carboxamide synthetic cannabinoid, Org 28611, but with a different cycloalkyl substitution on the carboxamide, and the cyclohexylmethyl group replaced by morpholinylethyl, as in JWH-200 or A-796,260. Early compounds such as these have subsequently led to the development of a large number of related indole-3carboxamide cannabinoid ligands.[7][8][9][10]
126.1 See also • A-834,735 • AB-001 • AM-1221
2-methyl derivative
126.2 References
• JTE 7-31
[1] CANNABINOID RECEPTOR MODULATORS, THEIR PROCESSES OF PREPARATION, AND USE OF CANNABINOID RECEPTOR MODULATORS IN TREATING RESPIRATORY AND NON-RESPIRATORY DISEASES. WO 2001/58869
• JWH-203 • MDA-19 • SR-144,528
[2] Rulin Zhao, et al. Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)−1Hindole-3-carboxylic acid, key intermediate in the synthesis
• UR-144 171
172
CHAPTER 126. N-(S)-FENCHYL-1-(2-MORPHOLINOETHYL)−7-METHOXYINDOLE-3-CARBOXAMIDE
3. Chin CL, et al. (January 2008). “Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI”. British Journal of [3] Hynes, J., et al. (2002). “C-3 Amido-Indole cannabinoid Pharmacology 153 (2): 367–79. doi :10.1038/ sj.bjp receptor modulators”. Bioorganic & Medicinal Chemistry Letters 12 (17): 2399–402. doi:10.1016/S0960- .0707506. PMC 2219521. PMID 17965748 of novel 3-amidoindole and indolopyridone cannabinoid ligands. ARKIVOC 2010 (vi):89-95.
894X(02)00466-3. PMID 12161142. [4] Wrobleski, Stephen T., et al. (2003). “Rational Design and Synthesis of an Orally Active Indolopyridone as a Novel Conformationally Constrained Cannabinoid Ligand Possessing Antiinflammatory Properties”. Journal of Medicinal Chemistry 46 (11): 2110–6. doi:10.1021/jm020329q. PMID 12747783. [5] Huffman, J. W.; Padgett, L. W. (2005). “Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes”. Current Medicinal Chemistry 12 (12): 1395–1411. doi:10.2174/0929867054020864. PMID 15974991. [6] Manera, C.; Tuccinardi, T.; Martinelli, A. (2008). “Indoles and Related Compounds as Cannabinoid Ligands”. Mini Reviews in Medicinal Chemistry 8 (4): 370–387. doi:10.2174/138955708783955935. PMID 18473928. [7] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a. [8] Kiyoi T, et al. (August 2010). “Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (16): 4918–21. doi:10.1016/j.bmcl.2010.06.067. PMID 20634067. [9] Moir EM, et al. (December 2010). “Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (24): 7327–30. doi:10.1016/j.bmcl.2010.10.061. PMID 21074434. [10] Blaazer, A. R. et al. (2011). “Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure–activity relationships, physicochemical properties and biological activity”. European Journal of Medicinal Chemistry 46 (10): 5086–5098. doi:10.1016/j.ejmech.2011.08.021. PMID 21885167.
126.3 Further reading 1. John Hynes., et al. C3 AMIDO-INDOLE CANNABINOID RECEPTOR MODULATORS. Bioorganic and Medical Chemistry Letters. Volume 12 issue 17, 2 September 2002 pages 2399-2402 2. Frost, J. M., et al. (2010). “Indol −3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi :10.1021/ jm901214q. PMID 19921781
Chapter 127
Nabazenil Nabazenil (SP-175) is a synthetic cannabinoid receptor agonist, which has anticonvulsant properties.[1]
127.1 References [1] Concise dictionary of pharmacological agents: properties and synonyms. p188. ISBN 0-7514-0499-3
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Chapter 128
Nabilone Main article: Medical cannabis
vealed that patients taking cisplatin chemotherapy preferred metoclopramide, while patients taking carboplatin chemotherapy preferred nabilone to control nausea and Nabilone is a synthetic cannabinoid with therapeutic [5] use as an antiemetic and as an adjunct analgesic for vomiting. neuropathic pain. It mimics the main chemical com- One study compared the efficacy and tolerability of pound of cannabis (THC), the active ingredient found in nabilone with that of dihydrocodeine in the treatment of naturally occurring Cannabis sativa L.[1] neuropathic pain.[6] The authors found that nabilone was In Canada, the United States, the United Kingdom and not as effective as dihydrocodeine in controlling pain, and Mexico, nabilone is marketed as Cesamet. It was ap- caused a higher incidence of minor adverse drug reactions proved in 1985 by the U.S. Food and Drug is- than did dihydrocodeine. One critic of the study has sugtration (FDA) for treatment of chemotherapy-induced gested that nabilone might be best suited for the treatment nausea and vomiting (CINV) that has not responded to of patients suffering from central and spasticity-related conventional antiemetics. Though it was approved by pain, for which there is stronger evidence for the benethe FDA in 1985, the drug only began marketing in the fits of cannabinoid therapy; however, these patients made United States in 2006. In Austria Nabilone is marketed up only a small fraction of the study’s population, and the study was not designed to identify subgroups which as Canemes and got its approval for CINV in 2013.[2] might have responded more favorably to treatment than Although it doesn't have any indication officially (except others.[7] in Mexico), nabilone is widely used as an adjunct therapy for chronic pain management. Numerous trials and A clinical trial performed in Canada reviewed the use of nabilone to treat nightmares in individuals suffering case studies have demonstrated modest effectiveness for from post-traumatic stress syndrome.[8] The study found [3] [4] relieving fibromyalgia and multiple sclerosis. that nighttime istration of nabilone reduced the Nabilone is a racemic mixture consisting of the (S,S) and frequency and/or intensity of nightmares in 34 out of the (R,R) isomers ("trans"). 47 (72%) of patients, with 28 reporting complete cessation of nightmares.[8] This study is limited to the extent that there was no placebo control, but warrants future investigation into the use of cannabinoid therapy 128.1 Medical uses in the treatment of post-traumatic stress syndrome and other disorders involving recurrent nightmares. As enNabilone has shown modest effectiveness in relieving docannabinoids play a significant role in regulating longfibromyalgia.[3] term depression, perhaps downregulating the CB1 sysThe main settings that have seen published clinical tem can help remove the highly potentiated, hippocamtrials of nabilone include movement disorders such pal/amydygalia memories of the fear. At the very least, as Parkinson’s syndrome, chronic pain, dystonia and CB1 agonists make one less likely to a dream, spasticity neurological disorders, multiple sclerosis, and or even make REM sleep happen without significant inthe nausea of cancer chemotherapy. Nabilone is also ef- volvement of the limbic system. fective in the treatment of inflammatory bowel disease, especially ulcerative colitis. Medical marijuana patients report that nabilone is more similar in effect to CBD than 128.2 Adverse effects THC, indicating that it has more of a therapeutic effect on the body than a “high” effect on the mind. Nabilone can increase, rather than decrease, postA study comparing nabilone with metoclopramide, operative pain; in the treatment of fibromyalgia, adconducted before the development of modern 5- verse effects limits the useful dose.[3] Adverse effects of HT3 antagonist anti-emetics such as ondansetron, re- nabilone include, but are not limited to dizziness/vertigo, 174
128.4. REFERENCES euphoria, drowsiness, dry mouth, ataxia, sleep disturbance, dysphoria, headache, nausea, disorientation, depersonalization, asthenia and increased appetite.[9]
128.3 See also • Dronabinol
128.4 References [1] “How to use Cesamet”. Artek LLC. 2008. [2] “Canemes (nabilone)". [3] Fine PG, Rosenfeld MJ (2013). “The endocannabiRamnoid system, cannabinoids, and pain”. bam Maimonides Med J (Review) 4 (4): e0022. doi:10.5041/RMMJ.10129. PMC 3820295. PMID 24228165. [4] Wissel J, et al. (2006). “Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial”. J Neurol. (Research article) 253 (10): 1337–41. doi:10.1007/s00415-006-0218-8. PMID 16988792. [5] Cunningham D, et al. (1988). “A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogues”. Eur J Cancer Clin Oncol (Randomized controlled trial) 24 (4): 685–9. doi:10.1016/0277-5379(88)90300-8. PMID 2838294. [6] Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D (January 2008). “Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study”. BMJ (Randomized controlled trial) 336 (7637): 199–201. doi:10.1136/bmj.39429.619653.80. PMC 2213874. PMID 18182416. [7] Cohen SP (January 2008). “Cannabinoids for chronic pain”. BMJ (Research article) 336 (7637): 167– 8. doi:10.1136/bmj.39434.444583.80. PMC 2213791. PMID 18182415. [8] Fraser, GA (2009). “The Use of a Synthetic Cannabinoid in the Management of Treatment-Resistant Nightmares in Posttraumatic Stress Disorder (PTSD)". CNS Neurosci Ther (Trial report) 15 (1): 84–88. doi:10.1111/j.17555949.2008.00071.x. PMID 19228182. [9] “Cesamet (nabilone) Prescribing Information”. http:// www.cesamet.com/pdf/Cesamet_PI_50_count.pdf. Meda Pharmaceuticals Inc. Retrieved 16 July 2014.
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Chapter 129
Nabitan Nabitan (Nabutam, Benzopyranoperidine, SP-106, Abbott 40656) is a synthetic cannabinoid analog of dronabinol (Marinol).[1] It exhibits antiemetic and analgesic effects, most likely by binding to and activating the CB1 and CB2 cannabinoid receptors, and reduced intraocular pressure in animal tests, making it potentially useful in the treatment of glaucoma.[2] Nabitan has the advantage of being water soluble unlike most cannabinoid derivatives, and was researched for potential use as an analgesic or sedative,[3] although it was never developed for clinical use and is not currently used in medicine, as dronabinol or nabilone were felt to be more useful. However it is sometimes used in research into the potential therapeutic applications of cannabinoids.
129.1 References [1] Razdan RK. The Total Synthesis of Cannabinoids. WileyInterscience 1980 [2] Razdan RK, Howes JF. “Drugs related to tetrahydrocannabinol.” Medicinal Research Reviews 1983; 3(2):119146. PMID 6134882 [3] Archer RA. “The cannabinoids: therapeutic potentials.” Annual Reports in Medicinal Chemistry 1974; 9: 253-259. PMID 12307093
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Chapter 130
Nabiximols tiate the marketing rights in other countries in European Union and selected other countries around the world.” In April 2011, GW licensed to Novartis the rights to commercialise nabiximols in Asia (excluding China and Japan), Africa and the Middle East (excluding Israel). [3]
130.1 Availability
Canadian packaging of a case of Sativex vials
Nabiximols (USAN,[1] trade name Sativex) is a patented cannabinoid oromucosal mouth spray developed by the UK company GW Pharmaceuticals for multiple sclerosis (MS) patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.[2] Nabiximols is distinct from all other pharmaceutically produced cannabinoids currently available because it is a mixture of compounds derived from Cannabis plants, rather than a mono-molecular synthetic product. The drug is a pharmaceutical product standardised in composition, formulation, and dose, although it is still effectively a tincture of the cannabis plant. Its principal active cannabinoid components are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD). The product is formulated as an oromucosal spray which is istered by spraying into the mouth. Each spray delivers a near 1:1 ratio of CBD to THC, with a fixed dose of 2.7 mg THC and 2.5 mg CBD. Nabiximols is also being developed in Phase III trials as a potential treatment to alleviate pain due to cancer. It has also been researched in various models of peripheral and central neuropathic pain. In May 2003 GW Pharmaceuticals and Bayer entered into an exclusive marketing agreement for GW’s cannabis-based medicinal extract product, to be marketed under the brand name Sativex. “Bayer has obtained exclusive rights to market Sativex in the UK. In addition, Bayer has the option for a limited period of time to nego-
In June 2010, the Medicines and Healthcare products Regulatory Agency of the United Kingdom licensed nabiximols as a prescription-only medicine for the treatment of spasticity due to multiple sclerosis. This regulatory authorization represents the world’s first full regulatory approval for the medicine. The spray is being marketed in the UK by Bayer Schering Pharma. Many MS patients cannot receive nabiximols due to local National Health Service (NHS) resistance to its funding.[4][5] but, in August 2014, the NHS in Wales agreed to fund Sativex for people with multiple sclerosis.[6] Nabiximols was also approved in Spain for MS spasticity in the second half of 2010 and was launched in that country in March 2011. It was approved in the Czech Republic in April 2011, in in May 2011, in Denmark in June 2011 and in Sweden in January 2012 to MS patients who have not responded adequately to other medication for spasticity.[7] It has also been recommended for approval in Italy and Austria with formal approvals expected in these countries during 2011. In Spain and other European markets (excluding the UK), nabiximols will be marketed by Almirall. In Canada, nabiximols has been approved by Health Canada for the treatment of MS spasticity. It has also received a licence with conditions (NOC/c) for two additional uses: as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis,[8] and also for pain due to cancer.[9][10] Nabiximols is available in a number of countries as an unlicensed medicine, which enables doctors to prescribe the product to individual patients who they consider may benefit. The product has been exported from the UK to a total of 28 countries to date. In February 2007, GW and Otsuka Pharmaceutical an-
177
178 nounced an exclusive agreement for Otsuka to develop and market the drug in the United States. The first large scale US Phase IIb trial, Spray Trial, for cancer patients reported positive results in March 2010. GW and Otsuka have now commenced the Phase III development of nabiximols in cancer pain. In 2013, legalized the use of cannabinoids in medicine, Sativex is the first one to be sold under prescription.
130.2 Effectiveness Of the two preliminary Phase III studies investigating the treatment of MS patients, one showed a reduction of spasticity of 1.2 points on the 0–10 points rating scale (versus 0.6 points under placebo), the other showed a reduction of 1.0 versus 0.8 points. Only the first study reached statistical significance. The Phase III approval study consisted of a run-in phase where the response of individuals to the drug was determined. The responders (42% of patients) showed a significant effect in the second, placebo controlled, phase of the trial.[11] A 2009 meta-analysis of six studies found large variations of effectiveness, with a – statistically non-significant – trend towards a reduction of spasticity.[12]
130.3 Side effects
CHAPTER 130. NABIXIMOLS • Dronabinol • GW Pharmaceuticals • Hortapharm B.V.
130.6 References [1] United States Adopted Names Coincil: Statement on a nonproprietary name [2] http://www.gwpharm.com/SPC.aspx [3] “GW signs Sativex cannabis-based drug deal with Novartis”. The Telegraph. 11 April 2011. Retrieved 12 July 2012. [4] Ryan, Siobhan (4 June 2011). “Sussex MS sufferers call for drug funding”. Argus (Sussex,UK). Retrieved 8 June 2011. [5] “Sativex rejected by healthcare provider”. Lincolnshire. 20 June 2011. Retrieved 20 June 2011. [6] “Wales NHS to offer MS cannabis drug Sativex”. 15 August 2014. Retrieved 18 August 2014. [7] Sativex (nabiximols), Swedish Medical Products Agency [8] GW Pharmaceuticals. "Multiple Sclerosis". Accessed 24 July 2011. [9] GW Pharmaceuticals. "Cancer Pain" Accessed 24 July 2011. [10] “Sativex - Investigational Cannabis-Based Treatment for Pain and Multiple Sclerosis Drug Development Technology”. www.drugdevelopment-technology.com. Retrieved 2008-08-08.
In early clinical trials, nabiximols has generally been well tolerated.[13][14][15] The most common adverse effects in Phase III trials were dizziness (25%), drowsiness (8.2%) and disorientation (4%). 12% of patients stopped taking [11] Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel the drug because of the side effects. No investigations 2011/2012 (German) regarding the potential for dependence are available, but such a potential is unlikely considering the pharmacolog- [12] Lakhan, Shaheen E; Rowland, Marie (2009). “Whole plant cannabis extracts in the treatment of spasticity in ical properties of the two components.[11]
130.4 Controversy
multiple sclerosis: a systematic review”. BMC Neurol 9: 59. doi:10.1186/1471-2377-9-59. PMC 2793241. PMID 19961570.
[13] Wade D, Makela P, Robson P, House H, Bateman C (2004). “Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients”. Mult Scler 10 (4): 434–41. doi:10.1191/1352458504ms1082oa. PMID 15327042.
GW Pharmaceuticals were issued a unique license to cultivate cannabis for the manufacturing of Sativex in the UK, granting them the sole legal right to research in aerosolized cannabis derived therapeutics, which in April 2013 became commercially viable when the UK Govern[14] Wade D, Makela P, House H, Bateman C, Robson P ment scheduled the Sativex formulation to part IV of the (2006). “Long-term use of a cannabis-based medicine UK Drugs Act.[16] in the treatment of spasticity and other symptoms in multiple sclerosis”. Mult Scler 12 (5): 639–45. doi:10.1177/1352458505070618. PMID 17086911.
130.5 See also • Medical cannabis • Nabilone
[15] Wade D, Robson P, House H, Makela P, Aram J (2003). “A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms”. Clin Rehabil 17 (1): 21–9. doi:10.1191/0269215503cr581oa. PMID 12617376.
130.7. EXTERNAL LINKS
[16] http://www.gwpharm.com/GW%20Pharmaceuticals% 20cannabinoid-medicine%20Sativex%20moved% 20to%20Schedule%204%20of%20UK%20Drugs% 20Act.aspx
130.7 External links • GW Pharmaceuticals Website
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Chapter 131
Naboctate Naboctate (SP-325) is a synthetic cannabinoid receptor agonist, which has antiemetic, sedative, anxiolytic and anti-glaucoma properties.[1]
131.1 References [1] Concise dictionary of pharmacological agents: properties and synonyms. p188. ISBN 0-7514-0499-3
180
Chapter 132
NESS-0327 NESS-0327 is a drug used in scientific research which acts as an extremely potent and selective antagonist of the cannabinoid receptor CB1 . It is much more potent an antagonist, and more selective for the CB1 receptor over CB2 , than the more commonly used ligand rimonabant, with a Kᵢ at CB1 of 350fM (i.e. 0.00035nM) and a selectivity of over 60,000x for CB1 over CB2 .[1] Independently, two other groups have described only modest nanomolar CB1 affinity for this compound (125nM[2] and 18.4nM[3] ). Also unlike rimonabant, NESS-0327 does not appear to act as an inverse agonist at higher doses, instead being a purely neutral antagonist which blocks the CB1 receptor but does not produce any physiological effect of its own.[4]
132.1 See also • Discovery and development of Cannabinoid Receptor 1 Antagonists • NESS-040C5
132.2 References [1] Ruiu S, Pinna GA, Marchese G, Mussinu JM, Saba P, Tambaro S, Casti P, Vargiu R, Pani L. Synthesis and characterization of NESS 0327: a novel putative antagonist of the CB1 cannabinoid receptor. Journal of Pharmacology and Experimental Therapeutics. 2003 Jul;306(1):363-70. PMID 12663689 [2] A.R. Stoit, J.H.M. Lange, A.P. den Hartog, E. Ronken, K. Tipker, H.H. van Stuivenberg, J.A.R. Dijksman, H.C. Wals, C.G. Kruse, Chem. Pharm. Bull. 50 (2002) 11091113 [3] Y. Zhang, J.P. Burgess, M. Brackeen, A. Gilliam, S.W. Mascarella, K. Page, H.H. Seltzman, B.F. Thomas, J. Med. Chem. 51 (2008) 3526-3539 [4] Tambaro S, Mongeau R, Dessi C, Pani L, Ruiu S. Modulation of ATP-mediated contractions of the rat vas deferens through presynaptic cannabinoid receptors. European Journal of Pharmacology. 2005 Nov 21;525(1-3):150-3. PMID 16271359
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Chapter 133
NESS-040C5 NESS-040C5 is a potent cannabinoid agonist which was developed for the treatment of glaucoma.[1] It has reasonable selectivity for the CB2 receptor subtype, having a CB2 affinity of 0.4nM, and 25x selectivity over the related CB1 receptor.[2]
133.1 See also • AB-FUBINACA • NESS-0327 • SR-144,528
133.2 References [1] Paolo Lazzari et al. Pharmaceutical Compounds. US Patent 8106218 [2] Hanus LO, Mechoulam R. Novel natural and synthetic ligands of the endocannabinoid system. Current Medicinal Chemistry. 2010;17(14):1341-59. PMID 20166928
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Chapter 134
NMP-7 NMP-7 is a drug which acts as both a non-selective agonist of the CB1 and CB2 cannabinoid receptors, and also as a blocker of T-type calcium channels, the target of anticonvulsant drugs such as ethosuximide. NMP-7 has an agonist EC50 of 96.9nM at CB1 and 10.5nM at CB2 , and an IC50 of 1.84μM for blocking Cav3.2 T-type calcium channels. In animal studies it produces potent analgesic effects in a variety of different tests.[1]
134.1 References [1] You H, Gadotti VM, Petrov RR, Zamponi GW, Diaz P. Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands. Molecular Pain. 2011 Nov 17;7:89. PMID 22093952
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Chapter 135
Nonabine Nonabine (BRL-4664) is a drug which is a cannabinoid derivative, which was developed for the prevention of nausea and vomiting associated with cancer chemotherapy.[1] It has strong antiemetic effects equivalent to those of chlorpromazine, and also produces some mild sedative effects, along with dry mouth and EEG changes typical of cannabinoid agonists, but with minimal changes in mood or perception, suggesting the abuse potential is likely to be low.[2][3]
135.1 References [1] Staquet M, Bron D, Rozencweig M, Kenis Y. Clinical studies with a THC analog (BRL-4664) in the prevention of cisplatin-induced vomiting. Journal of Clinical Pharmacology. 1981 Aug-Sep;21(8-9 Suppl):60S-63S. PMID 7197692 [2] Archer CB, Amlot PL, Trounce JR. Antiemetic effect of nonabine in cancer chemotherapy: a double blind study comparing nonabine and chlorpromazine. British Medical Journal (Clinical Research Edition). 1983 Jan 29;286(6362):350-1. PMID 6402096 [3] McClelland GR, Sutton JA. Pilot investigation of the quantitative EEG and clinical effects of ketazolam and the novel antiemetic nonabine in normal subjects. Psychopharmacology (Berlin). 1985;85(3):306-8. PMID 2860687
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Chapter 136
11-nor-9-Carboxy-THC Not to be confused with Tetrahydrocannabinolic acid. 11-nor−9-Carboxy-THC, also known as 11-nor−9carboxy-delta-9-tetrahydrocannabinol, 11-nor9-carboxy-delta-9-THC, 11-COOH-THC, THCCOOH, and THC-11-oic acid, is the main secondary metabolite of THC which is formed in the body after Cannabis is consumed. 11-COOH-THC is formed in the body by oxidation of the active metabolite 11-Hydroxy-THC (also known as 11OH-THC) by liver enzymes. It is then metabolized further by conjugation with glucuronide,[2] forming a watersoluble congener which can be more easily excreted by the body.[3]
While 11-COOH-THC does not have any psychoactive effects in its own right, it may still have a role in the analgesic and antiinflammatory effects of cannabis,[10][11][12] and has also been shown to moderate the effects of THC itself which may help explain the difference in subjective effects seen between occasional and regular s of cannabis.[13][14]
136.1 References
11-COOH-THC is not psychoactive itself, but has a long half-life in the body of up to several days (or even weeks in very heavy s),[4][5][6] making it the main metabolite tested for when blood or urine testing for cannabis use. More selective tests are able to distinguish between 11-OH-THC and 11-COOH-THC, which can help determine how recently cannabis was consumed;[7][8] if only 11-COOH-THC is present then the cannabis was used some time ago and any impairment in cognitive ability or motor function will have dissipated, whereas if both 11-OH-THC and 11-COOH-THC are present then the cannabis was consumed more recently and motor impairment may still be present. Some jurisdictions where cannabis use is decriminalized or permitted under some circumstances use such tests when determining whether drivers were legally intoxicated and therefore unfit to drive, with the comparative levels of THC, 11-OH-THC and 11-COOH-THC being used to derive a “blood cannabis level” analogous to the blood alcohol level used in prosecuting impaired drivers.[9] On the other hand in jurisdictions where cannabis is completely illegal, any detectable levels of 11COOH-THC may be deemed to constitute driving while intoxicated, even though this approach has been criticized as tantamount to prohibition of “driving whilst being a recent of cannabis” regardless of the presence or absence of any actual impairment that might impact on driving performance.
185
[1] http://www.clinchem.org/cgi/content/full/55/12/2180 [2] Skopp, G; Pötsch, L (2002). “Stability of 11-nor-delta(9)carboxy-tetrahydrocannabinol glucuronide in plasma and urine assessed by liquid chromatography-tandem mass spectrometry”. Clinical chemistry 48 (2): 301–6. PMID 11805011. [3] Law, B; Mason, PA; Moffat, AC; King, LJ (1984). “Confirmation of cannabis use by the analysis of delta 9tetrahydrocannabinol metabolites in blood and urine by combined HPLC and RIA”. Journal of analytical toxicology 8 (1): 19–22. doi:10.1093/jat/8.1.19. PMID 6323852. [4] Huestis, MA; Mitchell, JM; Cone, EJ (1995). “Detection times of marijuana metabolites in urine by immunoassay and GC-MS”. Journal of analytical toxicology 19 (6): 443–9. doi:10.1093/jat/19.6.443. PMID 8926739. [5] Pope Jr, HG; Gruber, AJ; Hudson, JI; Huestis, MA; Yurgelun-Todd, D (2001). “Neuropsychological performance in long-term cannabis s”. Archives of General Psychiatry 58 (10): 909–15. doi:10.1001/archpsyc.58.10.909. PMID 11576028. [6] Dietz, L; Glaz-Sandberg, A; Nguyen, H; Skopp, G; Mikus, G; Aderjan, R (2007). “The urinary disposition of intravenously istered 11-nor-9carboxy-delta-9-tetrahydrocannabinol in humans”. Therapeutic drug monitoring 29 (3): 368–72. doi:10.1097/FTD.0b013e31805ba6fd. PMID 17529896. [7] Huestis, MA; Henningfield, JE; Cone, EJ (1992). “Blood cannabinoids. II. Models for the prediction of time of marijuana exposure from plasma concentrations of delta 9-tetrahydrocannabinol (THC) and 11-nor9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH)".
186
CHAPTER 136. 11-NOR-9-CARBOXY-THC
Journal of analytical toxicology 16 (5): doi:10.1093/jat/16.5.283. PMID 1338216.
283–90.
[8] Huestis, MA; Elsohly, M; Nebro, W; Barnes, A; Gustafson, RA; Smith, ML (2006). “Estimating time of last oral ingestion of cannabis from plasma THC and THCCOOH concentrations”. Therapeutic drug monitoring 28 (4): 540–4. doi:10.1097/00007691-20060800000009. PMID 16885722. [9] Ménétrey, A; Augsburger, M; Favrat, B; Pin, MA; Rothuizen, LE; Appenzeller, M; Buclin, T; Mangin, P; Giroud, C (2005). “Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral istration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC”. Journal of analytical toxicology 29 (5): 327–38. doi:10.1093/jat/29.5.327. PMID 16105257. [10] Burstein, SH; Hull, K; Hunter, SA; Latham, V (1988). “Cannabinoids and pain responses: a possible role for prostaglandins”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 (14): 3022–6. PMID 2846397. [11] Doyle, SA; Burstein, SH; Dewey, WL; Welch, SP (1990). “Further studies on the antinociceptive effects of delta 6THC-7-oic acid”. Agents and actions 31 (1–2): 157–63. doi:10.1007/bf02003237. PMID 2178317. [12] Ujváry, I; Grotenhermen, F (2014). “11-Nor-9-carboxyΔ9-tetrahydrocannabinol – a ubiquitous yet underresearched cannabinoid. A review of the literature”. Cannabinoids 9 (1): 1–8. [13] Burstein, S; Hunter, SA; Latham, V; Renzulli, L (1987). “A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic effect in mice”. Experientia 43 (4): 402–3. doi:10.1007/BF01940427. PMID 3032669. [14] Burstein, S; Hunter, SA; Latham, V; Renzulli, L (1986). “Prostaglandins and cannabis--XVI. Antagonism of delta 1-tetrahydrocannabinol action by its metabolites”. Biochemical pharmacology 35 (15): 2553–8. doi:10.1016/0006-2952(86)90053-5. PMID 3017356.
Chapter 137
O-1057 O-1057 is an analgesic cannabinoid derivative created by Organix Inc. for use in scientific research. Unlike most cannabinoids discovered to date, it is water soluble, which gives it considerable advantages over many related cannabinoids. It has moderate affinity for both CB1 and CB2 receptors, with Kᵢ values of 8.36nM at CB1 and 7.95nM at CB2 .[1]
137.1 See also • AM-2232 • O-774 • O-1812 • O-2694
137.2 References [1] Pertwee RG, et al. O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. British Journal of Pharmacology. 2000 Apr;129(8):1577-84. PMID 10780961
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Chapter 138
O-1125 O-1125 (3-(1,1-dimethylhexyl-6dimethylcarboxamide)-Δ8-tetrahydrocannabinol) is a drug which is a cannabinoid derivative. It has analgesic effects and is used in scientific research. It is a potent CB1 full agonist with a Ki of 1.16nM.[1]
138.1 References [1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649
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Chapter 139
O-1238 O-1238 is a drug which is a cannabinoid derivative that is used in scientific research. It is a partial agonist at the cannabinoid receptor CB1 ,[1] producing a maximal stimulation of 58.3%[2] with a Ki of 8.45nM.[3]
139.1 References [1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649 [2] Griffin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ, Saha B, Razdan RK, Martin BR, Abood ME. An investigation into the structural determinants of cannabinoid receptor ligand efficacy. British Journal of Pharmacology. 1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469 PMID 10323589 [3] Ross RA, Gibson TM, Stevenson LA, Saha B, Crocker P, Razdan RK, Pertwee RG. Structural determinants of the partial agonist-inverse agonist properties of 6'azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabinoid receptors. British Journal of Pharmacology. 1999 Oct;128(3):735-43. PMID 10516656
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Chapter 140
O-1269 O-1269 is a drug that is a diarylpyrazole derivative, related to potent cannabinoid antagonist drugs such as rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full or partial agonists at the cannabinoid receptors rather than antagonists, and so produce the usual effects expected of cannabinoid agonists in animal tests, such as sedation and analgesic effects. The N-heptyl homologue O-1270 and the N-propyl homologue O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker binding affinity at cannabinoid receptors compared to the pentyl homologue O-1269.[1][2][3] Agonist-like and atypical cannabinoid activity has also been observed with a number of related compounds.[4][5]
140.1 References [1] Billy R. Martin, Raj K. Razdan, Anu Mahadevan. Pyrazole cannabinoid agonist and antagonists. US Patent 6509367, filed Sep 22, 2001, issued Jan 21, 2003. [2] Shim JY, Welsh WJ, Cartier E, Edwards JL, Howlett AC. Molecular interaction of the antagonist N-(piperidin1-yl)−5-(4-chlorophenyl)−1- (2,4-dichlorophenyl)−4methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor. Journal of Medicinal Chemistry. 2002 Mar 28;45(7):1447-59. PMID 11906286 [3] Francisco ME, Seltzman HH, Gilliam AF, Mitchell RA, Rider SL, Pertwee RG, Stevenson LA, Thomas BF. Synthesis and structure-activity relationships of amide and hydrazide analogues of the cannabinoid CB(1) receptor antagonist N-(piperidinyl)- 5-(4-chlorophenyl)−1-(2,4dichlorophenyl)−4-methyl-1H-pyrazole-3-carboxamide (SR141716). Journal of Medicinal Chemistry. 2002 Jun 20;45(13):2708-19. PMID 12061874 [4] Thomas, B. F.; Francisco, M. E. Y.; Seltzman, H. H.; Thomas, J. B.; Fix, S. E.; Schulz, A. K.; Gilliam, A. F.; Pertwee, R. G.; Stevenson, L. A. (2005). “Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist N-(piperidinyl)−5(4-chlorophenyl)−1-(2,4-dichlorophenyl)−4-methyl1H-pyrazole-3-carboxamide (SR141716) with unique binding selectivities and pharmacological activities”. Bioorganic & Medicinal Chemistry 13 (18): 5463–5474. doi:10.1016/j.bmc.2005.06.005. PMID 15994087.
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[5] Wiley, J. L.; Selley, D. E.; Wang, P.; Kottani, R.; Gadthula, S.; Mahadeven, A. (2011). “3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB1) Receptor Antagonist Rimonabant: Cannabinoid AgonistLike Effects in Mice via Non-CB1, Non-CB2 Mechanism”. Journal of Pharmacology and Experimental Therapeutics 340 (2): 433–444. doi:10.1124/jpet.111.187815. PMC 3263966. PMID 22085649.
Chapter 141
O-1602 O-1602 is a synthetic compound most closely related to abnormal cannabidiol, and more distantly related in structure to cannabinoid drugs such as THC. O-1602 does not bind to the classical cannabinoid receptors CB1 or CB2 with any significant affinity, but instead is an agonist at several other receptors which appear to be related to the cannabinoid receptors, particularly GPR18 and GPR55. These previously orphan receptors have been found to be targets for a number of endogenous and synthetic cannabinoid compounds, and are thought to be responsible for most of the non-CB1 , non-CB2 mediated effects that have become evident in the course of cannabinoid research. O-1602 produces some effects shared with classical cannabinoid compounds such as analgesic and antiinflammatory effects and appetite stimulation, but it does not produce sedation or psychoactive effects, and has several actions in the gut and brain that are not shared with typical cannabinoid agonists.[1][2][3][4][5][6][7]
141.1 See also • Cannabidiol
17 (8): 1651–1664. doi:10.1002/ibd.21538. 3116968. PMID 21744421.
PMC
[4] Díaz-Arteaga, A.; Vázquez, M. J.; Vazquez-Martínez, R.; Pulido, M. R.; Suarez, J.; Velásquez, D. A.; López, M.; Ross, R. A.; De Fonseca, F. R.; Bermudez-Silva, F. J.; Malagón, M. M.; Diéguez, C.; Nogueiras, R. (2012). “The atypical cannabinoid O-1602 stimulates food intake and adiposity in rats”. Diabetes, Obesity and Metabolism 14 (3): 234–243. doi:10.1111/j.14631326.2011.01515.x. PMID 21981246. [5] Kargl, J.; Haybaeck, J.; Stančić, A.; Andersen, L.; Marsche, G.; Heinemann, A.; Schicho, R. (2012). “O1602, an atypical cannabinoid, inhibits tumor growth in colitis-associated colon cancer through multiple mechanisms”. Journal of Molecular Medicine 91 (4): 449–58. doi:10.1007/s00109-012-0957-1. PMC 3529923. PMID 22965195. [6] McHugh, D.; Wager-Miller, J.; Page, J.; Bradshaw, H. B. (2012). “SiRNA knockdown of GPR18 receptors in BV2 microglia attenuates N-arachidonoyl glycine-induced cell migration”. Journal of Molecular Signaling 7 (1): 10. doi:10.1186/1750-2187-7-10. PMC 3493281. PMID 22834922. [7] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Bradshaw, H.; Kelly, M. E.; Straiker, A. (2013). “A GPR18-based signaling system regulates IOP in murine eye”. British Journal of Pharmacology 169 (4): 834– 43. doi:10.1111/bph.12136. PMC 3687663. PMID 23461720.
• O-1918
141.2 References [1] Ashton, J. C. (2012). “The atypical cannabinoid o-1602: Targets, actions, and the central nervous system”. Central nervous system agents in medicinal chemistry 12 (3): 233–239. doi:10.2174/187152412802430156. PMID 22831390. [2] Schuelert, N.; McDougall, J. J. (2011). “The abnormal cannabidiol analogue O-1602 reduces nociception in a rat model of acute arthritis via the putative cannabinoid receptor GPR55”. Neuroscience Letters 500 (1): 72–76. doi:10.1016/j.neulet.2011.06.004. PMID 21683763. [3] Schicho, R.; Bashashati, M.; Bawa, M.; McHugh, D.; Saur, D.; Hu, H. M.; Zimmer, A.; Lutz, B.; MacKie, K.; Bradshaw, H. B.; McCafferty, D. M.; Sharkey, K. A.; Storr, M. (2011). “The atypical cannabinoid O1602 protects against experimental colitis and inhibits neutrophil recruitment”. Inflammatory Bowel Diseases
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Chapter 142
O-1812 O-1812 is an eicosanoid derivative related to anandamide that acts as a potent and highly selective agonist for the cannabinoid receptor CB1 , with a Kᵢ of 3.4nM at CB1 and 3870nM at CB2 .[1] Unlike most related compounds, O-1812 is metabolically stable against rapid breakdown by enzymes, and produces a cannabinoid-like discriminative effect in rats, which is similar but not identical to that produced by cannabinoid drugs of other chemical classes.[2][3][4][5]
142.1 See also • AM-1235 • AM-2232 • AM-2389 • Methanandamide • O-774 • O-1057
142.2 References [1] Di Marzo V, et al. (February 2001). “Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor “hybrid” ligands”. Biochemical and Biophysical Research Communications 281 (2): 444–51. doi:10.1006/bbrc.2001.4354. PMID 11181068. [2] Baskfield CY, Martin BR, Wiley JL (April 2004). “Differential effects of delta9-tetrahydrocannabinol and methanandamide in CB1 knockout and wild-type mice”. The Journal of Pharmacology and Experimental Therapeutics 309 (1): 86–91. doi:10.1124/jpet.103.055376. PMID 14718593. [3] Wiley JL, et al. (August 2004). “A comparison of the discriminative stimulus effects of delta(9)tetrahydrocannabinol and O-1812, a potent and metabolically stable anandamide analog, in rats”. Experimental and Clinical Psychopharmacology 12 (3): 173–9. doi:10.1037/1064-1297.12.3.173. PMID 15301634.
192
[4] Wiley JL, Smith FL, Razdan RK, Dewey WL (March 2005). “Task specificity of cross-tolerance between Delta9-tetrahydrocannabinol and anandamide analogs in mice”. European Journal of Pharmacology 510 (12): 59–68. doi:10.1016/j.ejphar.2005.01.006. PMID 15740725. [5] Breivogel CS, et al. (July 2008). “Sensitivity to delta9tetrahydrocannabinol is selectively enhanced in betaarrestin2 -/- mice”. Behavioural Pharmacology 19 (4): 298–307. doi:10.1097/FBP.0b013e328308f1e6. PMC 2751575. PMID 18622177.
Chapter 143
O-1871 O-1871 is a potent cannabinoid agonist which was invented by Billy R Martin and Raj K Razdan in 2002. It has a CB1 receptor affinity of 2.0nM and a CB2 receptor affinity of 0.3nM.[1] Structurally, O-1871 is a cyclohexylphenol derivative related to 47,497, and so is illegal in most jurisdictions where 47,497 and its derivatives are banned. However the 3,3dimethylcyclohexyl substituent of O-1871 can be replaced by various other groups, producing other potent compounds such as the cycloheptyl derivative O-1656 and the 2-adamantyl derivative O-1660, as well as the corresponding 3,5-dichlorophenyl derivative,[2] which are not cyclohexylphenol derivatives.
143.1 See also • 55,940 • Cannabidiol • Cannabicyclohexanol
143.2 References [1] Billy R Martin, Raj K Razdan. CANNABINOIDS. Patent WO 2003/091189 [2] Xin-Zhong Lai, Dai Lu, Alexandros Makriyannis. Novel biphenyl and biphenyl-like cannabinoids. Patent US 2004/0087590
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Chapter 144
O-1918 O-1918 is a synthetic compound related to cannabidiol, which is an antagonist at two former orphan receptors GPR18 and GPR55, that appear to be related to the cannabinoid receptors. O-1918 is used in the study of these receptors, which have been found to be targets for a number of endogenous and synthetic cannabinoid compounds, and are thought to be responsible for most of the non-CB1 , non-CB2 mediated effects that have become evident in the course of cannabinoid research.[1][2][3][4][5]
144.1 See also • Abnormal cannabidiol • O-1602
144.2 References [1] Offertáler, L.; Mo, F. M.; Bátkai, S.; Liu, J.; Begg, M.; Razdan, R. K.; Martin, B. R.; Bukoski, R. D.; Kunos, G. (2003). “Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor”. Molecular Pharmacology 63 (3): 699–705. doi:10.1124/mol.63.3.699. PMID 12606780. [2] Zakrzeska, A.; Schlicker, E.; Baranowska, M.; Kozłowska, H.; Kwolek, G.; Malinowska, B. (2010). “A cannabinoid receptor, sensitive to O-1918, is involved in the delayed hypotension induced by anandamide in anaesthetized rats”. British Journal of Pharmacology 160 (3): 574–584. doi:10.1111/j.1476-5381.2009.00579.x. PMC 2931558. PMID 20105178. [3] Schuelert, N.; McDougall, J. J. (2011). “The abnormal cannabidiol analogue O-1602 reduces nociception in a rat model of acute arthritis via the putative cannabinoid receptor GPR55”. Neuroscience Letters 500 (1): 72–76. doi:10.1016/j.neulet.2011.06.004. PMID 21683763. [4] Szczesniak, A. M.; Maor, Y.; Robertson, H.; Hung, O.; Kelly, M. E. M. (2011). “Nonpsychotropic Cannabinoids, Abnormal Cannabidiol and CanabigerolDimethyl Heptyl, Act at Novel Cannabinoid Receptors to Reduce Intraocular Pressure”. Journal of Ocular Pharmacology and Therapeutics 27 (5): 427–435. doi:10.1089/jop.2011.0041. PMID 21770780.
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[5] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Bradshaw, H.; Kelly, M. E.; Straiker, A. (2013). “A GPR18-based signaling system regulates IOP in murine eye”. British Journal of Pharmacology 169 (4): 834– 43. doi:10.1111/bph.12136. PMC 3687663. PMID 23461720.
Chapter 145
O-2050 O-2050 is a drug that is a classical cannabinoid derivative, which acts as a silent antagonist for the CB1 receptor. This gives it an advantage in research over many commonly used cannabinoid antagonists such as rimonabant, which at higher doses act as inverse agonists at CB1 as well as showing off-target effects. However while O2050 acts as a silent antagonist in vitro, some tests in vivo have suggested it may show agonist activity under certain circumstances.[1][2][3][4][5][6]
145.1 See also • O-2113
145.2 References [1] Martin B, et al. Agonists and silent antagonists in a series of cannabinoid sulfonamides. 12th Annual Symposium on the Cannabinoids, 2002 [2] Martin et al. SULFONAMIDE CANNABINOID AGONISTS AND ANTAGONISTS. US Patent 7279500, Oct 9 2007 [3] Gardner A, Mallet PE. Suppression of feeding, drinking, and locomotion by a putative cannabinoid receptor 'silent antagonist'. European Journal of Pharmacology. 2006 Jan 13;530(1-2):103-6. PMID 16380113 [4] Higuchi S, Irie K, Mishima S, Araki M, Ohji M, Shirakawa A, Akitake Y, Matsuyama K, Mishima K, Mishima K, Iwasaki K, Fujiwara M. The cannabinoid 1receptor silent antagonist O-2050 attenuates preference for high-fat diet and activated astrocytes in mice. Journal of Pharmacological Sciences. 2010;112(3):369-72. PMID 20168044 [5] Higuchi S, Ohji M, Araki M, Furuta R, Katsuki M, Yamaguchi R, Akitake Y, Matsuyama K, Irie K, Mishima K, Mishima K, Iwasaki K, Fujiwara M. Increment of hypothalamic 2-arachidonoylglycerol induces the preference for a high-fat diet via activation of cannabinoid 1 receptors. Behavioural Brain Research. 2011 Jan 1;216(1):477-80. PMID 20817042 [6] Wiley JL, Breivogel CS, Mahadevan A, Pertwee RG, Cascio MG, Bolognini D, Huffman JW, Walentiny DM, Vann
195
RE, Razdan RK, Martin BR. Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB(1) receptor antagonist. European Journal of Pharmacology. 2011 Jan 25;651(1-3):96-105. PMID 21114999
Chapter 146
O-2113 O-2113 is a drug that is a classical cannabinoid derivative, which acts as a potent agonist for cannabinoid receptors, producing sedation, hypothermia and analgesia in animal studies.[1]
146.1 See also • O-2050 • O-2372 • O-2545
146.2 References [1] Martin, et al. SULFONAMIDE CANNABINOID AGONISTS AND ANTAGONISTS. US Patent 7279500, Oct 9 2007
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Chapter 147
O-2372 O-2372 is an analgesic cannabinoid derivative created by Organix Inc. for use in scientific research. It has high affinity for both CB1 and CB2 receptors, with Kᵢ values of 1.3nM at CB1 and 0.57nM at CB2 , but is only moderately soluble in water compared to other related compounds such as O-2694, which it is a metabolite of.[1]
147.1 See also • O-2113 • O-2545 • O-2694
147.2 References [1] Martin BR, et al. Pharmacological characterization of novel water-soluble cannabinoids. Journal of Pharmacology and Experimental Therapeutics. 2006 Sep;318(3):1230-9. PMID 16757541
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Chapter 148
O-2545 O-2545 is an analgesic cannabinoid derivative created by Organix Inc. for use in scientific research. Unlike most cannabinoids discovered to date, it is water soluble, which gives it considerable advantages over many related cannabinoids. It has high affinity for both CB1 and CB2 receptors, with Kᵢ values of 1.5nM at CB1 and 0.32nM at CB2 .[1]
148.1 See also • O-2113 • O-2372 • Tropoxane
148.2 References [1] Martin BR, et al. Pharmacological characterization of novel water-soluble cannabinoids. Journal of Pharmacology and Experimental Therapeutics. 2006 Sep;318(3):1230-9. PMID 16757541
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Chapter 149
O-2694 O-2694 is a drug that is a cannabinoid derivative. It has analgesic effects and is used in scientific research. Unlike most cannabinoids discovered to date, it is highly watersoluble, which gives it considerable advantages over many related drugs. It has high affinity for both CB1 and CB2 receptors, with Kᵢ values of 3.7nM at CB1 and 2.8nM at CB2 . However, it has complex pharmacokinetics as most of the istered dose is metabolised by hydrolysis of the ester link to the water-insoluble compound O-2372, thus producing a biphasic effects profile that is less suitable for research purposes than the related compound O2545.[1]
149.1 See also • O-1057 • O-2372
149.2 References [1] Martin BR, et al. Pharmacological characterization of novel water-soluble cannabinoids. Journal of Pharmacology and Experimental Therapeutics. 2006 Sep;318(3):1230-9. PMID 16757541
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Chapter 150
O-774 O-774 is a classical cannabinoid derivative which acts as a potent agonist for the cannabinoid receptors, with a Kᵢ of 0.6 nM at CB1 , and very potent cannabinoid effects in animal studies.[1][2]
150.1 See also • AM-2232 • O-1057 • O-1812
150.2 References [1] Singer M, et al. Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8tetrahydrocannabinol. Journal of Medicinal Chemistry. 1998 Oct 22;41(22):4400-7. PMID 9784115 [2] The Cannabinoid Receptors. Part I. Cannabinoid Receptor Ligands and Structure-Activity Relationships. pp 6-9. Edited by Patricia H Reggio. Humana Press 2009. ISBN 978-1-58829-712-9
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Chapter 151
O-806 O-806 is a drug which is a cannabinoid derivative that is used in scientific research. It is described as a mixed agonist/antagonist at the cannabinoid receptor CB1 , meaning that it acts as an antagonist when co-istered alongside a more potent CB1 agonist, but exhibits weak partial agonist effects when istered by itself.[1][2]
151.1 References [1] Griffin, G.; Wray, E.; Rorrer, W.; Crocker, P.; Ryan, W.; Saha, B.; Razdan, R.; Martin, B.; Abood, M. (1999). “An investigation into the structural determinants of cannabinoid receptor ligand efficacy”. British Journal of Pharmacology 126 (7): 1575–1584. doi:10.1038/sj.bjp.0702469. PMC 1565939. PMID 10323589. [2] Griffin, G.; Wray, E.; Martin, B.; Abood, M. (1999). “Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum”. British Journal of Pharmacology 128 (3): 684–688. doi:10.1038/sj.bjp.0702806. PMC 1571656. PMID 10516649.
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Chapter 152
O-823 O-823 is a drug which is a cannabinoid derivative that is used in scientific research. It is described as a mixed agonist/antagonist at the cannabinoid receptor CB1 , meaning that it acts as an antagonist when co-istered alongside a more potent CB1 agonist, but exhibits weak partial agonist effects when istered by itself.[1][2][3]
152.1 References [1] Pertwee RG, Fernando SR, Griffin G, Ryan W, Razdan RK, Compton DR, Martin BR. Agonistantagonist characterization of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol in two isolated tissue preparations. European Journal of Pharmacology. 1996 Nov 14;315(2):195-201. PMID 8960884 [2] Griffin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ, Saha B, Razdan RK, Martin BR, Abood ME. An investigation into the structural determinants of cannabinoid receptor ligand efficacy. British Journal of Pharmacology. 1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469 PMID 10323589 [3] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649
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Chapter 153
Org 27569 Org 27569 is a drug which acts as a potent and selective allosteric modulator of the cannabinoid CB1 receptor. Studies in vitro suggest that it binds to a regulatory site on the CB1 receptor target, causing a conformational change that increases the binding affinity of CB1 agonists such as 55,940, while decreasing the binding affinity of CB1 antagonists or inverse agonists such as rimonabant. However while Org 27569 increases the ability of CB1 agonists to bind to the receptor, it decreases their efficacy at stimulating second messenger signalling once bound, and so in practice behaves as an insurmountable antagonist of CB1 receptor function.[1]
153.1 References [1] Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, McLean A, McIntosh L, Goodwin G, Walker G, Westwood P, Marrs J, Thomson F, Cowley P, Christopoulos A, Pertwee RG, Ross RA (November 2005). “Allosteric modulation of the cannabinoid CB1 receptor”. Molecular Pharmacology 68 (5): 1484–95. doi:10.1124/mol.105.016162. PMID 16113085.
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Chapter 154
Org 28312 Org 28312 is a drug developed by Organon International which acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors. It was developed with the aim of finding a water soluble cannabinoid agonist suitable for intravenous use as an analgesic, but did not proceed to human trials, with the related compound Org 28611 chosen instead due to its better penetration into the brain.[1] The structure-activity relationships of these compounds have subsequently been investigated further leading to the development of a number of more potent analogues, derived by cyclisation around the indole or piperazine rings.[2][3]
154.1 See also • LBP-1 • Org 28611
154.2 References [1] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a. [2] Kiyoi T, York M, Francis S, Edwards D, Walker G, Houghton AK, Cottney JE, Baker J, Adam JM (August 2010). “Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (16): 4918–21. doi:10.1016/j.bmcl.2010.06.067. PMID 20634067. [3] Moir EM, Yoshiizumi K, Cairns J, Cowley P, Ferguson M, Jeremiah F, Kiyoi T, Morphy R, Tierney J, Wishart G, York M, Baker J, Cottney JE, Houghton AK, Mhail P, Osprey A, Walker G, Adam JM (December 2010). “Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (24): 7327–30. doi:10.1016/j.bmcl.2010.10.061. PMID 21074434.
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Chapter 155
Org 28611 Org 28611 (SCH-900,111) is a drug developed by Organon International which acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors. It was developed with the aim of finding a water soluble cannabinoid agonist suitable for intravenous use as an analgesic,[1] and while it achieved this aim and has progressed as far as Phase II clinical trials in humans as both a sedative and an analgesic, results against the comparison drugs (midazolam and morphine respectively) were not particularly favourable in initial testing.[2][3]
155.1 See also • LBP-1 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • Org 28312
155.2 References [1] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a. [2] Zuurman L, ier PC, de Kam M, Kleijn HJ, Cohen AF, van Gerven JM (August 2009). “Pharmacodynamic and pharmacokinetic effects of the intravenously istered CB1 receptor agonist Org 28611 in healthy male volunteers”. Journal of Psychopharmacology (Oxford, England) 23 (6): 633–44. doi:10.1177/0269881108091551. PMID 18635703. [3] A Comparison of Analgesic Efficacy Between a Single Dose of ORG 28611, Morphine, and Placebo After Dental Impaction Surgery
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Chapter 156
Otenabant Otenabant (-945,598) is a drug which acts as a potent and highly selective CB1 antagonist.[1] It was developed by Pfizer for the treatment of obesity,[2] but development for this application has been discontinued following the problems seen during clinical use of the similar drug rimonabant.[3]
156.1 See also • Cannabinoid receptor antagonist
156.2 References [1] Kim, M., et al. (2008), Design, chemical synthesis, and biological evaluation of novel triazolyl analogues of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist, Tetrahedron 64 (48): 10802–10809, doi:10.1016/j.tet.2008.09.057 [2] Woods SC. The endocannabinoid system: novel pathway for cardiometabolic Risk-factor reduction. Journal of the American Academy of Physician Assistants. 2007 Nov;Suppl Endocannabinoid:7-10. PMID 18047036 [3] http://www.pfizer.com
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Chapter 157
Parahexyl Parahexyl (Synhexyl, n-hexyl-Δ3 THC) is a synthetic homologue of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9 -THC, one of the active components of cannabis. [1][2] Parahexyl is similar in both structure and activity to THC, differing only in the position of one double bond, and the lengthening of the 3-pentyl chain by one CH2 group to n-hexyl. [3] Parahexyl produces classic cannabis agonist effects in animals. It has a somewhat higher oral bioavailability than THC itself but is otherwise very similar. [4] Presumably it acts as a CB1 agonist in the same way as THC but as there has been no research published using Parahexyl since the discovery of the CB1 receptor this has not been definitively confirmed.
157.2 See also • Tetrahydrocannabivarin • Tetrahydrocannabinol-C4
157.3 References
Parahexyl was made illegal under UN convention in 1982 on the basis of its structural similarity and similar effects profile to THC, despite never having had any recorded instances of abuse by humans or illicit sale. Parahexyl was placed into the most restrictive Schedule 1 as a compound with no medical use.
157.1 Isomerism
Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6Hbenzo[c]chromen-1-ol. See also: Tetrahydrocannabinol#Isomerism. 207
[1] Adams R, Harfenist M, Loewe S (1949). “New Analogs of Tetrahydrocannabinol. XIX”. J. Am. Chem. Soc. 71 (5): 1624–1628. doi:10.1021/ja01173a023. [2] Ask Dr. Shulgin Online March 7, 2001 [3] Ono M, Shimamine M, Takahashi K, Inoue T (1974). "[Studies on hallucinogens. VII Synthesis of parahexyl]". Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences (in Japanese) 49 (92): 46–50. PMID 4477495. [4] Fairchild MD, Jenden DJ, Mickey MR, Yale C (1980). “EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline”. Pharmacol. Biochem. Behav. 12 (1): 99–105. doi:10.1016/00913057(80)90422-0. PMID 6102770.
Chapter 158
UR-144 UR-144 (TM-018, KM-X1, MN-001, YX-17) is a drug invented by Abbott Laboratories,[1] that acts as a selective full agonist of the peripheral cannabinoid receptor CB2 , but with much lower affinity for the psychoactive CB1 receptor.
drug screens has been developed by Tulip Biolabs, Inc. An Homogeneous Immunoassay that runs on most Clinical Chemistry Analyzers and detects several UR and XLR synthetic cannabinoids has been developed and introduced by Immunalysis Inc. Pomona USA.
158.1 Pharmacology
158.4 See also • AB-001
UR-144 has high affinity for the CB2 receptor with a Kᵢ of 1.8 nM but 83x lower affinity for the CB1 receptor with a Kᵢ of 150 nM.[2] Although a later study found its CB1 affinity to be much higher than previously expected, with a Kᵢ of 28.9nM and an EC50 of 1295nM. Chemically it is closely related to other 2,2,3,3-tetramethylcyclopropyl synthetic cannabinoids like A-796,260 and A-834,735 but with a different substitution on the 1-position of the indole core, in these compounds its 1-pentyl group is replaced with alkylheterocycles like 1-(2-morpholinoethyl) and 1-(tetrahydropyran-4-ylmethyl).
• AM-1221 • 4-HTMPIPO • JTE 7-31 • JWH-018 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • XLR-11
158.5 References
158.2 History of use UR-144 has been detected as an ingredient of synthetic cannabis smoking blends in New Zealand, and subsequently banned from sale as a temporary class drug on 6 April 2012.[3] It has also been encountered in smoking blends and subsequently banned in Russia.[4] The chemical UR-144 has also been banned in the UK in 2013 along with RCS-4 and AM-2201. This is due to two people in Glasgow being itted to hospital after taking a legal high with the chemicals in it. Another person was itted to Brighton hospital after overdosing on the drug.
158.3 Detection A forensic standard of UR-144 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[5] An ELISA immunoassay technique for detecting UR-144 in urine as part of general 208
[1] WO application 2006069196, Pace JM, Tietje K, Dart MJ, Meyer MD, “3-Cycloalkylcarbonyl indoles as cannabinoid receptor ligands”, published 2006-06-29, assigned to Abbott Laboratories [2] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (January 2010). “Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity”. J. Med. Chem. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781. [3] Temporary Class Drug Notices. New Zealand Ministry of Health [4] Sobolevsky T, Prasolov I, Rodchenkov G (October 2012). “Detection of urinary metabolites of AM-2201 and UR144, two novel synthetic cannabinoids”. Drug Test Anal. doi:10.1002/dta.1418. PMID 23042760. [5] Southern Association of Forensic Scientists http://forendex.southernforensic.org/index.php/detail/ index/1218
158.6. FURTHER READING
158.6 Further reading • Poso A, Huffman JW (January 2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. Br. J. Pharmacol. 153 (2): 335–46. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473. • Chin CL, Tovcimak AE, Hradil VP, Seifert TR, Hollingsworth PR, Chandran P, Zhu CZ, Gauvin D, Pai M, Wetter J, Hsieh GC, Honore P, Frost JM, Dart MJ, Meyer MD, Yao BB, Cox BF, Fox GB (January 2008). “Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI”. Br. J. Pharmacol. 153 (2): 367–79. doi:10.1038/sj.bjp.0707506. PMC 2219521. PMID 17965748. • Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Miller LN, Li L, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (March 2008). “Indol3-yl-tetramethylcyclopropyl ketones: effects of indole ring substitution on CB2 cannabinoid receptor activity”. J. Med. Chem. 51 (6): 1904–12. doi:10.1021/jm7011613. PMID 18311894.
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Chapter 159
Perrottetinene Perrottetinene is a naturally occurring cannabinoid compound found in the New Zealand liverwort plant Radula marginata and other species from the Radula genus,[1] along with a number of similar compounds. Its chemical structure closely resembles that of THC, the main active component of marijuana, and it is thought that perrottetinene may also be an active cannabinoid agonist although detailed pharmacological investigation of the compound has yet to be reported.[2][3] Stereoselective synthesis of perrottinene has also been carried out to investigate the activity of its different enantiomers.[4]
159.1 References [1] Cullmann F, Becker H. Prenylated bibenzyls from the liverwort Radula laxiramea. Zeitschrift Fur Naturforschung. 1999; 54(3-4): 147-150. ISSN 09395075 [2] Toyota M, Kinugawa T, Asakawa Y. Bibenzyl Cannabinoid and Bisbibenzyl Derivative from the Liverwort Radula perrottetii. Phytochemistry 1994; 37(3):859-862. [3] Toyota M, Shimamura T, Ishii H, Renner M, Braggins J, Asakawa Y. New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata. Chemical and Pharmaceutical Bulletin (Tokyo). 2002 Oct;50(10):1390-2. PMID 12372871 [4] Song Y, Hwang S, Gong P, Kim D, Kim S. Stereoselective total synthesis of (-)-perrottetinene and assignment of its absolute configuration. Organic Letters. 2008 Jan 17;10(2):269-71. PMID 18085788
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Chapter 160
PF-03550096 PF-03550096 is a drug that acts as a potent agonist for the CB2 cannabinoid receptor, with good selectivity over CB1 having Kᵢ values of 7nM at CB2 and 1500nM at CB1 . It was originally developed by Pfizer in 2008 as a medication for irritable bowel syndrome,[1] but has only progressed to animal studies.[2]
160.1 See also • AB-FUBINACA • AB-PINACA
160.2 References [1] Ando K et al, BENZIMIDAZOLONE DERIVATIVES. WO 2008/032164 [2] Kikuchi, A.; Ohashi, K.; Sugie, Y.; Sugimoto, H.; Omura, H. (2008). “Pharmacological evaluation of a novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro and in vivo by using a rat model of visceral hypersensitivity”. Journal of pharmacological sciences 106 (2): 219– 224. doi:10.1254/jphs.FP0071599. PMID 18270474.
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Chapter 161
PF-514273 PF-514273 is a drug developed by Pfizer, which acts as an extremely selective antagonist for the CB1 receptor, with approximately 10,000x selectivity over the closely related CB2 receptor. This very high selectivity makes it useful for scientific research into these receptors, as many commonly used cannabinoid receptor antagonists also block the CB2 receptor to some extent.[1]
161.1 References [1] Dow RL, Carpino PA, Hadcock JR, Black SC, Iredale PA, DaSilva-Jardine P, Schneider SR, Paight ES, Griffith DA, Scott DO, O'Connor RE, Nduaka CI. Discovery of 2-(2-chlorophenyl)−3-(4-chlorophenyl)−7(2,2-difluoropropyl)−6,7-dihydro-2H-pyrazolo[3,4f][1,4]oxazepin-8(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity. Journal of Medicinal Chemistry. 2009 May 14;52(9):2652-5. PMID 19351113
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Chapter 162
PipISB PipISB is a drug used in scientific research which acts as a potent and selective inverse agonist of the cannabinoid receptor CB1 . It is highly selective for the CB1 receptor over CB2 , with a K at CB1 of 1.5nM vs over 7000nM at CB2 , has good blood-brain barrier penetration, and can be conveniently radiolabelled with either 11 C or 18 F, making it useful for mapping the distribution of CB1 receptors in the brain.[1][2]
162.1 References [1] Donohue, Sean R.; Halldin, Christer; Schou, Magnus; Hong, Jinsoo; Phebus, Lee; Chernet, Eyassu; Hitchcock, Stephen A.; Gardinier, Kevin M.; Ruley, Kevin M.; Krushinski, Joseph H.; Schaus, John; Pike, Victor W. (2008). “Radiolabeling of a high potency cannabinoid subtype-1 receptor inverse agonist, N-(4-fluoro-benzyl)−4-(3-(piperidin-1-yl-indole-1sulfonyl)benzamide (PipISB), with carbon-11 or fluorine18”. Journal of Labelled Compounds and Radiopharmaceuticals 51 (3): 146. doi:10.1002/jlcr.1491. [2] Finnema, S. J.; Donohue, S. R.; Zoghbi, S. S.; Brown, A. K.; Gulyás, B. Z.; Innis, R. B.; Halldin, C.; Pike, V. W. (2009). “Evaluation of \11C]PipISB and \18F]PipISB in monkey as candidate radioligands for imaging brain cannabinoid type-1 receptors in vivo”. Synapse 63 (1): 22–30. doi:10.1002/syn.20578. PMC 2587077. PMID 18925657.
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Chapter 163
Pirnabine Pirnabine (SP-304) is a synthetic cannabinoid receptor ligand, which was developed for the treatment of glaucoma.[1]
163.1 References [1]
214
Chapter 164
PSB-SB-1202 PSB-SB-1202 is a coumarin derivative which is an agonist at the cannabinoid receptors CB1 and CB2 , with a CB1 Ki of 32nM and a CB2 Ki of 49nM.[1] It is also a weak antagonist at the related receptor GPR55, with an IC50 of 6350nM, but has no significant affinity for GPR18.[2]
164.1 See also • PSB-SB-487
164.2 References [1] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I, Nieger M, Wenzel W, Bräse S, Müller CE. 7-Alkyl-3benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists. Journal of Medicinal Chemistry. 2012 Sep 27;55(18):7967-77. PMID 22916707 [2] Rempel, V.; Volz, N.; Gläser, F.; Nieger, M.; Bräse, S.; Müller, C. E. (2013). “Antagonists for the orphan G protein-coupled receptor GPR55 based on a coumarin scaffold”. Journal of Medicinal Chemistry 56 (11): 130516144836005. doi:10.1021/jm4005175. PMID 23679955.
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Chapter 165
PSB-SB-487 PSB-SB-487 is a coumarin derivative which is an antagonist at the former orphan receptor GPR55. Unlike older GPR55 antagonists such as O-1918, PSB-SB-487 has good selectivity over the related receptor GPR18, with an IC50 of 113nM at GPR55 vs 12500nM at GPR18.[1] However it has poorer selectivity over other related receptors, acting as a weak antagonist at CB1 with a Ki of 1170nM, and a partial agonist at CB2 with a Ki of 292nM.[2]
165.1 See also • PSB-SB-1202
165.2 References [1] Rempel, V.; Volz, N.; Gläser, F.; Nieger, M.; Bräse, S.; Müller, C. E. (2013). “Antagonists for the orphan G protein-coupled receptor GPR55 based on a coumarin scaffold”. Journal of Medicinal Chemistry 56 (11): 130516144836005. doi:10.1021/jm4005175. PMID 23679955. [2] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I, Nieger M, Wenzel W, Bräse S, Müller CE. 7-Alkyl-3benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists. Journal of Medicinal Chemistry. 2012 Sep 27;55(18):7967-77. PMID 22916707
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Chapter 166
QUCHIC QUCHIC (BB-22 or 1-(cyclohexylmethyl)−1Hindole-3-carboxylic acid 8-quinolinyl ester) is a designer drug offered by online vendors as a cannabimimetic agent, and was first detected being sold in synthetic cannabis products in Japan in early 2013,[1] and subsequently also in New Zealand.[2] The structure of QUCHIC appears to utilise an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. QUCHIC, along with QUPIC, represents a structurally unique synthetic cannabinoid chemotype since it contains an ester linker at the indole 3-position rather than the precedented ketone of JWH-018 and its analogues, or the amide of SDB-001 and its analogues. No information regarding the in vitro or in vivo activity of QUCHIC has been published, and only anecdotal reports are known of its pharmacology in humans or other animals.
166.1 See also • 5F-PB-22 • JWH-018 • PB-22 • QUPIC • SDB-001
166.2 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Dunne bans further two substances found in K2. Press Release: New Zealand Government. Tuesday, 30 April 2013
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Chapter 167
QUPIC QUPIC (PB-22 or 1-pentyl-1H-indole-3-carboxylic acid 8-quinolinyl ester) is a designer drug offered by online vendors as a cannabimimetic agent, and detected being sold in synthetic cannabis products in Japan in 2013.[1] The structure of QUPIC appears to use an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. QUPIC represents a structurally unique synthetic cannabinoid chemotype, since it contains an ester linker at the indole 3-position, rather than the precedented ketone of JWH-018 and its analogs, or the amide of SDB-001 and its analogs. No information regarding the in vitro activity of QUPIC has been published, however one in vivo study found PB-22 to cause seizures in humans and dogs.[2] QUPIC is an analog of JWH-018 which differs by having 8-hydroxyquinoline replacing the naphthalene group of JWH-018. QUPIC is now found in many herbal incense and potpourri products.
• SDB-001
167.4 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Gugelmann, H; Gerona, R; Li, C; Tsutaoka, B; Olson, KR; Lung, D (2014). "'Crazy Monkey' Poisons Man and Dog: Human and canine seizures due to PB-22, a novel synthetic cannabinoid.”. Clinical Toxicology 52 (6): 635–8. doi:10.3109/15563650.2014.925562. PMID 24905571. [3] Forendex entry, Southern Association of Forensic Scientists
167.1 Detection A forensic standard of PB-22 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[3]
[4] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G; Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C (2014). “Four Postmortem Case Reports with Quantitative Detection of the Synthetic Cannabinoid, 5F-PB-22”. Journal of analytical toxicology. doi:10.1093/jat/bku048. PMID 24876364.
167.2 Legal status
[5] “PB-22 and 5F-PB-22”. Drug Enforcement istration, Office of Diversion Control.
As of 9 May 2014, PB-22 is no longer legal in New Zealand.
[6] Jeremy Pelzer (April 17, 2014). “Ohio bans two synthetic marijuana drugs sold as “herbal incense"". cleveland.com.
In January 2014, QUPIC was designated as a Schedule I controlled substance in the United States.[4][5]
[7] “Statutes & Constitution :View Statutes : Online Sunshine”. Leg.state.fl.us. 1997-05-06. Retrieved 2014-0712.
In Ohio, QUPIC is illegal.[6] Florida also has banned QUPIC/P-22.[7]
167.3 See also • 5F-PB-22 • QUCHIC 218
Chapter 168
Rimonabant Rimonabant (also known as SR141716; trade name Acomplia) is an anorectic antiobesity drug that has been withdrawn from the market due to potentially serious side effects. It was approved for use in Europe and other countries, but never approved in the United States. Rimonabant is an inverse agonist for the cannabinoid receptor CB1.[3] Its main effect is reduction in appetite.
168.1 History
the anti-obesity treatment for approval.[2] Subsequently, Sanofi-Aventis announced it was suspending the new drug application (NDA) for rimonabant, and that it would resubmit an application at some point in the future. The EU’s approval was not a blanket approval, nor did it approve Acomplia for nonobesity-related problems, such as smoking cessation, although off-label use of the drug was still possible. The approval was, in combination with diet and exercise, for the treatment of obese patients (BMI greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.
See also: Discovery and development of Cannabinoid In October 2008, the European Medicines Agency's Receptor 1 Antagonists Committee for Medicinal Products for Human Use (CHMP) had determined that the risks of Acomplia outRimonabant was the first selective CB1 receptor blocker weighed its benefits. The Agency subsequently recomto be approved for use anywhere in the world. In Europe, mended that the product be suspended from the UK marit was indicated for use in conjunction with diet and ex- ket, and that doctors not prescribe the drug due to the risk ercise for patients with a body mass index (BMI) greater of serious psychiatric problems, and even suicide. Sanofithan 30 kg/m², or patients with a BMI greater than 27 Aventis then suspended sale of the drug.[1][6][7] Approval kg/m² with associated risk factors, such as type 2 diabetes of the drug was officially withdrawn by the European or dyslipidaemia. In the UK, it was available beginning Medicines Agency on 16 January 2009.[8] in July 2006. As of 2008, the drug was available in 56 India has prohibited the manufacture and sale of the countries. drug.[9] On 21 June 2006, the European Commission approved the sale of rimonabant in the then-25-member European Union. Pharmaceutical company Sanofi-Aventis, (which changed its name to Sanofi in 2011) announced the first country in which Acomplia would be sold was the United Kingdom as a prescription drug. Sales began in July 2006. Sanofi-Aventis also projected that the drug would 168.2 Uses/potential uses be sold shortly thereafter in Denmark, Ireland, , Finland, and Norway. It was expected in Belgium[4] and Sweden in 2007. Ordinary obesity would, according to 168.2.1 Obesity official medical recommendations, not be enough to acquire the prescription in Sweden; there would be ad- In a 2006 (2 year) study reported in JAMA, “Compared ditional requirements concerning abnormal blood lipid with the placebo group, the 20 mg of rimonabant group levels.[5] produced greater mean (SEM) reductions in weight (−6.3 Rimonabant was submitted to the Food and Drug istration (FDA) for approval in the United States. However, in 2007, the FDA’s Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending
[0.2] kg vs −1.6 [0.2] kg; P<.001), waist circumference (−6.1 [0.2] cm vs −2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, −5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001).” [10]
219
220
168.2.2
CHAPTER 168. RIMONABANT
Smoking cessation
Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapy. The Studies with Rimonabant and Tobacco Use (STRATUS) program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy. According to a Cochrane Collaboration review in 2007, rimonabant “may increase the odds of quitting approximately 11/2-fold”.[11]
168.4 Negative side effects Shortly after market introduction, press reports and independent studies suggested that side effects occurred more intensely and more commonly than had been found by the manufacturer in their clinical studies. Reports of severe depression and suicidal thoughts were frequent.[18] As the drug’s target CB1 receptors are fairly ubiquitous throughout the central nervous system, it is not currently understood where the inverse agonist is acting to cause these side-effects. In 2007, it was reported that the committee advising the U.S. FDA had voted not to recommend the drug’s approval because of concerns over suicidality, depression, and other related side effects associated with use of the drug.[19]
168.5 Preparation 168.2.3
Addiction behaviors
Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans: priming and cues. It may also reduce ethanol- and opiate-seeking behavior.[12]
168.2.4
The chemical synthesis of rimonabant is described as follows:[20]
Short-term memory
Tetrahydrocannabinol (THC) is known to impair shortterm memory. It was therefore hypothesised that rimonabant may reduce or inhibit the atrophic effects of cannabinoids. Indeed, in animal studies, it significantly improved the ability of rats to encode information into short-term memory.[13]
168.2.5
Blockage of cannabis effects
Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9 -tetrahydrocannabinol (THC) in humans without affecting the pharmacokinetics.[14] Rimonabant has been described colloquially as “reverse marijuana”, having a depressing effect on appetite inverse to the increased appetite created by cannabinoids.[15]
168.3 Other effects Rimonabant reduces voluntary wheel running in laboratory mice.[16] Rimonabant significantly increased human sperm motility and viability in vitro.[17]
168.6 Brand names Brand names for rimonabant include Acomplia, Bethin, Monaslim, Remonabent, Riobant, Slimona, and Rimoslim. The proposed brand name if it had been approved for use in the United States was Zimulti.
168.7 References [1] “Anti-obesity drug use suspended”. BBC News. 23 October 2008. Retrieved 4 March 2010.
168.7. REFERENCES
[2] “Zimulti Acomplia Report - Diet Drug Acomplia / Zimulti Gets Thumbs Down From FDA ”. Acompliareport.com. 2007-06-13. Retrieved 2010-03-19. [3] Fong TM, Heymsfield SB (September 2009). “Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions”. Int J Obes (Lond) 33 (9): 947–55. doi:10.1038/ijo.2009.132. PMID 19597516.
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[16] Keeney BK, et al. (2008). “Differential response to a selective cannabinoid receptor antagonist (SR141716: rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behavior”. Behavioural Pharmacology 19 (8): 812– 820. doi:10.1097/FBP.0b013e32831c3b6b. PMID 19020416.
[4] Auteur: Femke Gebruers. “Article from the Belgian newspaper De Standaard”. Standaard.be. Retrieved 2010-03-19.
[17] Aguila S, et al. (2010). “Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm”. Br J Pharmacol 159 (4): 831–41. doi:10.1111/j.1476-5381.2009.00570.x. PMC 2829209. PMID 20067470.
[5] “Article from the Swedish TV station TV 4 website”. Tv4.se. 2008-03-06. Retrieved 2010-03-19.
[18] “Kassen müssen nicht für “Acomplia” zahlen”. tagesschau.de. 2006-10-17. Retrieved 2007-06-13.
[6] “European Medicines Agency”. Ema.europa.eu/ema/. 2010-02-15. Retrieved 2010-03-19.
[19] “Suicide risk fears over diet pill”. BBC News. 15 June 2007. Retrieved 4 March 2010.
[7] “Sanofi-aventis - A diversified healthcare company, focused on patients’ needs”. En.sanofi-aventis.com. Retrieved 2010-03-19.
[20] Yoshioka, T., et al. (1989). “Studies on hindered phenols and analogs. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation”. Journal of Medicinal Chemistry 32 (2): 421. doi:10.1021/jm00122a022. PMID 2913302.
[8] “Microsoft Word - Zimulti _Rimonabant_ Public Statement” (PDF). Retrieved 2010-03-19. [9] “Drugs banned in India”. Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Retrieved 2013-09-17. [10] JAMA. 2006 Feb 15;295(7):761-75. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J; RIO-North America Study Group. PMID 16478899 [11] Cahill K, Ussher M (2007). Cahill, Kate, ed. “Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation”. Cochrane database of systematic reviews (Online) (4): CD005353. doi:10.1002/14651858.CD005353.pub3. PMID 17943852. [12] Maldonado R, Valverde O, Berrendero F (2006). “Involvement of the endocannabinoid system in drug addiction”. Trends Neurosci. 29 (4): 225–32. doi:10.1016/j.tins.2006.01.008. PMID 16483675. [13] Deadwyler SA, Goonawardena AV, Hampson RE (2007). “Short-term memory is modulated by the spontaneous release of endocannabinoids: evidence from hippocampal population codes”. Behavioural Pharmacology 18 (5–6): 571–80. doi:10.1097/FBP.0b013e3282ee2adb. PMID 17762525. [14] Huestis MA, et al. (2001). “Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716”. Arch. Gen. Psychiatry 58 (4): 322–8. doi:10.1001/archpsyc.58.4.322. PMID 11296091. [15] Stephan Guyenet, PhD (9 March 2012) Seduced by Food: Obesity and the Human Brain Boing Boing
Chapter 169
Rosonabant Rosonabant (INN; E-6776) is a drug acting as a CB1 receptor antagonist/inverse agonist that was under investigation by Esteve as an appetite suppressant for the treatment of obesity.[1][2] Development of the drug for clinical use was apparently halted shortly after the related CB1 antagonist rimonabant was discontinued, likely due to the reports of severe psychiatric adverse effects such as anxiety, depression, and suicidal ideation associated with it and with similarly-acting agents.[3][4]
169.1 See also • Cannabinoid receptor antagonist
169.2 References [1] Janero DR, Makriyannis A (March 2009). “Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis”. Expert Opinion on Emerging Drugs 14 (1): 43–65. doi:10.1517/14728210902736568. PMID 19249987. [2] Tim C. Kirkham; S. J. Cooper (2007). Appetite and Body Weight: Integrative Systems and the Development of AntiObesity Drugs. Academic Press. p. 325. ISBN 978-0-12370633-1. Retrieved 12 May 2012. [3] Heal DJ, Gosden J, Smith SL (December 2009). “Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders”. British Journal of Clinical Pharmacology 68 (6): 861–74. doi:10.1111/j.13652125.2009.03549.x. PMC 2810797. PMID 20002080. [4] Lee HK, Choi EB, Pak CS (2009). “The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents”. Current Topics in Medicinal Chemistry 9 (6): 482–503. doi:10.2174/156802609788897844. PMID 19689362.
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Chapter 170
S-444,823 S-444,823 is a drug developed by Shionogi which is a cannabinoid agonist.[1] It was developed as an antipruritic, and has moderate selectivity for the CB2 subtype, having a CB2 affinity of 18nM, and 32x selectivity over the CB1 receptor. In animal studies it showed analgesic effects and strongly reduced itching responses, but without producing side effects such as sedation and catalepsy that are seen with centrally acting CB1 agonists.[2]
170.1 See also • JTE 7-31
170.2 References [1] Arimura A. Novel Use of Cannabinoid Receptor Agonist. Patent WO 2005/016351 [2] Odan M, et al. Discovery of S-444823, a potent CB1/CB2 dual agonist as an antipruritic agent. Bioorganic and Medicinal Chemistry Letters. 2012 Apr 15;22(8):2898901. PMID 22421019
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Chapter 171
SDB-001 This article is about the cannabinoid drug. For the South Korean girl band, see 2NE1. For the metabotropic glutamate receptor antagonist, see APICA (drug). SDB-001 (2NE1, APICA, N-(1-adamantyl)−1pentyl-1H-indole-3-carboxamide) is a drug that acts as a potent agonist for the cannabinoid receptors. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in Japan in March 2012 as an ingredient in synthetic cannabis smoking blends, along with a related compound APINACA (sold as “AKB48”).[1] Structurally it closely resembles cannabinoid compounds from patent WO 2003/035005 but with an indole core instead of indazole, and a simple pentyl chain on the indole 1-position. Pharmacological testing determined SDB-001 to have an IC50 of 175nM at CB1 , only slightly less potent than JWH-018 which had an IC50 of 169nM, but over four times more tightly binding than AKB48, which had an IC50 of 824nM.[2] The first published synthesis and pharmacological evaluation of SDB-001 revealed that it acts as a full agonist at CB1 (EC50 = 34 nM) and CB2 receptors (EC50 = 29 nM).[3] Furthermore, SDB-001 possesses cannabis-like effects in rats, and appears to be less potent than JWH-018 but more potent than THC.[3]
171.1 See also • AB-001 • QUCHIC • JWH-018 • SDB-006 • STS-135 (drug)
171.2 References [1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “Identification of two newtype synthetic cannabinoids, N-(1-adamantyl)−1pentyl-1H-indole-3-carboxamide (APICA) and N-(1-
224
adamantyl)−1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products”. Forensic Toxicology 30 (2): 114. doi:10.1007/s11419-012-01367. [2] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [3] Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. (2013). “The synthesis and pharmacological evaluation of adamantanederived indoles: Novel cannabimimetic drugs of abuse”. ACS Chemical Neuroscience 4 (7): 130403084729007. doi:10.1021/cn400035r.
Chapter 172
SDB-006 SDB-006 is a drug that acts as a potent agonist for the cannabinoid receptors, with an EC50 for CB1 activation of 19nM, and 7x selectivity for CB1 over CB2 . It was discovered during research into the related compound SDB001 which had been sold illicitly as “2NE1”.[1]
172.1 See also • APINACA • SDB-001 • STS-135_(drug)
172.2 References [1] Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. (2013). “The synthesis and pharmacological evaluation of adamantanederived indoles: Novel cannabimimetic drugs of abuse”. ACS Chemical Neuroscience 4 (7): 130403084729007. doi:10.1021/cn400035r.
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Chapter 173
SER-601 SER-601 (COR-167) is a drug which acts as a potent and selective cannabinoid CB2 receptor agonist, based on a quinolone−3-carboxylic acid core structure, with 190x selectivity for CB2 over the related CB1 receptor. It has analgesic effects in animal studies, as well as neuroprotective effects,[1] but without cannabis-like behavioural effects due to its low affinity for CB1 .[2] A number of related compounds are known, almost all of which have high selectivity for CB2 .[3]
173.1 See also • A-836,339 • CBS-0550
173.2 References [1] Contartese, A.; Valoti, M.; Corelli, F.; Pasquini, S.; Mugnaini, C.; Pessina, F.; Aldinucci, C.; Sgaragli, G.; Frosini, M. (2012). “A novel CB2 agonist, COR167, potently protects rat brain cortical slices against OGD and reperfusion injury”. Pharmacological Research 66 (6): 555–563. doi:10.1016/j.phrs.2012.08.003. PMID 23036353. [2] Pasquini S,et al. (August 2008). “Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo”. Journal of Medicinal Chemistry 51 (16): 5075–84. doi:10.1021/jm800552f. PMID 18680276. [3] Pasquini S,et al. (August 2010). “Investigations on the 4-quinolone-3-carboxylic acid motif. 3. Synthesis, structure-affinity relationships, and pharmacological characterization of 6-substituted 4-quinolone-3carboxamides as highly selective cannabinoid-2 receptor ligands”. Journal of Medicinal Chemistry 53 (16): 5915– 28. doi:10.1021/jm100123x. PMID 20718492.
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Chapter 174
Serinolamide A Serinolamide A is a naturally occurring eicosanoid derivative related to anandamide, which has been isolated from the marine cyanobacteria Lyngbya majuscula and related species in the Oscillatoria family. Testing established that serinolamide A is an active cannabinoid agonist with moderate potency, having a Ki of 1300nM at CB1 and 5x selectivity over the related CB2 receptor.[1]
174.1 See also • Methanandamide • O-1812 • Perrottetinene
174.2 References [1] Gutiérrez, M.; Pereira, A. R.; Debonsi, H. M.; Ligresti, A.; Di Marzo, V.; Gerwick, W. H. (2011). “Cannabinomimetic Lipid from a Marine Cyanobacterium”. Journal of Natural Products 74 (10): 2313– 2317. doi:10.1021/np200610t. PMC 3325759. PMID 21999614.
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Chapter 175
SR-144,528 SR144528 is a drug that acts as a potent and highly selective CB2 receptor inverse agonist, with a Kᵢ of 0.6nM at CB2 and 400nM at the related CB1 receptor.[1][2] It is used in scientific research for investigating the function of the CB2 receptor,[3][4][5] as well as for studying the effects of CB1 receptors in isolation, as few CB1 agonists that do not also show significant activity as CB2 agonists are available.[6][7][8] It has also been found to be an inhibitor of acyl-coenzymeA:cholesterol acyltransferase, an effect that appears to be independent from its action on CB2 receptors.[9]
175.1 See also
747–57. doi:10.1016/S0306-4522(03)00126-X. PMID 12809695. [5] Páldy E, et al. (December 2008). “CB(2) cannabinoid receptor antagonist SR144528 decreases mu-opioid receptor expression and activation in mouse brainstem: role of CB(2) receptor in pain”. Neurochemistry International 53 (6-8): 309–16. doi:10.1016/j.neuint.2008.08.005. PMID 18804501. [6] Lay L, Angus JA, Wright CE (March 2000). “Pharmacological characterisation of cannabinoid CB(1) receptors in the rat and mouse”. European Journal of Pharmacology 391 (1-2): 151–61. doi:10.1016/S0014-2999(00)000625. PMID 10720647. [7] Germanò MP, et al. (February 2001). “Cannabinoid CB1-mediated inhibition of stress-induced gastric ulcers in rats”. Naunyn-Schmiedeberg’s Archives of Pharmacology 363 (2): 241–4. doi:10.1007/s002100000360. PMID 11218077.
• NESS-040C5 • SR141716 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
[8] Abalo R, et al. (June 2010). “The cannabinoid antagonist SR144528 enhances the acute effect of WIN 55,212-2 on gastrointestinal motility in the rat”. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society 22 (6): 694– e206. doi:10.1111/j.1365-2982.2009.01466.x. PMID 20132133.
175.2 References [1] Rinaldi-Carmona M, et al. (February 1998). “SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor”. The Journal of Pharmacology and Experimental Therapeutics 284 (2): 644–50. PMID 9454810. [2] Portier M, et al. (February 1999). “SR 144528, an antagonist for the peripheral cannabinoid receptor that behaves as an inverse agonist”. The Journal of Pharmacology and Experimental Therapeutics 288 (2): 582–9. PMID 9918562. [3] Gouldson P, et al. (July 2000). “Mutational analysis and molecular modelling of the antagonist SR 144528 binding site on the human cannabinoid CB(2) receptor”. European Journal of Pharmacology 401 (1): 17–25. doi:10.1016/S0014-2999(00)00439-8. PMID 10915832. [4] Nackley AG, Makriyannis A, Hohmann AG (2003). “Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation”. Neuroscience 119 (3):
228
[9] Thewke D, et al. (April 2009). “AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors”. Biochemical and Biophysical Research Communications 381 (2): 181–6. doi:10.1016/j.bbrc.2009.02.020. PMC 2665256. PMID 19338772.
Chapter 176
Stearoylethanolamide Stearoylethanolamide (SEA) is an endocannabinoid neurotransmitter.
176.1 References Binding, degradation and apoptotic activity stearoylethanolamide in rat C6 glioma cells
of
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Chapter 177
STS-135 (drug) STS-135 (N-(adamantan-1-yl)−1-(5fluoropentyl)−1H-indole-3-carboxamide) is a designer drug offered by online vendors as a cannabimimetic agent. The structure of STS-135 appears to utilise an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. STS-135 is the terminally-fluorinated analogue of SDB-001, just as AM-2201 is the terminally-fluorinated analogue of JWH-018, and XLR-11 is the terminally-fluorinated analogue of UR-144. No information regarding the in vitro or in vivo activity of STS-135 has been published, and only anecdotal reports are known of its pharmacology in humans or other animals.
177.1 Detection A forensic standard of STS-135 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[1]
177.2 See also • AB-001 • APINACA • AM-2201 • JWH-018 • SDB-001
177.3 References [1] Southern Association of Forensic Scientists
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Chapter 178
Surinabant Surinabant (SR147778) is a cannabinoid receptor type 1 antagonist developed by Sanofi-Aventis.[1] It is being investigated as a potential treatment for nicotine addiction, to assist smoking cessation. It may also be developed as an anorectic drug to assist with weight loss, however there are already several CB1 antagonists or inverse agonists on the market or under development for this application,[2] so surinabant is at present mainly being developed as an anti-smoking drug,[3] with possible application in the treatment of other addictive disorders such as alcoholism.[4][5] Other potential applications such as treatment of ADHD have also been proposed.[6]
178.1 See also • Cannabinoid receptor antagonist • O-1269
178.2 References [1] Rinaldi-Carmona M, Barth F, Congy C, Martinez S, Oustric D, Pério A, Poncelet M, Maruani J, Arnone M, Finance O, Soubrié P, Le Fur G. SR147778 [5-(4-bromophenyl)−1-(2,4-dichlorophenyl)−4-ethylN-(1-piperidinyl)−1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization. Journal of Pharmacology and Experimental Therapeutics. 2004 Sep;310(3):905-14. PMID 15131245 [2] Doggrell SA. Will the new CB1 cannabinoid receptor antagonist SR-147778 have advantages over rimonabant? Expert Opinion on Investigational Drugs. 2005 Mar;14(3):339-42. PMID 15833065 [3] Lamota L, Bermudez-Silva FJ, Marco EM, Llorente R, Gallego A, Rodríguez de Fonseca F, Viveros MP. Effects of adolescent nicotine and SR 147778 (Surinabant) istration on food intake, somatic growth and metabolic parameters in rats. Neuropharmacology. 2008 Jan;54(1):194-205. PMID 17720206 [4] Gessa GL, Serra S, Vacca G, Carai MA, Colombo G. Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational prop-
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erties of alcohol in alcohol-preferring sP rats. Alcohol and Alcoholism. 2005 Jan-Feb;40(1):46-53. PMID 15582988 [5] Lallemand F, De Witte P. SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats. Alcohol. 2006 Jul;39(3):125-34. PMID 17127132 [6] Louis C, Terranova JP, Decobert M, Bizot JC, Francon D, Alonso R, Cohen C, Griebel G. Surinabant, a new CB1 receptor antagonist, displays efficacy in animal models of attention deficit/hyperactivity disorder. Behavioural Pharmacology 2005; 16:S42.
Chapter 179
Taranabant Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 inverse agonist being investigated as a potential treatment for obesity due to its anorectic effects.[1][2] It was discovered by Merck & Co. In October 2008, Merck has stopped its phase III clinical trials with the drugs due to high level of central side effects, mainly depression and anxiety.[3][4][5][6]
179.1 See also • Cannabinoid receptor antagonist
179.2 References [1] Armstrong HE, Galka A, Lin LS, Lanza TJ Jr, Jewell JP, Shah SK, et al. “Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists.” Bioorganic & Medicinal Chemistry Letters. 2007 Apr 15;17(8):21847. PMID 17293109. doi:10.1016/j.bmcl.2007.01.087 [2] Fong TM, Guan XM, Marsh DJ, Shen , Stribling DS, Rosko KM, et al. “Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)−3-(4-chlorophenyl)−2-(3-cyanophenyl)−1methylpropyl]−2-methyl-2-[[5-(trifluoromethyl)pyridin2-yl]oxy]propanamide (MK-0364), in rodents.” Journal of Pharmacology and Experimental Therapeutics. 2007 Jun;321(3):1013-22. PMID 17327489. doi:10.1124/jpet.106.118737 [3] “Press release by Merck”. Retrieved October 2008. [4] Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N, Suryawanshi S, Molony C, Sieberts S, Nayee J, Meehan AG, Shapiro D, Heymsfield SB, Kaufman KD, Amatruda JM (May 2010). “A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study”. International Journal of Obesity (2005) 34 (5): 919–35. doi:10.1038/ijo.2010.21. PMID 20157323. [5] Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T, Erondu N, Shentu Y, Lu K, Suryawanshi S, Chou M, Johnson-Levonas AO, Heymsfield SB, Shapiro D, Kaufman KD, Amatruda JM (June 2010). “A one-year study
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to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes”. Diabetes, Obesity & Metabolism 12 (6): 517–31. doi:10.1111/j.1463-1326.2009.01188.x. PMID 20518807. [6] Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q, Suryawanshi S, Jones ME, Johnson-Levonas AO, Heymsfield SB, Kaufman KD, Amatruda JM (August 2010). “A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study”. International Journal of Obesity (2005) 34 (8): 1243–54. doi:10.1038/ijo.2010.38. PMID 20212496.
Chapter 180
Tedalinab Tedalinab (GRC-10693) is a drug developed by Glenmark Pharmaceuticals for the treatment of osteoarthritis and neuropathic pain, which acts as a potent and selective cannabinoid CB2 receptor agonist. It has a very high selectivity of 4700x for CB2 over the related CB1 receptor, has good oral bioavailability and has shown promising safety results and effective analgesic and antiinflammatory actions in early clinical trials.[1] A large number of related compounds are known, most of which also show high CB2 selectivity.[2]
180.1 See also • CBS-0550 • SER-601
180.2 References [1] Glenmark’s Molecule for Neuropathic Pain, Osteoarthritis - GRC 10693, Successfully Completes Phase I Trials. April 13, 2009. [2] Glenmark Pharmaceuticals. NOVEL CANNABINOID RECEPTOR LIGANDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS FOR THEIR PREPARATION, Filed June 1st, 2006. WO 2006/129178.
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Chapter 181
Tetrad test The tetrad test is a series of behavioral paradigms in which rodents treated with cannabinoids such as THC show effects.[1] It is widely used for screening drugs that induce cannabinoid receptor-mediated effects in rodents. The four behavioral components of the tetrad are spontaneous activity, catalepsy, hypothermia, and analgesia. Common assays for these behavioral paradigms are as follows:
181.1 References
• Spontaneous activity (or hypomotility) is determined by an open field test, in which a mouse is placed in a cage with perpendicular grid lines, usually spaced by approx. 1 inch. An experimenter counts the number of line crossings by the mouse in a given amount of time. • Catalepsy is determined by the bar test. The mouse is placed on a bar oriented parallel to and approximately 1 inch off of the ground. If the mouse remains immobile on the bar for typically more than 20 seconds, it is considered cataleptic. • Hypothermia is determined by using a rectal probe to measure the rectal temperature. • Analgesia is usually determined by the hot plate or tail immersion test. In the hot plate test, the mouse is placed on a heated plate, typically between 54 and 58°C. An experimenter measures the time it takes for the mouse to jump off of the hot plate. In the tail immersion test, the mouse is immobilized and its tail is placed into a warm water bath, typically also between 54 and 58°C. An experimenter measures the time it takes for the mouse to remove its tail from the water bath. Direct CB1 agonists, such as THC (the psychoactive component of marijuana), or WIN 55,212-2, have effects in all components of the tetrad and induce hypomotility, catalepsy, hypothermia, and analgesia in rodents. Accordingly, all true “tetrad effects” are not observed following treatment with antagonists of CB1 such as rimonabant. 234
[1] Little, P.J.; Compton, D.R.; Johnson, M.R.; Melvin, L.S.; Martin, B.R. (1988). Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. J Pharmacol Exp Ther 247: 1046–51.
Chapter 182
Tetrahydrocannabinol “THC” redirects here. For other uses, see THC (disam- the periaqueductal gray.[16] Other effects include relaxbiguation). ation, alteration of visual, auditory, and olfactory senses, fatigue, and appetite stimulation. THC has marked antiemetic properties. It may acutely reduce aggression Tetrahydrocannabinol (THC), or more precisely and increase aggression during withdrawal.[17] 9 its main isomer (−)-trans-Δ -tetrahydrocannabinol ( (6aR,10aR)-delta-9-tetrahydrocannabinol), is the principal psychoactive constituent (or cannabinoid) of the cannabis plant. First isolated in 1964 by Israeli scientists Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science[8][9][10] it is a water-clear glassy solid when cold, which becomes viscous and sticky if warmed. A pharmaceutical formulation of (−)-trans-Δ9 -tetrahydrocannabinol, known by its INN dronabinol, is available by prescription in the U.S. and Canada under the brand name Marinol. An aromatic terpenoid, THC has a very low solubility in water, but good solubility in most organic solvents, specifically lipids and alcohols.[7] Along with CBD, CBN, CBC, CBG and other 80 molecules make up the phytocannabinoid family, found in different quantities in Cannabis Sativa plants.[11]
Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug’s therapeutic window.[18] However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamateinduced excitotoxicity.[19]
Like most pharmacologically-active secondary metabolites of plants, THC in cannabis is assumed to be involved in self-defense, perhaps against herbivores.[12] THC also possesses high UV-B (280–315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.[13][14][15]
182.1.1 Appetite and taste
Tetrahydrocannabinol with double bond isomers and their stereoisomers is one of only three cannabinoids scheduled by Convention on Psychotropic Substances (the other two are dimethylheptylpyran and parahexyl). Cannabis as a plant is scheduled by the Single Convention on Narcotic Drugs (Schedule I and IV).
182.1 Effects See also: Effects of cannabis, Long-term effects of cannabis and Cannabis in pregnancy THC has mild to moderate analgesic effects, and cannabis can be used to treat pain by altering transmitter release on dorsal root ganglion of the spinal cord and in
It has long been known that, in humans, cannabis increases appetite and consumption of food. The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis. CB1 activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger hormone ghrelin increase prior to consuming a meal. After chyme is ed into the duodenum, signaling hormones such as cholecystokinin and leptin are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus. Cannabinoid activity is reduced through the satiety signals induced by leptin release. A study in mice suggested that based on the connection between palatable food and stimulation of dopamine (DA) transmission in the shell of the nucleus accumbens (NAc), cannabis may not only stimulate taste, but possibly the hedonic (pleasure) value of food as well. The study later demonstrates habitual use of THC lessening this heightened pleasure response, indicating a possible similarity in humans.[20] The inconsistency between DA
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CHAPTER 182. TETRAHYDROCANNABINOL
habituation and enduring appetite observed after THC application suggests that cannabis-induced appetite stimulation is not only mediated by enhanced pleasure from palatable food, but through THC stimulation of another appetitive response as well.
182.2 Chemistry 182.2.1
Discovery and structure identification
The discovery of THC by team of researchers from Hebrew University Pharmacy School was first described in “Isolation, structure and partial synthesis of an active constituent of hashish”, published in the Journal of the American Chemical Society in 1964.[8] Research was also published in the academic journal Science, with “Marijuana chemistry” by Raphael Mechoulam in June 3D rendering of the THC molecule 1970,[21] In the latter, the team of researchers from Hebrew University and Tel Aviv University experimented on monkeys to isolate the active compounds in hashish. Their results provided evidence that, except for tetrahydrocannabinol, no other major active compounds were present in hashish.
182.2.2
Isomerism
A hybrid Cannabis strain (White Widow) flower coated with trichomes, which contain more THC than any other part of the plant
Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6Hbenzo[c]chromen-1-ol. • Further reading on cannabanoid isomerism: John C. Leffingwell (May 2003). “Chirality & Bioactivity I.: Pharmacology” 3 (1). pp. 18–20. Retrieved 12 January 2014. Closeup of THC-filled trichomes on a Cannabis sativa leaf
182.3 Medical uses medical marijuana and marijuana-derived products in In April 2014 the American Academy of Neurology pub- certain neurological disorders.[22] The review identified lished a systematic review of the efficacy and safety of 34 studies meeting inclusion criteria, of which 8 were
182.4. ADVERSE EFFECTS
237
rated as Class I quality.[22] The study found evidence sup• Epilepsy. Data was considered insufficient to judge porting the effectiveness of cannabis extracts and THC in the utility of cannabis products in reducing seizure treating certain symptoms of multiple sclerosis, but found frequency or severity.[22] insufficient evidence to determine the effectiveness of cannabis products in treating several other neurological 182.3.4 Other studies in humans diseases.[22]
182.3.1
Multiple sclerosis symptoms
• Spasticity. Based on the results of 3 high quality trials and 5 of lower quality, oral cannabis extract was rated as effective, and THC as probably effective, for improving patient’s subjective experience of spasticity. Oral cannabis extract and THC both were rated as possibly effective for improving objective measures of spasticity.[22] • Centrally mediated pain and painful spasms. Based on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.[22] • Bladder dysfunction. Based on a single high quality study, oral cannabis extract and THC were rated as probably ineffective for controlling bladder complaints in multiple sclerosis[22]
182.3.2
Neurodegenerative disorders
Evidence suggests that THC helps alleviate symptoms suffered both by AIDS patients, and by cancer patients undergoing chemotherapy, by increasing appetite and decreasing nausea.[24][25][26][27] It has also been shown to assist some glaucoma patients by reducing pressure within the eye, and is used in the form of cannabis by a number of multiple sclerosis patients, who use it to alleviate neuropathic pain and spasticity. The National Multiple Sclerosis Society is currently ing further research into these uses.[28] Studies in humans have been limited by federal and state laws criminalizing marijuana. In August 2009 a phase IV clinical trial by the Hadassah Medical Center in Jerusalem, Israel started to investigate the effects of THC on post-traumatic stress disorders.[29] Studies have been conducted with spinal injury patients and THC.[30]
182.4 Adverse effects 182.4.1 Acute toxicity
There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form.[31] However, numerous reports have suggested an association of cannabis smoking with an increased risk of myocardial infarction.[32][33] Information about the toxicity of THC is primarily based on results from animal studies. The toxicity depends on the route • Parkinson disease. Based on a single study, oral of istration and the laboratory animal. cannabis extract was rated probably ineffective in The estimated lethal dose of intravenous dronabinol in treating levodopa-induced dyskinesia in Parkinson humans is 30 mg/kg,[34] meaning lethality is unlikely. disease.[22] The typical medicinal dosage istered is two 2.5 mg capsules daily; for an 80 kg man (~170 lb). A lethal dose • Alzheimer’s disease. A 2011 Cochrane Review for such a person would be 960 of those capsules infused found insufficient evidence to conclude whether intravenously. Non-fatal overdoses have occurred: “Sigcannabis products have any utility in the treatment nificant CNS symptoms in antiemetic studies followed of Alzheimer’s disease.[23] oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules.”[34] • Huntington disease. No reliable conclusions could be drawn regarding the effectiveness of THC or oral cannabis extract in treating the symptoms of Huntington disease as the available trials were too small to reliably detect any difference[22]
182.3.3
Other neurological disorders
• Tourette syndrome. The available data was determined to be insufficient to allow reliable conclusions to be drawn regarding the effectiveness of oral cannabis extract or THC in controlling tics.[22] • Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[22]
A meta analysis of cannabis and THC clinical trials conducted by the American Academy of Neurology found that of 1619 persons treated with cannabis products (including some treated with smoked cannabis and nabiximols), 6.9% discontinued due to side effects, compared to 2.2% of 1,118 treated
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CHAPTER 182. TETRAHYDROCANNABINOL with placebo. Detailed information regarding side effects was not available from all trials, but nausea, increased weakness, behavioral or mood changes, suicidal ideation, hallucinations, dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication were each described as side effects in at least 2 trials. There was a single death rated by the investigator as “possibly related” to treatment. This person had a seizure followed by aspiration pneumonia. The paper does not describe whether this was one of the patients from the epilepsy trials.[22]
182.4.2
Cognitive effects
cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is “neither necessary nor sufficient” to cause psychosis.[41] A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.[42] Some studies have suggested that cannabis s have a greater risk of developing psychosis than non-s. This risk is most pronounced in cases with an existing risk of psychotic disorder.[43][44] A 2005 paper from the Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene.[45] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.[46] A 2008 German review reported that cannabis was a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis.[47]
Its status as an illegal drug in most countries can make research difficult; for instance in the United States where 182.4.4 Other potential long-term effects the National Institute on Drug Abuse was the only legal source of cannabis for researchers until it recently became A 2008 National Institutes of Health study of 19 chronic legalized in Colorado and Washington state.[35] heavy marijuana s with cardiac and cerebral abnorA 2011 systematic review evaluated published studies of malities (averaging 28 g to 272 g (1 to 9+ oz) weekly) the acute and long-term cognitive effects of cannabis. and 24 controls found elevated levels of apolipoprotein [48] An inTHC intoxication is well established to impair cognitive C-III (apoC-III) in the chronic smokers. functioning on an acute basis, including effects on the crease in apoC-III levels induces the development of ability to plan, organize, solve problems, make decisions, hypertriglyceridemia. and control impulses. The extent of this impact may be greater in novice s, and paradoxically, those habituated to high level ingestion may have reduced cognition Detection in body fluids during withdrawal. Studies of long-term effects on cognition have provided conflicting results, with some studies THC, 11-OH-THC and THC-COOH can be detected and finding no difference between long-term abstainers and quantitated in blood, urine, hair, oral fluid or sweat usnever-s and others finding long term deficits. The dis- ing a combination of immunoassay and chromatographic crepancies between studies may reflect greater long term techniques as part of a drug use testing program or in a effects among heavier s relative to occasional s, forensic investigation of a traffic or other criminal offense and greater duration of effect among those with heavy or suspicious death.[49][50][51] use as adolescents compared to later in life.[36] A second systematic review focused on neuroimaging studies found little evidence ing an effect of cannabis use 182.4.5 Interactions on brain structure and function.[37] A 2003 meta analysis concluded that any long term cognitive effects were relatively modest in magnitude and limited to certain aspects The effects of the drug can be reduced by the CB1 receptor inverse agonist rimonabant (SR141716A) as well of learning and memory.[38] as opioid receptor antagonists (opioid blockers) naloxone and naloxonazine.[20][52] The α7 nicotinic receptor antagonist methyllycaconitine can block self-istration of 182.4.3 Impact on psychosis THC in rates comparable to the effects of varenicline on nicotine istration.[53] A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use.[39] A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related.[40] A 2004 literature review on the subject concluded that
Cannabidiol, the second most abundant cannabinoid found in cannabis, is an indirect antagonist against cannabinoid agonists; thus reducing the effects of anandamide and THC agonism on the CB1 and CB2 receptors.
182.7. CHEMICAL SYNTHESIS
239
182.5 Mechanism of action For a review of the mechanisms behind endocannabinoid synaptic transmission, see Endocannabinoid system. The pharmacological actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Kᵢ=10nM[54] ), located mainly in the central nervous system, and the CB2 receptor (Kᵢ=24nM[54] ), mainly expressed in cells of the immune system.[19] The psychoactive effects of THC are primarily mediated by its activation of CB1 G-protein coupled receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyBiosynthesis of THC clase.[16] The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.[18] THC is a lipophilic molecule[55] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[56][57]
is decarboxylated, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops.[62][63]
182.7 Chemical synthesis
Total chemical syntheses largely depend on carefully controlled acid catalyzed condensation of selected monoterpenes with olivetol. If citral is used as start material only the racemic product is formed. The condensation is acid catalyzed, but 0.0005 N hydrogen chloride THC, similarly to cannabidiol, albeit less potently, is an only affords a 12% yield. ∴ 1% boron trifluoride is used allosteric modulator of the μ- and δ-opioid receptors.[58] as the catalyst.
182.5.1
Pharmacokinetics
THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.[59] More than 55% of THC is excreted in the feces and ~20% in the urine. The main metabolite in urine is the ester of glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[60]
Since isomerization of Δ1 THC to virtually inactive Δ6 THC takes place readily in acid or upon heating, the cyclizations must be carefully controlled. Optically active verbenol can be used instead of citral. Please note the attached citations:[64][65][66]
182.8 Marinol
Dronabinol is the INN for a pure isomer of THC, (–)trans-Δ9 -tetrahydrocannabinol,[67] which is the main isomer found in cannabis. It is sold as Marinol (a ed trademark of Solvay Pharmaceuticals). Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies. Synthesized THC may be 182.6 Biosynthesis generally referred to as dronabinol. It is available as a prescription drug (under Marinol[68] ) in several countries In the cannabis plant, THC occurs mainly as including the United States and . In the United tetrahydrocannabinolic acid (THCA, 2-COOH-THC). States, Marinol is a Schedule III drug, available by preGeranyl pyrophosphate and olivetolic acid react, catal- scription, considered to be non-narcotic and to have a ysed by an enzyme to produce cannabigerolic acid,[61] low risk of physical or mental dependence. Efforts to which is cyclized by the enzyme THC acid synthase get cannabis rescheduled as analogous to Marinol have to give THCA. Over time, or when heated, THCA not succeeded thus far, though a 2002 petition has been
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accepted by the DEA. As a result of the rescheduling ics like nabilone.[79] of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol has been approved by the U.S. Food and Drug istration (FDA) in the treatment of anorexia in AIDS patients, as well as for refractory nausea and vomiting of patients undergoing chemotherapy, which has raised much controversy[69] as 182.9 Regulatory to why natural THC is still a schedule I drug.[70]
history
An overdose usually presents with lethargy, decreased motor coordination, slurred speech, and postural hy- For more details on this topic, see Removal of cannabis potension. The FDA estimates the lethal human dose from Schedule I of the Controlled Substances Act. of intravenous dronabinol to be 30 mg/kg (2100 mg/ 70 kg).[71] Since at least 1986, the trend has been for THC in genAn analog of dronabinol, nabilone, is available commer- eral, and especially the Marinol preparation, to be downcially in Canada under the trade name Cesamet, manu- graded to less and less stringently-controlled schedules of factured by Valeant Pharmaceuticals. Cesamet has also controlled substances, in the U.S. and throughout the rest received FDA approval and began marketing in the U.S. of the world. in 2006. Nabilone is a Schedule II drug.[72] On May 13, 1986, the Drug Enforcement istration (DEA) issued a Final Rule and Statement of Pol182.8.1 Comparisons with medical mari- icy authorizing the “Rescheduling of Synthetic Dronabinol in Sesame Oil and Encapsulated in Soft Gelatin juana Capsules From Schedule I to Schedule II” (DEA 51 FR 17476-78). This permitted medical use of Marinol, alFurther information: Medical cannabis beit with the severe restrictions associated with Schedule II status.[80] For instance, refills of Marinol prescripFemale cannabis plants contain more than 60 cannabi- tions were not permitted. At its 1045th meeting, on noids, including cannabidiol (CBD), thought to be April 29, 1991, the Commission on Narcotic Drugs, in the major anticonvulsant that helps multiple sclero- accordance with article 2, paragraphs 5 and 6, of the sis patients;[73] and cannabichromene (CBC), an anti- Convention on Psychotropic Substances, decided that Δ9 inflammatory which may contribute to the pain-killing tetrahydrocannabinol (also referred to as Δ9 -THC) and effect of cannabis.[74] its stereochemical variants should be transferred from It takes over one hour for Marinol to reach full systemic Schedule I to Schedule II of that Convention. This reeffect,[75] compared to seconds or minutes for smoked leased Marinol from the restrictions imposed by Article or vaporized cannabis.[76] Some patients accustomed to 7 of the Convention (See also United Nations Convention inhaling just enough cannabis smoke to manage symp- Against Illicit Traffic in Narcotic Drugs and Psychotropic toms have complained of too-intense intoxication from Substances). Marinol’s predetermined dosages. Many patients have An article published in the April–June 1998 issue of the said that Marinol produces a more acute psychedelic ef- Journal of Psychoactive Drugs found that “Healthcare fect than cannabis, and it has been speculated that this professionals have detected no indication of scrip-chasing disparity can be explained by the moderating effect of or doctor-shopping among the patients for whom they the many non-THC cannabinoids present in cannabis. have prescribed dronabinol”. The authors state that MariFor that reason, alternative THC-containing medications nol has a low potential for abuse.[81] based on botanical extracts of the cannabis plant such as nabiximols are being developed. Mark Kleiman, di- In 1999, Marinol was rescheduled from Schedule II to III rector of the Drug Policy Analysis Program at UCLA’s of the Controlled Substances Act, reflecting a finding that School of Public Affairs said of Marinol, “It wasn't any THC had a potential for abuse less than that of cocaine fun and made the feel bad, so it could be approved and heroin. This rescheduling constituted part of the arwithout any fear that it would penetrate the recreational gument for a 2002 petition for removal of cannabis from market, and then used as a club with which to beat back Schedule I of the Controlled Substances Act, in which pethe advocates of whole cannabis as a medicine.”[77] Mr. titioner Jon Gettman noted, “Cannabis is a natural source Kleiman’s opinion notwithstanding, clinical trials com- of dronabinol (THC), the ingredient of Marinol, a Schedcannabis paring the use of cannabis extracts with Marinol in the ule III drug. There are no grounds to schedule [82] in a more restrictive schedule than Marinol”. treatment of cancer cachexia have demonstrated equal efficacy and well-being among patients in the two treat- At its 33rd meeting, in 2003, the World Health Organiment arms.[78] United States federal law currently regis- zation Expert Committee on Drug Dependence recomters dronabinol as a Schedule III controlled substance, but mended transferring THC to Schedule IV of the Convenall other cannabinoids remain Schedule I, except synthet- tion, citing its medical uses and low abuse potential.[83]
182.11. REFERENCES
182.10 See also • Anandamide • Cannabis (drug) • Psychoactive drug • Cannabinoids • 11-Hydroxy-THC, metabolite of THC • Anandamide, 2-Arachidonoylglycerol, endogenous cannabinoid agonists • Cannabidiol (CBD), an isomer of THC • Cannabinol (CBN), a metabolite of THC • Dimethylheptylpyran • Parahexyl • Tetrahydrocannabinolic acid, the biosynthetic precursor for THC • HU-210, WIN 55,212-2, JWH-133, synthetic cannabinoid agonists • Medical cannabis • War on Drugs • Cannabis rescheduling in the United States • Health issues and the effects of cannabis
182.11 References [1] http://www.fda.gov/ohrms/dockets/dockets/05n0479/ 05N-0479-emc0004-04.pdf
241
[7] Garrett ER, Hunt CA (July 1974). “Physicochemical properties, solubility, and protein binding of Δ9 tetrahydrocannabinol”. J. Pharm. Sci. 63 (7): 1056–64. doi:10.1002/jps.2600630705. PMID 4853640. [8] Gaoni Y, Mechoulam R (1964). “Isolation, structure and partial synthesis of an active constituent of hashish”. Journal of the American Chemical Society 86 (8): 1646–1647. doi:10.1021/ja01062a046. [9] “Interview with the winner of the first ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel”. February 2007. [10] Geller, Tom (2007). “Cannabinoids: A Secret History”. Chemical Heritage Newsmagazine 25 (2). Archived from the original on 19 June 2008. [11] Alchimiaweb Blog, Cannabinoids and their medicinal properties [12] Pate, David W. (1994). “Chemical ecology of Cannabis”. Journal of the International Hemp Association 1 (29): 32– 37. [13] Pate, David W. (1983). “Possible role of ultraviolet radiation in evolution of Cannabis chemotypes”. Economic Botany 37 (4): 396–405. doi:10.1007/BF02904200. [14] Lydon, John; Teramura, Alan H. (1987). “Photochemical decomposition of cannabidiol in its resin base”. Phytochemistry 26 (4): 1216–1217. doi:10.1016/S00319422(00)82388-2. [15] Lydon J, Teramura AH, Coffman CB (1987). “UVB radiation effects on photosynthesis, growth and cannabinoid production of two Cannabis sativa chemotypes”. Photochemistry and Photobiology 46 (2): 201– 206. doi:10.1111/j.1751-1097.1987.tb04757.x. PMID 3628508.
[2] Marlowe, Douglas B. (December 2010). “The Facts On Marijuana”. NAD. “Based upon several nationwide epidemiological studies, marijuana’s dependence liability has been reliably determined to be 8 to 10 percent.”
[16] Elphick MR, Egertová M (2001). “The neurobiology and evolution of cannabinoid signalling”. Philosophical Transactions of the Royal Society B: Biological Sciences 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486.
[3] Grotenhermen, F (2003). “Pharmacokinetics and pharmacodynamics of cannabinoids”. Clin Pharmacokinet 42 (4): 327–60. doi:10.2165/00003088-200342040-00003. PMID 12648025. (subscription required (help)).
[17] Hoaken PN, Stewart SH (2003). “Drugs of abuse and the elicitation of human aggressive behavior”. Addictive Behaviors 28 (9): 1533–1554. doi:10.1016/j.addbeh.2003.08.033. PMID 14656544.
[4] The Royal Pharmaceutical Society of Great Britain (30 November 2006). “Cannabis”. In Sean C. Sweetman. Martindale: The Complete Drug Reference: Single (35th ed.). Pharmaceutical Press. ISBN 978-0-85369703-9.
[18] Pertwee RG (2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin”. British Journal of Pharmacology 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291.
[5] “Tetrahydrocannabinol – Compound Summary”. National Center for Biotechnology Information. PubChem. Retrieved 12 January 2014. “Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%.” [6] “Marijuana Water Pipe and Vaporizer Study”. Multidisciplinary Association for Psychedelic Studies. Retrieved 15 May 2014.
[19] Pertwee RG (2006). “The pharmacology of cannabinoid receptors and their ligands: An overview”. International Journal of Obesity 30: S13–S18. doi:10.1038/sj.ijo.0803272. PMID 16570099. [20] De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G (2011). “Cannabinoid facilitation of behavioral and biochemical hedonic taste reNeuropharmacology 63 (1): 161–168. sponses”.
242
CHAPTER 182. TETRAHYDROCANNABINOL
doi:10.1016/j.neuropharm.2011.10.018. PMC 3705914. PMID 22063718. [21] Mechoulam R (1970). “Marihuana chemistry”. Science 168 (3936): 1159–66. Bibcode:1970Sci...168.1159M. doi:10.1126/science.168.3936.1159. PMID 4910003. [22] Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D (April 2014). “Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology”. Neurology 82 (17): 1556– 63. doi:10.1212/WNL.0000000000000363. PMID 24778283. [23] Krishnan S, Cairns R, Howard R (2009). “Cannabinoids for the treatment of dementia”. In Krishnan, Sarada. “Cochrane Database of Systematic Reviews”. Cochrane database of systematic reviews (Online) (2): CD007204. doi:10.1002/14651858.CD007204.pub2. PMID 19370677. [24] “Cannabis and Cannabinoids”. National Cancer Institute. Retrieved 12 January 2014. [25] Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, Foltin RW (2007). “Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep”. Journal of Acquired Immune Deficiency Syndromes 45 (5): 545– 54. doi:10.1097/QAI.0b013e31811ed205. PMID 17589370. [26] Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M (2003). “Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial”. Annals of Internal Medicine 139 (4): 258–66. doi:10.7326/0003-4819-1394-200308190-00008. PMID 12965981. [27] Grotenhermen, Franjo; Russo, Ethan, eds. (2002). “Review of Therapeutic Effects”. Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. New York City: Psychology Press. p. 124. ISBN 978-0-7890-1508-2. “The only approved preparations to date, Marinol (dronabinol, Δ9 -THC) and Cesamet (nabilone), are approved for the indication of nausea and vomiting associated with cancer chemotherapy. Marinol is also approved for anorexia and cachexia in HIV/AIDS.” [28] “Marijuana (Cannabis)". National Multiple Sclerosis Society. Retrieved 5 September 2009.
[31] Walker JM, Huang SM (August 2002). “Cannabinoid analgesia”. Pharmacol. Ther. 95 (2): 127–35. doi:10.1016/S0163-7258(02)00252-8. PMID 12182960. "...to date, there are no deaths known to have resulted from overdose of cannabis. (p. 128)" [32] Thomas G, Kloner RA, Rezkalla S (January 2014). “Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know”. Am. J. Cardiol. 113 (1): 187–90. doi:10.1016/j.amjcard.2013.09.042. PMID 24176069. [33] Aryana A, Williams MA (May 2007). “Marijuana as a trigger of cardiovascular events: speculation or scientific certainty?". Int. J. Cardiol. 118 (2): 141–4. doi:10.1016/j.ijcard.2006.08.001. PMID 17005273. [34] “DRONABINOL capsule [American Health Packaging]". National Library of Medicine. Daily Med. July 2012. Retrieved 12 January 2014. “The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules.” [35] “Medical Marijuana”. Multidisciplinary Association for Psychoactive Substances. Retrieved 12 January 2014. [36] Crean RD, Crane NA, Mason BJ (March 2011). “An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions”. J Addict Med 5 (1): 1–8. doi:10.1097/.0b013e31820c23fa. PMC 3037578. PMID 21321675. [37] Martín-Santos R, Fagundo AB, Crippa JA, Atakan Z, Bhattacharyya S, Allen P, Fusar-Poli P, Borgwardt S, Seal M, Busatto GF, McGuire P (March 2010). “Neuroimaging in cannabis use: a systematic review of the literature”. Psychol Med 40 (3): 383–98. doi:10.1017/S0033291709990729. PMID 19627647. [38] Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T (2003). “Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study”. Journal of the International Neuropsychological Society 9 (5). doi:10.1017/S1355617703950016. PMID 12901774. Lay summary – WebMD (1 July 2003). [39] Large M, Sharma S, Compton MT, Slade T, Nielssen O (June 2011). “Cannabis use and earlier onset of psychosis: a systematic meta-analysis”. Arch. Gen. Psychiatry 68 (6): 555–61. doi:10.1001/archgenpsychiatry.2011.5. PMID 21300939.
[29] ClinicalTrials.gov NCT00965809 Add on Study on Δ9THC Treatment for Posttraumatic Stress Disorders (PTSD) (THC_PTSD)
[40] Semple DM, McIntosh AM, Lawrie SM (March 2005). “Cannabis as a risk factor for psychosis: systematic review”. J. Psychopharmacol. (Oxford) 19 (2): 187–94. doi:10.1177/0269881105049040. PMID 15871146.
[30] Hannigan WC, Destree R, Truong XT (1986). “The effect of delta-9-THC on human spasticity”. American Society for Clinical Pharmacology and Therapeutics, Eightyseventh Annual Meeting, March 20–22, 1986 39: 198, abstract B45.
[41] Arseneault L, Cannon M, Witton J, Murray RM (2004). “Causal association between cannabis and psychosis: examination of the evidence”. The British Journal of Psychiatry 184 (2): 110–117. doi:10.1192/bjp.184.2.110. PMID 14754822.
182.11. REFERENCES
243
[42] Laqueille X (2009). “Le cannabis est-il un facteur de vulnérabilité des troubles schizophrènes?" [Is cannabis is a vulnerability factor of schizophrenic disorders?]. Archives de Pédiatrie 16 (9): 1302–5. doi:10.1016/j.ared.2009.03.016. PMID 19640690. (registration required (help)).
[51] Baselt, R. (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 1644–8.
[43] Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G (2007). “Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review”. The Lancet 370 (9584): 319–28. doi:10.1016/S0140-6736(07)61162-3. PMID 17662880.
[52] Lupica CR, Riegel AC, Hoffman AF (2004). “Marijuana and cannabinoid regulation of brain reward circuits”. British Journal of Pharmacology 143 (2): 227–34. doi:10.1038/sj.bjp.0705931. PMC 1575338. PMID 15313883.
[44] Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J (2005). “Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people”. BMJ 330 (7481): 11– 0. doi:10.1136/bmj.38267.664086.63. PMC 539839. PMID 15574485.
[53] Solinas M, Scherma M, Fattore L, Stroik J, Wertheim C, Tanda G, Fratta W, Goldberg SR (2007). “Nicotinic 7 Receptors as a New Target for Treatment of Cannabis Abuse”. Journal of Neuroscience 27 (21): 5615– 20. doi:10.1523/JNEUROSCI.0027-07.2007. PMID 17522306. Lay summary – New Scientist (22 May 2007).
[45] Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW (2005). “Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the CatecholO-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction”. Biological Psychiatry 57 (10): 1117–27. doi:10.1016/j.biopsych.2005.01.026. PMID 15866551.
[54] “PDSP Database – UNC”. NIMH Psychoactive Drug Screening Program. Retrieved 11 June 2013.
[46] Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ; Spurlock (2007). “Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use”. The British Journal of Psychiatry 191 (5): 402–7. doi:10.1192/bjp.bp.107.036129. PMID 17978319. Lay summary – MedWireNews. [47] Kawohl W, Rössler W (2008). “Cannabis and Schizophrenia: new findings in an old debate”. Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater 22 (4): 223–9. PMID 19080993. [48] Jayanthi S, Buie S, Moore S, Herning RI, Better W, Wilson NM, Contoreggi C, Cadet JL (2008). “Heavy marijuana s show increased serum apolipoprotein C-III levels: evidence from proteomic analyses”. Molecular Psychiatry 15 (1): 101–112. doi:10.1038/mp.2008.50. PMC 2797551. PMID 18475272. Lay summary – Reuters (May 13, 2008). [49] Schwilke EW, Schwope DM, Karschner EL, Lowe RH, Darwin WD, Kelly DL, Goodwin RS, Gorelick DA, Huestis MA (2009). "Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous HighDose Oral THC”. Clinical Chemistry 55 (12): 2180–2189. doi:10.1373/clinchem.2008.122119. PMC 3196989. PMID 19833841. [50] Röhrich J, Schimmel I, Zörntlein S, Becker J, Drobnik S, Kaufmann T, Kuntz V, Urban R (2010). “Concentrations of Δ9 -Tetrahydrocannabinol and 11-Nor-9Carboxytetrahydrocannabinol in Blood and Urine After ive Exposure to Cannabis Smoke in a Coffee
Shop”. Journal of Analytical Toxicology 34 (4): 196–203. doi:10.1093/jat/34.4.196. PMID 20465865.
[55] Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R, Duetz WA (November 2009). “Hydroxylation and Further Oxidation of Δ9-Tetrahydrocannabinol by AlkaneDegrading Bacteria” (PDF). Appl Environ Microbiol 75 (22): 7135–7141. doi:10.1128/AEM.01277-09. PMC 2786519. PMID 19767471. "Δ9-THC and many of its derivatives are highly lipophilic and poorly water soluble. Calculations of the n-octanol/water partition coefficient (Ko/w) of Δ9-THC at neutral pH vary between 6,000, using the shake flask method, and 9.44 × 106, by reversephase high-performance liquid chromatography estimation.” [56] Ashton CH (February 2001). “Pharmacology and effects of cannabis: a brief review”. Br J Psychiatry 178: 101– 106. doi:10.1192/bjp.178.2.101. PMID 11157422. “Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4–5 days. They are then slowly released back into other body compartments, including the brain. ... Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas.” [57] Huestis MA (August 2007). “Human cannabinoid pharmacokinetics”. Chem Biodivers 4 (8): 1770–804. doi:10.1002/cbdv.200790152. PMC 2689518. PMID 17712819. “THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver.” [58] Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (February 2006). “Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors”. Naunyn Schmiedebergs Arch. Pharmacol. 372 (5): 354–61. doi:10.1007/s00210-006-0033-x. PMID 16489449. [59] Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I (March 2007). “Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes”. Life Science 80 (15): 1415–9. doi:10.1016/j.lfs.2006.12.032. PMID 17303175.
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[60] Huestis MA (2005). “Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ9 -Tetrahydrocannabinol, Cannabidiol and Cannabinol”. Cannabinoids. Handbook of Experimental Pharmacology 168 (168): 657–90. doi:10.1007/3-540-26573-2_23. ISBN 3-540-22565-X. PMID 16596792. [61] Fellermeier M, Zenk MH (1998). “Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol”. FEBS Letters 427 (2): 283–5. doi:10.1016/S0014-5793(98)00450-5. PMID 9607329. [62] Marks MD, Tian L, Wenger JP, Omburo SN, SotoFuentes W, He J, Gang DR, Weiblen GD, Dixon RA (2009). “Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa”. Journal of Experimental Botany 60 (13): 3715– 26. doi:10.1093/jxb/erp21. PMC 2736886. PMID 19581347. [63] Baker PB, Taylor BJ, Gough TA (June 1981). “The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products”. J Pharm Pharmacol. 33 (6): 369–72. doi:10.1111/j.2042-7158.1981.tb13806.x. PMID 6115009. [64] Razdan RK (1970). “Hashish. V. A stereospecific synthesis of (-)−.DELTA.1-and (-).DELTA.1(6)tetrahydrocannabinols”. Journal of the American Chemical Society 92 (20): 6061–6062. doi:10.1021/ja00723a044. [65] Petrzilka T (1969). “Synthese von HaschischInhaltsstoffen. 4. Mitteilung”. Helvetica Chimica Acta 52 (4): 1102–1134. doi:10.1002/hlca.19690520427. [66] Jen T (1967). “Total synthesis of (.DELTA.1(6)-tetrahydrocannabinol, a active constituent of hashish (marijuana)". the American Chemical Society 89 (17): doi:10.1021/ja00993a071.
.DELTA.8biologically Journal of 4551–4552.
[67] “List of psychotropic substances under international control” (PDF). International Narcotics Control Board. p. 5. Archived from the original on 7 September 2005. Retrieved 20 April 2011. “This international non-proprietary name refers to only one of the stereochemical variants of delta-9-tetrahydrocannabinol, namely (-)-trans-delta-9tetrahydrocannabinol” [68] “Marinol – the Legal Medical Use for the Marijuana Plant”. Drug Enforcement istration. Archived from the original on 21 October 2002. Retrieved 20 April 2011. [69] Downs, David (21 October 2014). “War on marijuana unconstitutional, doctors testify in federal court Monday”. sfgate.com. Retrieved 21 October 2014. [70] Eustice, Carol (12 August 1997). “Medicinal Marijuana: A Continuing Controversy”. About.com. Retrieved 20 April 2011. [71] “Marinol”. FDA.gov. Retrieved 14 March 2014.
[72] “Title 21 of the Code of Federal Regulations – PART 1308 — SCHEDULES OF CONTROLLED SUBSTANCES”. US Department of Justice. DEA Office of Diversion Control. Retrieved 12 January 2014. With changes through 77 F.R. 4235 (January 27, 2012). [73] Pickens JT (1981). “Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content”. British Journal of Pharmacology 72 (4): 649–56. doi:10.1111/j.1476-5381.1981.tb09145.x. PMC 2071638. PMID 6269680. [74] Burns TL, Ineck JR (2006). “Cannabinoid Analgesia as a Potential New Therapeutic Option in the Treatment of Chronic Pain”. Annals of Pharmacotherapy 40 (2): 251– 260. doi:10.1345/aph.1G217. PMID 16449552. [75] MARINOL (dronabinol) capsule drug label/data at Daily Med from U.S. National Library of Medicine, National Institutes of Health. [76] McKim, William A (2002). Drugs and Behavior: An Introduction to Behavioral Pharmacology (5th ed.). Prentice Hall. p. 400. ISBN 0-13-048118-1. [77] Greenberg, Gary (1 November 2005). “Respectable Reefer”. Mother Jones. Retrieved 8 April 2010. [78] “Cannabis and Cannabinoids (PDQ®)". Cancer Topics. National Cancer Institute, U.S. Department of Health and Human Services. [79] “Government eases restrictions on pot derivative”. Online Athens. Retrieved 12 January 2014. [80] 51 Fed. Reg. 17476 (1986), Tuesday, May 13, 1986, pages 17476-17478 [81] Calhoun SR, Galloway GP, Smith DE (1998). “Abuse potential of dronabinol (Marinol)". Journal of Psychoactive Drugs 30 (2): 187–96. doi:10.1080/02791072.1998.10399689. PMID 9692381. [82] “Petition to Reschedule Cannabis (Marijuana)". Coalition for Rescheduling Cannabis. 9 October 2002. [83] “WHO Expert Committee on Drug Dependence”. World Health Organization. Retrieved 12 January 2014.
182.12 Further reading • Calhoun SR, Galloway GP, Smith DE (1998). “Abuse potential of dronabinol (Marinol)". J Psychoactive Drugs 30 (2): 187–96. doi:10.1080/02791072.1998.10399689. PMID 9692381. • DEA Moves Marinol To Schedule Three, But Leaves Marijuana in Schedule One. The Magic of Sesame Oil, Richard Cowan, MarijuanaNews.com.
182.13. EXTERNAL LINKS • Petition to Reschedule Cannabis (Marijuana) per 21 CFR § 1308.44(b) at the Wayback Machine (archived December 6, 2002), Filed October 9, 2002 with the DEA by the Coalition for Rescheduling Cannabis.
182.13 External links • U.S. National Library of Medicine: Drug Information Portal – Tetrahydrocannabinol
245
Chapter 183
Tetrahydrocannabinol-C4 Tetrahydrocannabinol-C4, also known as THC-C4 and butyl-THC, is a homologue of tetrahydrocannabinol (THC), the active component of cannabis. They are only different by the pentyl side chain being replaced by a butyl side chain. It is unknown whether THCC4 is an agonist, partial agonist, or antagonist at the cannabinoid receptors. The propyl analog, THCV, is a cannabinoid receptor type 1 and cannabinoid receptor type 2 antagonist,[1] while THC is a CB1 agonist. THCC4 has rarely been isolated from cannabis samples,[2] but appears to be less commonly present than THC or THCV. It is metabolised in a similar manner to THC.[3] Similarly to THC, it has 7 double bond isomers and 30 stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
183.1 See also • Cannabinoids • Cannabis • Parahexyl
183.2 References [1] Thomas, Adèle; Stevenson, Lesley A; Wease, Kerrie N; Price, Martin R; Baillie, Gemma; Ross, Ruth A; Pertwee, Roger G (December 2005). “Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist”. British Journal of Pharmacology 146 (7): 917–926. doi:10.1038/sj.bjp.0706414. PMID 16205722. [2] Harvey DJ. Characterization of the butyl homologues of delta1-tetrahydrocannabinol, cannabinol and cannabidiol in samples of cannabis by combined gas chromatography and mass spectrometry. Journal of Pharmacy and Pharmacology. 1976 Apr;28(4):280-5. PMID 6715 [3] Brown NK, Harvey DJ. In vivo metabolism of the n-butylhomologues of delta 9-tetrahydrocannabinol and delta 8tetrahydrocannabinol by the mouse. Xenobiotica. 1988 Apr;18(4):417-27. PMID 2840781
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Chapter 184
Tetrahydrocannabinolic acid Not to be confused with 11-nor-9-Carboxy-THC.
39767–74, 15190053
Tetrahydrocannabinolic acid (THCA, 2COOH-THC), is a biosynthetic precursor of tetrahydrocannabinol (THC), the active component of Cannabis.[1][2][3][4] THCA is found in variable quantities in fresh, undried cannabis, but is progressively decarboxylated to THC with drying, and especially under intense heating such as when cannabis is smoked.[5] While THCA does not have psychoactive effects in its own right, it does have antiinflammatory and neuroprotective effects.[6][7] Despite the ready decarboxylation by drying or heating ex vivo, conversion of THCA to THC in vivo appears to be very limited, giving it only very slight efficacy as a prodrug for THC.[8] Consequently it is believed to be important in less-psychoactive preparations of cannabis used for medical use, such as cannabis tea.[9] It is also commonly used as a biomarker in drug testing along with THCV, to distinguish between prescribed synthetic Delta-9tetrahydrocannabinol, such as Marinol, and cannabis plant material which may also be used by patients.[10]
184.1 See also
doi:10.1074/jbc.M403693200,
PMID
[3] Moore C, Rana S, Coulter C. (2007-06-01), Simultaneous identification of 2-carboxy-tetrahydrocannabinol, tetrahydrocannabinol, cannabinol and cannabidiol in oral fluid, J Chromatogr B Analyt Technol Biomed Life Sci. 852 (12): 459–64, doi:10.1016/j.jchromb.2007.02.016, PMID 17321807 [4] Taura F. (Jun 2009), Studies on tetrahydrocannabinolic acid synthase that produces the acidic precursor of tetrahydrocannabinol, the pharmacologically active cannabinoid in marijuana, Drug Discoveries and Therapeutics 3 (3): 83–7, PMID 22495534 [5] Dussy FE, Hamberg C, Luginbühl M, Schwerzmann T, Briellmann TA. (2005-04-20), Isolation of Delta9THCA-A from hemp and analytical aspects concerning the determination of Delta9-THC in cannabis products, Forensic Science International 149 (1): 3–10, doi:10.1016/j.forsciint.2004.05.015, PMID 15734104 [6] Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. (2011), Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa, Biological and Pharmaceutical Bulletin 34 (5): 774–8, doi:10.1248/bpb.34.774, PMID 21532172 [7] Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, Rausch WD. (2012-05-07), Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)tetrahydrocannabinolic acid and cannabidiol in MPP(+) affected murine mesencephalic cultures, Phytomedicine 19 (8-9): 819–24, doi:10.1016/j.phymed.2012.04.002, PMID 22571976
• Cannabinoids • Cannabidiol
184.2 References [1] Baker PB, Taylor BJ, Gough TA. (Jun 1981), The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products, Journal of Pharmacy and Pharmacology 33 (6): 369–72, doi:10.1111/j.20427158.1981.tb13806.x, PMID 6115009 [2] Sirikantaramas S, Morimoto S, Shoyama Y, Ishikawa Y, Wada Y, Shoyama Y, Taura F. (2004-09-17), The gene controlling marijuana psychoactivity: molecular cloning and heterologous expression of Delta1tetrahydrocannabinolic acid synthase from Cannabis sativa L., Journal of Biological Chemistry 279 (38):
247
[8] Jung J, Meyer MR, Maurer HH, Neusüss C, Weinmann W, Auwärter V. (Oct 2009), Studies on the metabolism of the Delta-9-tetrahydrocannabinol precursor delta-9-tetrahydrocannabinolic acid A (Delta9-THCA-A) in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniques, Journal of Mass Spectrometry 44 (10): 1423–33, doi:10.1002/jms.1624, PMID 19728318 [9] Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte R. (2007-07-15), Cannabis tea revisited: a systematic evaluation of the cannabinoid composition of cannabis tea, Journal of Ethnopharmacology 113 (1): 85–90, doi:10.1016/j.jep.2007.05.019, PMID 17604926
248
[10] Radünz L, Westphal F, Maser E, Rochholz G. (201202-10), THCVA-A - a new additional marker for illegal cannabis consumption, Forensic Science International 215 (1-3): 171–4, doi:10.1016/j.forsciint.2011.03.001, PMID 21454026
CHAPTER 184. TETRAHYDROCANNABINOLIC ACID
Chapter 185
Tetrahydrocannabivarin Tetrahydrocannabivarin (THCV, THV) is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain. This terpeno-phenolic compound is found naturally in Cannabis, sometimes in significant amounts. The psychoactive effects of THCV in Cannabis preparations are not well characterized.
185.3 See also • Cannabinoids • Cannabis • Medical marijuana
Similarly to THC, it has 7 double bond isomers and 30 stereoisomers (see: Tetrahydrocannabinol#Isomerism). It is not scheduled by Convention on Psychotropic Substances.
• Rimonabant (synthetic CB1 antagonist) • Tetrahydrocannabinol-C4 • Parahexyl
185.1 Description
185.4 References [1] Turner, C.E., Hadley, K.W., and Fetterman, P. 1973. Constituents of Cannabis Sativa L., VI: Propyl Homologues in Samples of Known Geographical Origin. J. Pharm. Sci. 62(10):1739-1741
Plants with elevated levels of propyl cannabinoids (including THCV) have been found in populations of Cannabis sativa L. ssp. indica (= Cannabis indica Lam.) from China, India, Nepal, Thailand, Afghanistan, and Pakistan, as well as southern and western Africa. THCV levels up to 53.7% of total cannabinoids have been reported. [1] [2]
[2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). American Journal of Botany 91(6): 966975.
THCV is a cannabinoid receptor type 1 antagonist and cannabinoid receptor type 2 partial agonist.[3] Δ8-THCV has also been shown to be a CB1 antagonist.[4] Both papers describing the antagonistic properties of THCV were demonstrated in murine models.
[3] Pertwee, Roger G (September 2007). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9tetrahydrocannabivarin”. British Journal of Pharmacology 153 (2): 199–215. doi:10.1038/sj.bjp.0707617. [4] Pertwee RG, Thomas A, Stevenson LA, et al. 2007. The psychoactive plant cannabinoid, Δ9tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo. Br. J. Pharmacol. 150(5): 586–94.
185.2 Biosynthesis Unlike THC, cannabidiol (CBD), and cannabichromene (CBC), THCV doesn’t begin as cannabigerolic acid (CBGA). Instead of combining with olivetolic acid to create CBGA, geranyl pyrophosphate s with divarinolic acid, which has 2 less carbon molecules. The result is cannabigerovarin acid (CBGVA). Once CBGVA is created, the process continues exactly same as it would for THC. CBGVA is broken down to tetrahydrocannabivarin carboxylic acid (THCVA) by the enzyme THCV synthase. At that point, THCVA can be decarboxylated with heat or UV light to create THCV.[5]
[5] MedicalJane. “What is Tetrahydrocannabivarin?".
185.5 External links
249
• Erowid Compounds found in Cannabis sativa • www.tetrahydrocannabivarin.com THCV
Article
on
Chapter 186
THC-O-acetate THC acetate ester is a derivative of THC which has been found by the DEA as an apparent controlled substance analogue of THC. It was apparently made by extracting and purifying THC from cannabis plant material using a soxhlet extractor, followed by reaction with acetic anhydride in an analogous manner to how heroin is made from morphine.[1] A similar case was reported in June 1995 in the UK and THC-O-acetate was ruled to be a Class A drug.[2] THC acetate was also reported to have been found by New Zealand police in 1995, again made by acetylation of purified cannabis extracts with acetic anhydride.[3] The acetylation of THC does not change the properties of the compound to the same extent as with other acetate esters (e.g. morphine vs heroin), as the parent compound is already highly lipophilic, but potency is nonetheless increased to some extent. This derivative of THC is interesting as one of the few analogues of THC to have been encountered as a recreational drug sold and used in a highly pure smokable form. THC acetate ester was also investigated as a possible nonlethal incapacitating agent, as part of the Edgewood Arsenal experiments.[4]
186.1 References [1] Donald A. Cooper. Future Synthetic Drugs of Abuse. Drug Enforcement istration, McLean, Virginia [2] David T. Brown. Cannabis: The Genus Cannabis. p82 ISBN 90-5702-291-5 [3] Valentine MD. Δ9-THC acetate from acetylation of cannabis oil. Science and Justice 1995; 36(3):195–197. [4] Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants (1984) Commission on Life Sciences. The National Academies Press. pp79-99.
250
Chapter 187
THC-O-phosphate THC-O-phosphate is a water-soluble phosphate ester derivative of THC, invented in 1978 in an attempt to get around the poor water solubility of THC and make it easier to inject for the purposes of animal research into its pharmacology and mechanism of action. The main disadvantage of THC phosphate ester is the slow rate of hydrolysis of the ester link, resulting in delayed onset of action and lower potency than the parent drug. THC phosphate ester is made by reacting THC with phosphoryl chloride using pyridine as a solvent, following by quenching with water to produce THC phosphate ester. In the original research the less active but more stable isomer Δ8THC was used, but the same reaction scheme could be used to make the phosphate ester of the more active isomer Δ9THC. [1]
187.1 References [1] Yoshimura H, Watanabe K, Oguri K, Fujiwara M, Ueki S. Synthesis and pharmacological activity of a phosphate ester of delta8-tetrahydrocannabinol. Journal of Medicinal Chemistry. 1978 Oct;21(10):1079-81.
251
Chapter 188
Tinabinol Tinabinol (INN; SP-119) is a synthetic cannabinoid drug and analogue of dronabinol which was patented as an antihypertensive but was never marketed.[1][2]
188.1 See also • Dronabinol • Nabitan
188.2 References [1] David T. Brown (19 November 1998). Cannabis: The Genus Cannabis. CRC Press. p. 80. ISBN 978-90-5702291-3. Retrieved 27 April 2012. [2] Martin Negwer (1994). Organic-chemical drugs and their synonyms: an international survey. Indices. Akad.-Verl. p. 2242. ISBN 978-3-05-501629-5. Retrieved 27 April 2012.
252
Chapter 189
URB602 URB602 ([1,1'-biphenyl]−3-yl-carbamic acid, cyclohexyl ester) is a compound that has been found to inhibit hydrolysis of monoacyl glycerol compounds, such as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG). It was first described in 2003.[1] A study performed in 2005 found that the compound had specificity for metabolizing 2-AG over anandamide (another cannabinoid ligand) in rat brain presumably by inhibiting the enzyme monoacylglycerol lipase (MAGL), which is the primary metabolic enzyme of 2-AG.[2] However, subsequent studies have shown that URB602 lacks specificity for MAGL inhibition in vitro.[3]
189.1 References [1] Tarzia, G; Duranti, A; Tontini, A; Piersanti, G; Mor, M; Rivara, S; Plazzi, PV; Park, C et al. (2003). “Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors”. Journal of Medical Chemistry 46 (12): 2352–60. doi:10.1021/jm021119g. PMID 12773040. [2] Hohmann, Andrea G.; Suplita, Richard L.; Bolton, Nathan M.; Neely, Mark H.; Fegley, Darren; Mangieri, Regina; Krey, Jocelyn F.; Michael Walker, J. et al. (2005). “An endocannabinoid mechanism for stress-induced analgesia”. Nature 435 (7045): 1108–12. Bibcode:2005Natur.435.1108H. doi:10.1038/nature03658. PMID 15973410. [3] Vandevoorde, S; Jonsson, K-O; Labar, G; Persson, E; Lambert, D M; Fowler, C J (2007). “Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysisin vitro”. British Journal of Pharmacology 150 (2): 186–91. doi:10.1038/sj.bjp.0706971. PMC 2042901. PMID 17143303.
253
Chapter 190
URB754 URB754 was originally reported by Piomelli et al. to be a potent, noncompetitive inhibitor of monoacylglycerol lipase.[1] However, recent studies have shown that URB754 failed to inhibit recombinant MGL, and brain FAAH activity was also resistant to URB754.[2] In a later study by Piomelli et al. showed that the MGL-inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane.[3]
190.1 References [1] Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D (2005). “Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus”. Nat. Neurosci. 8 (9): 1139–41. doi:10.1038/nn1521. PMID 16116451. [2] Saario SM, Palomäki V, Lehtonen M, Nevalainen T, Järvinen T, Laitinen JT (2006). “URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain”. Chem. Biol. 13 (8): 811–4. doi:10.1016/j.chembiol.2006.07.008. PMID 16931330. [3] Tarzia, G; et al. (2007). “Identification of a bioactive impurity in a commercial sample of 6-methyl-2-ptolylaminobenzo[d][1,3]oxazin-4-one (URB754.”. Ann Chim. 97 (9): 887–94.
254
Chapter 191
VCHSR VCHSR is a drug used in scientific research which acts as a selective antagonist of the cannabinoid receptor CB1 . It is derived from the widely used CB1 antagonist rimonabant, and has similar potency and selectivity for the CB1 receptor, but has been modified to remove the hydrogen bonding capability in the C-3 substituent region, which removes the inverse agonist effect that rimonabant produces at high doses, so that VCHSR instead acts as a neutral antagonist, blocking the receptor but producing no physiological effect of its own.[1][2]
191.1 References [1] Hurst, DP; Lynch, DL; Barnett-Norris, J; Hyatt, SM; Seltzman, HH; Zhong, M; Song, ZH; Nie, J et al. (2002). “N-(piperidin-1-yl)−5-(4-chlorophenyl)−1-(2,4dichlorophenyl)−4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor”. Molecular Pharmacology 62 (6): 1274–87. doi:10.1124/mol.62.6.1274. PMID 12435794. [2] Hurst, D; Umejiego, U; Lynch, D; Seltzman, H; Hyatt, S; Roche, M; McAllister, S; Fleischer, D et al. (2006). “Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction”. Journal of Medical Chemistry 49 (20): 5969–87. doi:10.1021/jm060446b. PMID 17004712.
255
Chapter 192
VDM-11 VDM-11 is a potent cannabinoid reuptake inhibitor. It is light-sensitive and therefore must be stored within an inert gas such as argon, in a dark place and at an ideal temperature of −20°C.[1] This gold-colored substance is rarely found outside research laboratories.
192.1 See also • AM-404
192.2 References [1] VDM 11 at Sigma-Aldrich
256
Chapter 193
WIN 54,461 WIN 54,461 (6-Bromopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2 .[1]
193.1 See also • AM-630 (6-Iodopravadoline) • WIN 48,098 (Pravadoline) • WIN 55,212-2
193.2 References [1] Howlett AC, Berglund B, Melvin LS (October 1995). “Cannabinoid Receptor Agonists and Antagonists”. Current Pharmaceutical Design 1 (3): 343–352.
257
Chapter 194
WIN 55,212-2 WIN 55,212-2, along with HU-210 and JWH-133, may prevent the inflammation caused by amyloid beta proteins involved in Alzheimer’s disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through agonist action at cannabinoid receptors, which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglial activation in rat models. WIN 55,212-2 is a full agonist at the CB1 cannabinoid receptor (Kᵢ = 1.9 nM) and has much higher affinity than THC (Kᵢ = 41 nM) for this receptor.[10] WIN 55,212-2 reduces voluntary wheel running in laboratory mice, but with effects that depend on both genetic background and sex.[11]
194.1 See also • WIN 48,098 • WIN 54,461 • WIN 55,225 • WIN 56,098
Pancreatic stellate cells. The cells in the lower frame are under the action of WIN 55,212-2. They are thought to assume a more "quiescent" phenotype. From Michalski et al., 2008.[1]
194.2 References
WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.[2][3][4] WIN 55,212-2 is a potent cannabinoid receptor agonist[5] that has been found to be a potent analgesic[6] in a rat model of neuropathic pain.[7] It activates p42 and p44 MAP kinase via receptor-mediated signaling.[8] At 5 µM WIN 55,212-2 inhibit ATP production in sperm in a CB1 receptor-dependent fashion.[9] 258
[1] Michalski, C., et al. (2008). Gluud, Christian, ed. “Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells”. PLoS ONE 3 (2): e1701. Bibcode:2008PLoSO...3.1701M. doi:10.1371/journal.pone.0001701. PMC 2253501. PMID 18301776. [2] Compton DR, et al. Aminoalkylindole Analogs: Cannabimimetic Activity of a Class of Compounds Structurally Distinct from Δ9 -Tetrahydrocannabinol. Journal of Pharmacology and Experimental Therapeutics. 1992; 263(3):1118-1126. [3] Ferraro, L.; Tomasini, M. C.; Gessa, G. L.; Bebe, B. W.; Tanganelli, S.; Antonelli, T. (2001). “The Cannabinoid Receptor Agonist WIN 55,212-2 Regulates Glutamate Transmission in Rat Cerebral Cortex: An in Vivo
194.3. EXTERNAL LINKS
and in Vitro Study”. Cerebral Cortex 11 (8): 728–733. doi:10.1093/cercor/11.8.728. PMID 11459762. [4] Zhang, Q., et al. (2002). “In vitro metabolism of R(+)−2,3-dihydro-5-methyl-3(morpholinyl)methylpyrrolo 1,2,3-de1,4-benzoxazinyl(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist”. Drug metabolism and disposition: the biological fate of chemicals 30 (10): 1077–1086. doi:10.1124/dmd.30.10.1077. PMID 12228183. [5] Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; MacKie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R. L. (1995). “Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors”. Molecular pharmacology 48 (3): 443–450. PMID 7565624. [6] Meng, I. D.; Manning, B. H.; Martin, W. J.; Fields, H. L. (1998). “An analgesia circuit activated by cannabinoids”. Nature 395 (6700): 381–383. doi:10.1038/26481. PMID 9759727. [7] Herzberg, U.; Eliav, E.; Bennett, G. J.; Kopin, I. J. (1997). “The analgesic effects of R(+)-WIN 55,212–2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain”. Neuroscience Letters 221 (2–3): 157–160. doi:10.1016/S0304-3940(96)13308-5. PMID 9121688. [8] Bouaboula, M.; Poinot-Chazel, C.; Bourrié, B.; Canat, X.; Calandra, B.; Rinaldi-Carmona, M.; Le Fur, G.; Casellas, P. (1995). “Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1”. The Biochemical journal. 312 ( Pt 2) (Pt 2): 637– 641. PMC 1136308. PMID 8526880. [9] Morgan, D. J.; Muller, C. H.; Murataeva, N. A.; Davis, B. J.; MacKie, K. (2012). "Δ9-Tetrahydrocannabinol (Δ9THC) attenuates mouse sperm motility and male fecundity”. British Journal of Pharmacology 165 (8): 2575– 2583. doi:10.1111/j.1476-5381.2011.01506.x. PMC 3423255. PMID 21615727. [10] Kuster, J. E., et al. (1993). “Aminoalkylindole binding in rat cerebellum: selective displacement by natural and synthetic cannabinoids”. The Journal of Pharmacology and Experimental Therapeutics 264 (3): 1352–1363. PMID 8450470. [11] Keeney BK, et al. (2012). “Sex differences in cannabinoid receptor-1 (CB1) pharmacology in mice selectively bred for high voluntary wheel-running behavior”. Pharmacology, Biochemistry and Behavior 101: 528–537. doi:10.1016/j.pbb.2012.02.017.
194.3 External links • Enzo Life Sciences Win 55,212-2 Data Sheet • The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. 2006 Jul 18; PubMed 16849427
259 • JNeurosci.org Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation • New Scientist: Hope for cannabis-based drug for Alzheimer’s
Chapter 195
WIN 56,098 WIN 56,098 is a chemical that is considered to be an aminoalkylindole derivative. It is a tricyclic aryl derivative that acts as a competitive antagonist at the CB2 cannabinoid receptor. Its activity at CB1 was significantly less effective. WIN 56,098 failed to antagonize any of the in vivo effects of THC.[1]
195.1 See also • WIN 55,212-2 • WIN 55,225
195.2 References [1] Howlett AC, Berglund B, Melvin LS (October 1995). “Cannabinoid Receptor Agonists and Antagonists”. Current Pharmaceutical Design 1 (3): 343–352.
260
Chapter 196
XLR-11 (drug) 196.4 See also
Not to be confused with Reaction Motors XLR11. XLR-11 (5"-fluoro-UR-144) is a drug that acts as a potent agonist for the cannabinoid receptors CB1 and CB2 with a Kᵢ of 24.2nM and a EC50 of 359nM at CB1 . It is a 3-(tetramethylcyclopropylmethanoyl)indole derivative related to compounds such as UR-144, A-796,260 and A-834,735, but it is not specifically listed in the patent or scientific literature alongside these other similar compounds,[2][3] and appears to have not previously been made by Abbott Laboratories, despite falling within the claims of patent WO 2006/069196.
• JWH-018 • STS-135 • UR-144
196.5 References [1] SD HB1024 [2] WO application 2006069196, Pace JM, Tietje K, Dart MJ, Meyer MD, “3-Cycloalkylcarbonyl indoles as cannabinoid receptor ligands”, published 2006-06-29, assigned to Abbott Laboratories
196.1 Detection A forensic standard for this compound is available, and a representative mass spectrum has been posted on Forendex.[4] An ELISA immunoassay technique for detecting XLR-11 and UR-144 in blood and urine as part of general drug screens has been developed by Randox Laboratories and Tulip Biolabs, Inc.[5]
[3] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (January 2010). “Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity”. J. Med. Chem. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781. [4] “XLR-11”. Structural, chemical, and analytical data on controlled substances. Southern Association of Forensic Scientists (SAFS).
196.2 Recreational use XLR-11 was instead first identified by laboratories in 2012 as an ingredient in synthetic cannabis smoking blends, and appears to be a novel compound invented specifically for grey-market recreational use. It was banned in New Zealand by being added to the temporary class drug schedule, effective from 13 July 2012.[6] It has also been banned in Florida as of 11 December 2012.[7] Arizona banned XLR-11 on April 3, 2013.[8]
[5] “Randox Toxicology launches ELISA for the detection of new generation Synthetic Cannabinoids (Spice) drugs UR144 and XLR-11”. Press Release. Randox Laboratories Ltd. 2013-04-29. [6] “CB-13, MAM-2201, AKB48, and XLR11 are classified as temporary class drugs”. Temporary Class Drug Notice. The Department of Internal Affairs: New Zealand Gazette. 2012-07-05. [7] “News Release - Attorney General Pam Bondi Outlaws Additional Synthetic Drugs”. News Release. State of Florida. 2012-12-11.
196.3 Toxicity XLR-11 has been linked to acute kidney injury in some s,[9] along with AM-2201.[10][11] 261
[8] State of Arizona, Office of the Governor. azgovernor.gov http://azgovernor.gov/dms//PR_040313_ SyntheticDrugs.pdf |url= missing title (help). Retrieved 2014-08-27.
262
[9] “Alphabet Soup, or the newer synthetic cannabinoids...”. The Dose Makes The Poison Blog. 11 December 2013. Retrieved 18 September 2014. [10] Bhanushali GK, Jain G, Fatima H, Leisch LJ, ThornleyBrown D (April 2013). “AKI associated with synthetic cannabinoids: a case series”. Clin J Am Soc Nephrol 8 (4): 523–6. doi:10.2215/CJN.05690612. PMID 23243266. [11] “Acute Kidney Injury Associated with Synthetic Cannabinoid Use — Multiple States, 2012”. Morbidity and Mortality Weekly Report. U.S. Centers for Disease Control and Prevention (CDC). 2013-92-13. Retrieved 2013-02-15. Check date values in: |date= (help)
CHAPTER 196. XLR-11 (DRUG)
Chapter 197
AM251 AM-251 is an inverse agonist at the CB1 cannabinoid receptor. AM-251 is structurally very close to SR141716A (rimonabant); both are biarylpyrazole cannabinoid receptor antagonists. In AM-251 the p-chloro group attached to the phenyl substituent at C-5 of the pyrazole ring is replaced with a p-iodo group. The resulting compound exhibits slightly better binding affinity for the CB1 receptor (with a Kᵢ value of 7.5nM) than SR141716A, which has a Kᵢ value of 11.5nM, AM-251 is, however, about twofold more selective for the CB1 receptor when compared to SR141716A.[1]
197.1 See also • Discovery and development of Cannabinoid Receptor 1 Antagonists
197.2 References [1] Lan, R., Liu, Q., Fan, P., et al. Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42 769-776 (1999). PubMed 10052983
263
Chapter 198
Aminoalkylindole Aminoalkylindoles (AAIs) are a family of cannabinergic compound that act as a cannabinoid receptor agonist. They were invented by pharmaceutical company Sterling-Winthrop in the early 1990s as potential non-steroidal anti-inflammatory agents.[1]
198.1 Legality Aminoalkylindole are now commonly found in synthetic cannabis designer drugs.[2] In the United States, the DEA added the aminoalkylindole JWH-200 to Schedule I of the Controlled Substances Act on 1 March 2011 for 12 months.[2][3]
198.2 References [1] Emmanuel S. Onaivi (2006). Marijuana and Cannabinoid Research: Methods and Protocols. Springer. pp. 128–. ISBN 978-1-59259-999-8. [2] “Synthetic Cannabinoids”. American Association for Clinical Chemistry. 2013-02-01. Retrieved 2013-11-17. [3] “Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I”. Federal . 2011-03-01. Retrieved 2013-11-17.
198.3 External links • Aminoalkylindoles, ChEBI
264
Chapter 199
Cannabipiperidiethanone Cannabipiperidiethanone, (E, or 1(N-methylpiperidin-2-ylmethyl)−3-(2methoxyphenylacetyl)indole), is a synthetic cannabinoid that has been found as an ingredient of “herbal” synthetic cannabis blends sold in Japan, alongside JWH122 and JWH-081. Its binding affinity was measured at the CB1 and CB2 receptors and it was found to have an IC50 of 591nM at CB1 and 968nM at CB2 , making it 2.3x and 9.4x weaker than JWH-250 at these two targets respectively.[1]
199.1 See also • AM-1220 • AM-1248 • AM-2233 • JWH-203 • RCS-8
199.2 References [1] Uchiyama N, Kikura-Hanajiri R, Goda Y (2011). “Identification of a novel cannabimimetic phenylacetylindole, cannabipiperidiethanone, as a designer drug in a herbal product and its affinity for cannabinoid CB₁ and CB₂ receptors”. Chemical & Pharmaceutical Bulletin 59 (9): 1203–5. doi:10.1248/b.59.1203. PMID 21881274.
265
Chapter 200
JWH-193 JWH-193 is a drug from the aminoalkylindole family which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sanofi-Winthrop in the early 1990s. JWH-193 has a binding affinity at the CB1 receptor of 6nM, binding around seven times more tightly than the parent compound JWH-200,[1] though with closer to twice the potency of JWH-200 in activity tests. A structural isomer of JWH-193 with the methyl group on the indole ring instead of the naphthoyl ring, was also found to be of similarly increased potency over JWH-200.[2][3]
• JWH-198
200.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. [2] Eissenstat MA, et al. (August 1995). “Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics”. Journal of Medicinal Chemistry 38 (16): 3094–105. doi:10.1021/jm00016a013. PMID 7636873. [3] Shim JY, et al. (November 1998). “Three-dimensional quantitative structure-activity relationship study of the cannabimimetic (aminoalkyl)indoles using comparative molecular field analysis”. Journal of Medicinal Chemistry 41 (23): 4521–32. doi:10.1021/jm980305c. PMID 9804691.
6-Methyl-JWH-200
200.1 See also • JWH-122 266
Chapter 201
JWH-198 JWH-198 is a drug from the aminoalkylindole family which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sanofi-Winthrop in the early 1990s. JWH-198 has a binding affinity at the CB1 receptor of 10nM, binding around four times more tightly than the parent compound JWH-200, which has no substitution on the naphthoyl ring.[1] It has been used mainly in molecular modelling of the cannabinoid receptors.[2][3]
201.1 See also • JWH-081 • JWH-193
201.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. [2] Eissenstat MA, et al. (August 1995). “Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics”. Journal of Medicinal Chemistry 38 (16): 3094–105. doi:10.1021/jm00016a013. PMID 7636873. [3] Shim JY, et al. (November 1998). “Three-dimensional quantitative structure-activity relationship study of the cannabimimetic (aminoalkyl)indoles using comparative molecular field analysis”. Journal of Medicinal Chemistry 41 (23): 4521–32. doi:10.1021/jm980305c. PMID 9804691.
267
Chapter 202
JWH-200 JWH-200 (WIN 55,225)[1] is an analgesic chemical from the aminoalkylindole family that acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is 42nM, around the same as that of THC,[2] but its analgesic potency in vivo was higher than that of other analogues with stronger CB1 binding affinity in vitro,[3] around 3 times that of THC but with less sedative effect,[4] most likely reflecting favourable pharmacokinetic characteristics. It was discovered by, and named after, Dr. John W. Huffman. The US DEA temporarily declared JWH-200 a schedule I controlled substance on 1 March 2011 through 76 FR 11075, and permanently instated the same schedule on 9 July 2012 in the Section 1152 of the Food and Drug istration Safety and Innovation Act.[5] As of 26 June 2011, the drug is legal in Canada.[6]
202.1 See also • JWH-018 • JWH-073 • -47,497 • HU-210 • A-796,260 • WIN 55,212-2
202.2 References [1] Dutta, A. K. , E. A. ; Ryan, W.; Thomas, B. F.; Singer, M.; Compton, D. R.; Martin, B. R.; Razdan, R. K. (1997). “Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs)". Bioorganic & Medicinal Chemistry 5 (8): 1591–1600. doi:10.1016/S0968-0896(97)00111-9. PMID 9313864. [2] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411.
268
[3] Bell, MR, et al.. “Antinociceptive (aminoalkyl)indoles”. Journal of Medicinal Chemistry 34 (3): 1099–1110. doi:10.1021/jm00107a034. PMID 1900533. [4] Compton, DR, et al. (1992). “Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol”. Journal of Pharmacology and Experimental Therapeutics 263 (3): 1118–26. PMID 1335057. [5] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [6] http://laws.justice.gc.ca/en/C-38.8/
Chapter 203
Pravadoline Pravadoline (WIN 48,098) is an antiinflammatory and analgesic drug with an IC50 of 4.9 µM and a Kᵢ of 2511nM at CB1 , related in structure to non-steroidal antinflammtory drugs (NSAIDs) such as indometacin. It was developed in the 1980s as a new antiinflammatory and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase (COX). However, pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as a COX inhibitor. These effects were not blocked by opioid antagonists such as naloxone,[1] and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonists, the aminoalkylindoles.[2] Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself),[3] however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drug WIN 55,212-2, which is now widely used in scientific research.[4][5]
The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadolineinduced antinociception was not antagonized by naloxone (1 mg/kg, s.c.) and pravadoline did not bind to the opioid receptors at concentrations up to 10μM.[1]
203.2 See also • AM-630 (6-iodopravadoline) • WIN 54,461 (6-bromopravadoline) • WIN 55,212-2 • RCS-4 (1-pentyl-3-(4-methoxybenzoyl)indole)
203.3 References [1] Haubrich DR, et al. (1990). “Pharmacology of pravadoline: a new analgesic agent”. J. Pharmacol. Exp. Ther. 255 (2): 511–22. PMID 2243340. [2] Bell MR, et al. (1991). “Antinociceptive (aminoalkyl)indoles”. J. Med. Chem. 34 (3): 1099–110. doi:10.1021/jm00107a034. PMID 1900533. [3] Everett RM, et al. (1993). “Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: evidence of maleic acid-induced acute tubular necrosis”. Fundam Appl Toxicol 21 (1): 59–65. doi:10.1006/faat.1993.1072. PMID 8365586.
203.1 Animal studies istration of pravadoline on rats showed:[1] • Prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees Celsius (minimum effective dose, 100 mg/kg s.c.) • Prevented hyperalgesia in rats with Brewer’s Yeast injections during (Randall-Selitto test) (minimum effective dose, 1 mg/kg, p.o.) • Prevented the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50,41 mg/kg, p.o.) • Prevented the nociceptive response of bradykinininduced head and forepaw flexion (ED50, 78 mg/kg, p.o.) 269
[4] D'Ambra TE, et al. (1992). “Conformationally restrained analogues of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor”. J. Med. Chem. 35 (1): 124–35. doi:10.1021/jm00079a016. PMID 1732519. [5] Compton DR, et al. (1992). “Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol”. J. Pharmacol. Exp. Ther. 263 (3): 1118–26. PMID 1335057.
Chapter 204
RCS-4 RCS-4, or 1-pentyl-3-(4-methoxybenzoyl)indole, is a synthetic cannabinoid drug sold under the names SR-19, BTM-4, or Eric-4 (later shortened to E-4), but originally, OBT-199.
204.2 See also • AM-630 • AM-679 • RCS-8 • Pravadoline (WIN 48,098)
204.1 Legality RCS-4 was banned in Sweden on 1 October 2010 as a hazardous good harmful to health, after being identified as an ingredient in “herbal” synthetic cannabis products.[2][3] It was outlawed in Denmark on 11 March 2011.[4] In August 2011, New Zealand added not only RCS-4 but also its 1-butyl homologue, and the 2methoxybenzoyl isomers of both these compounds, to a temporary class drug schedule (i.e. equivalent to Class C but reviewed after 12 months, and with personal possession and use of small amounts decriminalised), which was newly created under the Misuse of Drugs Amendment Act 2011 ed a week earlier.[5][6][7]
204.3 References [1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 12 June 2011. [2] Swedish Code of Statutes Regulation (2010:1086). [3] Swedish Code of Statutes Regulation (2010:1086). (pdf) [4] http://laegemiddelstyrelsen.dk/~{}/media/ AC4F04EB48F74523A76BA84DAB9B6067.ashx [5] “Kronic ban ed by Parliament”. The New Zealand Herald. NZPA. 4 August 2011. Retrieved 4 November 2011. [6] “Synthetic cannabis off shelves by Wednesday”. The New Zealand Herald. NZPA. 9 August 2011. Retrieved 4 November 2011. [7] New Zealand Gazette. Tuesday 9 August 2011. Issue No 122, pp 3365-3366. Departmental Notices. Health. Misuse of Drugs Act 1975. Temporary Class Drug Notice.
RCS-4 and related analogues detected in synthetic cannabis blends
270
Chapter 205
Anandamide Anandamide, also known as Narachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word (and Hinduistic religious term) ananda, which means “joy, bliss, delight", and amide.[1][2] It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.[3] It is degraded primarily by the fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.[4][5]
205.1 History It was isolated and its structure first described in 1992 by W. A. Devane, Lumír Hanuš et al. who were working in a team led by Raphael Mechoulam at the Hebrew University of Jerusalem.[6]
205.2 Physiological functions Anandamide’s effects can be either central, in the brain, or peripheral, in other parts of the body. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[7] The latter are mainly involved in functions of the immune system. Cannabinoid receptors were originally discovered as being sensitive to Δ9 -tetrahydrocannabinol (Δ9 -THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors.
uterus. Therefore cannabinoids such as Δ9 -THC might influence processes during the earliest stages of human pregnancy.[9] Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and gonadotrophin levels, suggesting that these may be involved in the regulation of AEA (anandamide) levels.[10] Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.[11] Anandamide plays a role in the regulation of feeding behavior, and the neural generation of motivation and pleasure. In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[7][12] A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.[13] Some studies have linked anandamide release as a mechanism of analgesic effects induced by exercise, particularly by running.[14] In 1996, researchers discovered anandamide in chocolate. They also detected the presence of two substances that might mimic the effects of anandamide, Noleoylethanolamine and N-linoleoylethanolamine.[15]
205.3 Synthesis and degradation The human body synthesizes anandamide from Narachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.[16][17] Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD.[3]
Anandamide has been shown to impair working memory in rats.[8] Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief.
Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free arachidonic acid and ethanolamine. StudAnandamide is also important for implantation of the ies of piglets show that dietary levels of arachidonic acid early stage embryo in its blastocyst form into the and other essential fatty acids affect the levels of anan271
272 damide and other endocannabinoids in the brain.[18] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[19] This suggests that anandamide may play a role in the development of obesity, at least in rodents. Paracetamol (or acetaminophen in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form AM404.[20] This metabolite of paracetamol is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. As a result, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the analgesic effects of paracetamol.[21][22] There have been identified transport proteins for anandamide and its sister molecule 2-arachidonoylglycerol. These include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs).[23][24]
205.4 Medical benefits The Royal Society of Chemistry have stated that research indicates that AM1172 could potentially be developed into a drug that would increase the brain’s anandamide levels to help treat anxiety and depression.[25]
205.5 See also • Cannabinoids • Virodhamine • Tetrahydrocannabinol (THC) • 2-Arachidonoylglycerol • Fatty acid amide hydrolase • Endocannabinoid transporters • Raphael Mechoulam
205.6 References [1] Devane WA et al. (December 1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science 258 (5090): 1946–9. doi:10.1126/science.1470919. PMID 1470919. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help); |first8= missing |last8= in Authors list (help); |first9= missing |last9= in Authors list (help); |first10= missing |last10= in Authors list (help)
CHAPTER 205. ANANDAMIDE
[2] Mechoulam R, Fride E (1995). “The unpaved road to the endogenous brain cannabinoid ligands, the anandamides”. In Pertwee RG. Cannabinoid receptors. Boston: Academic Press. pp. 233–258. ISBN 0-12-551460-3. [3] Wang, J.; Ueda, N. (2009). “Biology of endocannabinoid synthesis system”. Prostaglandins & Other Lipid Mediators 89 (3–4): 112–119. doi:10.1016/j.prostaglandins.2008.12.002. PMID 19126434. [4] Gaetani, S.; Dipasquale, P.; Romano, A.; Righetti, L.; Cassano, T.; Piomelli, D.; Cuomo, V. (2009). “Chapter 5 The Endocannabinoid System as A Target for Novel Anxiolytic and Antidepressant Drugs”. “International Review of Neurobiology - 85”. International Review of Neurobiology 85. pp. 57–13. doi:10.1016/S00747742(09)85005-8. ISBN 9780123748935. [5] Hwang, J.; Adamson, C.; Butler, D.; Janero, D. R.; Makriyannis, A.; Bahr, B. A. (2009). “Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: A neuroprotective therapeutic Life Sciences 86 (15–16): 615–623. modality”. doi:10.1016/j.lfs.2009.06.003. PMC 2848893. PMID 19527737. [6] Mechoulam, WA; Hanus L; Breuer A; Pertwee RG; Stevenson LA; Griffin G; Gibson D; Mandelbaum A; Etinger A; Mechoulam R (December 1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science 258 (5090): 1946–9. Bibcode:1992Sci...258.1946D. doi:10.1126/science.1470919. PMID 1470919. [7] Pacher P, Batkai S, Kunos G; Bátkai; Kunos (2006). “The Endocannabinoid System as an Emerging Target of Pharmacotherapy”. Pharmacol Rev. 58 (3): 389– 462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947. [8] allet PE, Beninger RJ; Beninger (1996). “The endogenous cannabinoid receptor agonist anandamide impairs memory in rats”. Behavioural Pharmacology 7 (3): 276–284. doi:10.1097/00008877-199605000-00008. [9] Piomelli D (January 2004). “THC: moderation during implantation”. Nat. Med. 10 (1): 19–20. doi:10.1038/nm0104-19. PMID 14702623. [10] El-Talatini MR, Taylor AH, Konje JC; Taylor; Konje (April 2010). “The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle”. Fertil. Steril. 93 (6): 1989–96. doi:10.1016/j.fertnstert.2008.12.033. PMID 19200965. [11] Rapino, C.; Battista, N.; Bari, M.; Maccarrone, M. (2014). “Endocannabinoids as biomarkers of human reproduction”. Human Reproduction Update 20 (4): 501– 516. doi:10.1093/humupd/dmu004. ISSN 1355-4786. PMID 24516083. [12] Mahler SV, Smith KS, Berridge KC; Smith; Berridge (November 2007). “Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances 'liking' of a sweet
205.7. EXTERNAL LINKS
reward”. Neuropsychopharmacology 32 (11): 2267–78. doi:10.1038/sj.npp.1301376. PMID 17406653. [13] De Petrocellis L et al. (July 1998). “The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation”. Proc. Natl. Acad. Sci. U.S.A. 95 (14): 8375–80. doi:10.1073/pnas.95.14.8375. PMC 20983. PMID 9653194. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help) [14] http://www.harford.de/arne/articles/NeuroReport.pdf [15] di Tomaso E, Beltramo M, Piomelli D.; Beltramo; Piomelli (Aug 1996). “Brain cannabinoids in chocolate”. Nature 382 (6593): 677–8. doi:10.1038/382677a0. PMID 8751435. [16] Natarajan V, Reddy PV, Schmid PC, Schmid HH; Reddy; Schmid; Schmid (August 1982). “NAcylation of ethanolamine phospholipids in canine myocardium”. Biochim. Biophys. Acta 712 (2): 342–55. doi:10.1016/0005-2760(82)90352-6. PMID 7126608. [17] Cadas H, di Tomaso E, Piomelli D; Di Tomaso; Piomelli (February 1997). “Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain”. J. Neurosci. 17 (4): 1226–42. PMID 9006968. [18] Berger A et al. (May 2001). “Anandamide and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding Nacylethanolamines in piglets”. Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6402–6. doi:10.1073/pnas.101119098. PMC 33480. PMID 11353819. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help) [19] Osei-Hyiaman D et al. (May 2005). “Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity”. J. Clin. Invest. 115 (5): 1298–305. doi:10.1172/JCI23057. PMC 1087161. PMID 15864349. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help); |first8= missing |last8= in Authors list (help); |first9= missing |last9= in Authors list (help); |first10= missing |last10= in Authors list (help); |first11= missing |last11= in Authors list (help) [20] Högestätt, E. D.; Jönsson, B. A.; Ermund, A.; Andersson, D. A.; Björk, H.; Alexander, J. P.; Cravatt, B. F.; Basbaum, A. I.; Zygmunt, P. M. (2005). “Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System” (pdf). Journal of Biological Chemistry 280 (36): 31405–31412. doi:10.1074/jbc.M501489200. PMID 15987694.
273
[21] Bertolini A et al. (2006). “Paracetamol: new vistas of an old drug”. CNS Drug Rev 12 (3–4): 250– 75. doi:10.1111/j.1527-3458.2006.00250.x. PMID 17227290. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help) [22] Sinning C et al. (December 2008). “New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra5,8,11,14-enamide”. J. Med. Chem. 51 (24): 7800–5. doi:10.1021/jm800807k. PMID 19053765. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help); |first8= missing |last8= in Authors list (help) [23] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). “Identification of intracellular carriers for the endocannabinoid anandamide”. Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565. [24] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgro, A.; Maccarrone, M. (2009). “Molecular identification of albumin and Hsp70 as cytosolic anandamidebinding proteins”. Chemistry & Biology 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. [25] http://www.rsc.org/chemistryworld/Issues/2004/July/ anandamide.asp
205.7 External links • Could anandamide be the missing link to “runner’s high"? Accessed 2008-10-18
Chapter 206
N-Arachidonoyl dopamine N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor[1] and the transient receptor potential V1 (TRPV1) ion channel. Its discovery was described in 2002 by an academic research group from Italy and the USA. It was found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50nM. The high potency makes it the putative endogenous TRPV1 agonist.[2]
206.1 See also • Endocannabinoid
206.2 References [1] Ralevic V (July 2003). “Cannabinoid modulation of peripheral autonomic and sensory neurotransmission”. European Journal of Pharmacology 472 (1–2): 1–21. doi:10.1016/S0014-2999(03)01813-2. PMID 12860468. [2] Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V (June 2002). “An endogenous capsaicinlike substance with high potency at recombinant and native vanilloid VR1 receptors”. Proceedings of the National Academy of Sciences of the United States of America 99 (12): 8400–5. doi:10.1073/pnas.122196999. PMC 123079. PMID 12060783.
206.3 External links • General information about NADA.
274
Chapter 207
2-Arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor.[1][2] It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994-1995, although had been discovered some time before that. The activities of Phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).
207.3 Pharmacology
Unlike anandamide, formation of 2-AG is calciumdependent and is mediated by the activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL).[2] 2-AG acts as a full agonist at the CB1 receptor.[10] At a concentration of 0.3nM, 2-AG induces a rapid, transient increase in intracellular free calcium in NG108-15 neuroblastoma X glioma cells through a CB1 receptor-dependent mechanism.[2] 2-AG is hydrolyzed in vitro by monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and the uncharacterized serine hydrolase enzymes ABHD6 and ABHD12.[11] The exact contribution of each of these enzymes to the termination of 2-AG signaling in vivo is unknown, 207.1 Occurrence though it is estimated that MAGL is responsible for ~85% of this activity in the brain.[12] There have been 2-AG, unlike anandamide (another endocannabinoid), is identified transport proteins for 2-arachidonoylglycerol present at relatively high levels in the central nervous sys- and anandamide. These include the heat shock proteins tem; it is the most abundant molecular species of monoa- (Hsp70s) and fatty acid binding proteins (FABPs).[13][14] cylglycerol found in mouse and rat brain (~5-10 nmol/g tissue).[2][3] Detection of 2-AG in brain tissue is complicated by the relative ease of its isomerization to 1-AG 207.4 Biosynthesis during standard lipid extraction conditions. It has been found in maternal bovine and human milk.[4] 2-Arachidonoylglycerol is synthesized from arachidonic acid-containing diacylglycerol (DAG), which is derived from the increase of inositol phospholipid metabolism by the action of diacylglycerol lipase. The molecule 207.2 Discovery can also be formed from pathways like the hydrolysis Shimon Ben-Shabat, of Ben-Gurion University, discov- derived (by diglyceride) from both phosphatidylcholine ered the chemical.[5] 2-AG was a known chemical com- (PC) and phosphatidic acid (PAs) by the action of DAG pound but its occurrence in mammals and its affinity for lipase and the hydrolysis of arachidonic acid-containing [15] the cannabinoid receptors were first described in 1994- lysophosphatidic acid by the action of a phosphatase. 1995. A research group at Teikyo University reported the affinity of 2-AG for the cannabinoid receptors in 1994-1995,[6][7] but the isolation of 2-AG in the canine gut was first reported in 1995 by the research group of Raphael Mechoulam at the Hebrew University of Jerusalem, which additionally characterized its pharmacological properties in vivo.[8] 2-Arachidonoylglycerol, next with Anandamide, was the second endocannabinoid discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system.[9]
207.5 See also • 2-Arachidonoyl glyceryl ether • Endocannabinoid transporters
207.6 References
275
276
207.6.1
CHAPTER 207. 2-ARACHIDONOYLGLYCEROL
Notes
[1] Stella N, Schweitzer P, Piomelli D (August 1997). “A second endogenous cannabinoid that modulates longterm potentiation”. Nature 388 (6644): 773–8. doi:10.1038/42015. PMID 9285589. [2] Sugiura T, Kodaka T, Nakane S, et al. (January 1999). “Evidence that the cannabinoid CB1 receptor is a 2arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds”. The Journal of Biological Chemistry 274 (5): 2794–801. doi:10.1074/jbc.274.5.2794. PMID 9915812. [3] Kondo S, Kondo H, Nakane S, et al. (June 1998). “2Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and independent mechanisms”. FEBS Letters 429 (2): 152–6. doi:10.1016/S0014-5793(98)00581-X. PMID 9650580. [4] Fride E, Bregman T, Kirkham TC. (April 2005). “Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood”. Experimental Biology and Medicine 230 (4): 225–234. PMID 15792943. [5] Pizzorno, Lara; MDiv; MA; LMT. “New Developments in Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam”. Longevity Medicine Review. Retrieved 2011-05-26. [6] Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Proceedings of Japanese conference on the Biochemistry of Lipids, 36, 71-74 (in Japanese) [7] Sugiura T, Kondo S, Sukagawa A, et al. (October 1995). “2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain”. Biochem. Biophys. Res. Commun. 215 (1): 89–97. doi:10.1006/bbrc.1995.2437. PMID 7575630. Retrieved 2009-01-27. [8] Mechoulam R, Ben-Shabat S, Hanuš L, et al. (June 1995). “Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors”. Biochemical pharmacology 50 (1): 83–90. doi:10.1016/0006-2952(95)00109-D. PMID 7605349. [9] Marzo, Vincenzo Di (2004). Cannabinoids (Neuroscience Intelligence Unit) (1st ed.). Georgetown, Texas: Springer. pp. 99, 181. ISBN 978-0-306-48228-1. [10] Savinainen JR, Järvinen T, Laine K, Laitinen JT (October 2001). “Despite substantial degradation, 2arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes”. British Journal of Pharmacology 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC 1572991. PMID 11588122. [11] Blankman JL, Simon GM, Cravatt BF (Decem“A comprehensive profile of brain ber 2007). enzymes that hydrolyze the endocannabinoid 2arachidonoylglycerol”. Chemistry & biology 14 (12): 1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC 2692834. PMID 18096503.
[12] Savinainen, JR; Saario, SM; Laitinen, JT (2012). “The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors”. Acta physiologica (Oxford, England) 204 (2): 267–76. doi:10.1111/j.17481716.2011.02280.x. PMC 3320662. PMID 21418147. [13] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). “Identification of intracellular carriers for the endocannabinoid anandamide”. Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565. [14] Oddi, S.; Fezza, F.; Pasquariello, N.; d'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgrò, A.; MacCarrone, M. (2009). “Molecular identification of albumin and Hsp70 as cytosolic anandamidebinding proteins”. Chemistry & Biology 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. [15] Köfalvi, Attila (2008). Cannabinoids and the Brain. New York City: Axel Springer AG. p. 15. ISBN 978-0-38774348-6. “2-Arachidonoylglycerol can be synthesized from arachidonic acid-containing diacylglycerol derived from increaded inositol phospholid metabolism by the action of a diacylglycerol lipase. 2-Arachidonoylglycerol can also be formed via other pathways such as the hydrolysis of the diaclygly derived from PC and phosphatidic acid by the action of a diacyglycerol lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic acid by the action of a phosphatase. The relative importance of these pathways may depend on the types of cells and stimuli.”
207.6.2 General references • Dinh TP, Carpenter D, Leslie FM, et al. (August 2002). “Brain monoglyceride lipase participating in endocannabinoid inactivation”. Proceedings of the National Academy of Sciences of the United States of America 99 (16): 10819– 24. doi:10.1073/pnas.152334899. PMC 125056. PMID 12136125.
Chapter 208
2-Arachidonyl glyceryl ether 2-Arachidonyl glyceryl ether (2-AGE, Noladin ether) is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem, Israel. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001.[1]
208.1 Discovery
receptors.[2] The presence of 2-AGE in body tissue is disputed. Although a research group from Teikyo University, Kanagawa, Japan could not detect it in the brains of mice, hamsters, guinea-pigs or pigs,[3] two other research groups successfully detected it in animal tissues.[4][5]
208.3 Pharmacology
Lumír Hanuš, Saleh Abu-Lafi, Ester Fride, Aviva Breuer, Zvi Vogel, Deborah E. Shalev, Irina Kustanovich, and Raphael Mechoulam found the endogenous agonist of the cannabinoid receptor type 1 (CB1) in 2000. The discovery was 100 gram of porcine brain, (approximately a single brain) was added to a mixture of 200 mL of chloroform and 200 mL of methanol and mixed in a laboratory blender for 2 minutes. 100 mL of Water was then added, and the mixing process continued for another minute. After this, the mixture was filtered. Two layers then formed and the layer of water-methanol was separated and evaporated when pressure was reduced. Synaptosomal membranes were prepared from 250g of the brains of Sabra male rats. A Hewlett Packard G 1800B GCD system that has a HP-5971 GC with electron ionization detector was used.[1]
2-AGE binds with a Kᵢ of 21 nM to the CB1 receptor[1] and 480 nM to the CB2 receptor.[6] It shows agonistic behaviour on both receptors and is a partial agonist for the TRPV1 channel.[7] After binding to CB2 receptors it inhibits adenylate cyclase and stimulates ERK-MAPK and regulates calcium transients.[8] In comparison to 2arachidonoyl glycerol, noladin is metabolically more stable resulting in a longer half-life.[9] It lowers Intraocular pressure,[9] increases the uptake of GABA in the globus pallidus of rats[10] and is neuroprotective by binding to and activation of PPARα.[11]
208.4 See also • 2-Arachidonoylglycerol
208.2 Production 208.5 References The production of the endocannabinoid is enhanced in normal, but not in endothelium-denuded rat aorta on reacting with carbachol, an parasympathomimetic drug. It potently reduces blood pressure in rats and may represent an endothelium-derived hypotension factor.[1] 2-Arachidonyl glyceryl ether’s structure can be determined by mass spectrometry and Rutherford backscattering spectrometry. It was confirmed by comparison with a synthetic sample of the endocannabinoid. It binds to the Cannabinoid receptor type 1 (Ki = 21.2 ± 0.5 nM), which causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice.[1] The endocannabinoid exhibits Ki values of 21.2 nM and >3 µM at the Cannabinoid receptor type 1 and the peripheral cannabinoid 277
[1] Hanus, L.; Abu-Lafi, S.; Fride, E.; Breuer, A.; Vogel, Z.; Shalev, D.; Kustanovich, I.; Mechoulam, R. (2001). “2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor”. Proceedings of the National Academy of Sciences 98 (7): 3662–3665. doi:10.1073/pnas.061029898. PMC 31108. PMID 11259648. [2] “2-Arachidonyl Glycerol ether · Noladin; 2-AG ether (CAS 222723-55-9) || Cayman Chemical”. Cayman Chemical. Retrieved 2011-05-29. [3] Oka S, Tsuchie A, Tokumura A et al. (2003). “Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various
278
CHAPTER 208. 2-ARACHIDONYL GLYCERYL ETHER
mammalian species”. J. Neurochem. 85 (6): 1374– 81. doi:10.1046/j.1471-4159.2003.01804.x. PMID 12787057. [4] Fezza F, Bisogno T, Minassi A, Appendino G, Mechoulam R, Di Marzo V (2002). “Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues”. FEBS Lett. 513 (2–3): 294–8. doi:10.1016/S00145793(02)02341-4. PMID 11904167. [5] Richardson D, Ortori CA, Chapman V, Kendall DA, Barrett DA (2007). “Quantitative profiling of endocannabinoids and related compounds in rat brain using liquid chromatography-tandem electrospray ionization mass spectrometry”. Anal. Biochem. 360 (2): 216–26. doi:10.1016/j.ab.2006.10.039. PMID 17141174. [6] Shoemaker JL, Joseph BK, Ruckle MB, Mayeux PR, Prather PL (2005). “The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors”. J. Pharmacol. Exp. Ther. 314 (2): 868–75. doi:10.1124/jpet.105.085282. PMID 15901805. [7] Duncan M, Millns P, Smart D, Wright JE, Kendall DA, Ralevic V (2004). “Noladin ether, a putative endocannabinoid, attenuates sensory neurotransmission in the rat isolated mesenteric arterial bed via a non-CB1/CB2 Gi/o linked receptor”. Br. J. Pharmacol. 142 (3): 509– 18. doi:10.1038/sj.bjp.0705789. PMC 1574960. PMID 15148262. [8] Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL (2005). “Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors”. J. Pharmacol. Exp. Ther. 315 (2): 828–38. doi:10.1124/jpet.105.089474. PMID 16081674. [9] Laine K, Järvinen K, Mechoulam R, Breuer A, Järvinen T (2002). “Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid”. Invest. Ophthalmol. Vis. Sci. 43 (10): 3216–22. PMID 12356827. [10] Venderova K, Brown TM, Brotchie JM (2005). “Differential effects of endocannabinoids on [(3)H]-GABA uptake in the rat globus pallidus”. Exp. Neurol. 194 (1): 284–7. doi:10.1016/j.expneurol.2005.02.012. PMID 15899265. [11] Sun Y, Alexander SP, Garle MJ et al. (2007). “Cannabinoid activation of PPARα; a novel neuroprotective mechanism”. Br. J. Pharmacol. 152 (5): 734– 43. doi:10.1038/sj.bjp.0707478. PMC 2190030. PMID 17906680.
208.6 External links • Commercial supplier of Noladin ether
Chapter 209
Oleamide Oleamide is an amide of the fatty acid oleic acid. It is an endogenous substance: it occurs naturally in the body of animals. It accumulates in the cerebrospinal fluid during sleep deprivation and induces sleep in animals.[4] It is being studied as a potential medical treatment for mood and sleep disorders, and cannabinoidregulated depression.[5][6]
[2] http://www.chemicalbook.com/ ProductChemicalPropertiesCB3238286_EN.htm [3] http://www.chemspider.com/Chemical-Structure. 4446508.html [4] Salvador Huitron-Resendiz, Lhys Gombart, Benjamin F. Cravatt, and Steven J. Henriksen (2001). “Effect of Oleamide on Sleep and Its Relationship to Blood Pressure, Body Temperature, and Locomotor Activity in Rats”. Experimental Neurology 172 (1): 235–243. doi:10.1006/exnr.2001.7792. PMID 11681856.
The mechanism of action of oleamide’s sleep inducing effects is an area of current research. It is likely that oleamide interacts with multiple neurotransmitter systems.[7] Oleamide is structurally related to the endogenous cannabinoid anandamide, and has the ability to bind to the CB1 receptor as a full agonist.
[5] Methods of treating anxiety and mood disorders with oleamide - US Patent 6359010 [6] Raphael Mechoulam, Ester Fride, Lumír Ondřej Hanuš, Tzviel Sheskin, Tiziana Bisogno, Vincenzo Di Marzo, Michael Bayewitch and Zvi Vogel (1997). “Anandamide may mediate sleep induction”. Nature 389 (6646): 25–26. doi:10.1038/37891. PMID 9288961.
Synthetically produced oleamide has a variety of industrial uses including as a slip agent, a lubricant, and a corrosion inhibitor.[8] Oleamide was originally characterized as an endogenous bioactive substance, isolated from the cerebrospinal fluid of sleep deprived cats. It was characterised in 1995 by Benjamin Cravatt III and Richard Lerner at The Scripps Research Institute in La Jolla, CA.[9]
[7] Fedorova I, Hashimoto A, Fecik RA et al. (2001). “Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems”. J. Pharmacol. Exp. Ther. 299 (1): 332–42. PMID 11561096.
Oleamide was found by researchers to be leaking out of polypropylene plastics used in laboratory experiments, affecting experimental results.[10] Since polypropylene is used in a wide number of food containers such as those for yogurt, the problem is being studied.[11]
[8] Surfactants : Westco Oleamide a Slip Agent In Polyethylene Films [9] Cravatt BF, et al. (June 1995). “Chemical characterization of a family of brain lipids that induce sleep”. Science 268 (5216): 1506–9. doi:10.1126/science.7770779. PMID 7770779.
A chemical analysis of 44 products containing synthetic cannabinoid drugs marketed as “herbal incense” revealed oleamide in 7 of the products tested.[12] [10] McDonald, RG. et al. (2008). “Bioactive Contaminants
Leach from Disposable Laboratory Plasticware”. Science 322 (5903): 917. doi:10.1126/science.1162395. PMID 18988846.
209.1 See also • Anandamide • Fatty acid amide hydrolase • Virodhamine
209.2 References
[11] Mittelstaedt, Martin (6 November 2008). “Researchers Raise Alarm After Chemical Leak Found In Common Plastic”. Globe and Mail. Retrieved 10 June 2013. [12] Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Ogata, Jun; Goda, Yukihiro (2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1–3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892.
[1] Oleamide at chemicalland21.com
279
Chapter 210
RVD-Hpα RVD-Hpα is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-ValAsn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist.[1] All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide.[2] Recently it was shown that RVD-Hpα (also called Pepcan-12) is an potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans) [3]
210.1 References [1] Heimann, A.; Gomes, I.; Dale, C.; Pagano, R.; Gupta, A.; De Souza, L.; Luchessi, A.; Castro, L.; Giorgi, R.; Rioli, V.; Ferro, E. S.; Devi, L. A. (2007). “Hemopressin is an inverse agonist of CB1 cannabinoid receptors”. Proceedings of the National Academy of Sciences of the United States of America 104 (51): 20588–20593. Bibcode:2007PNAS..10420588H. doi:10.1073/pnas.0706980105. PMC 2154475. PMID 18077343. [2] Gomes, I.; Grushko, J.; Golebiewska, U.; Hoogendoorn, S.; Gupta, A.; Heimann, A.; Ferro, E.; Scarlata, S.; Fricker, L.; Devi, L. A. (2009). “Novel endogenous peptide agonists of cannabinoid receptors”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 (9): 3020– 3029. doi:10.1096/fj.09-132142. PMC 2735371. PMID 19380512. [3] Bauer, M.; Chicca, A.; Tamborrini, M.; Eisen, D.; Lerner, R.; Lutz, B.; Poetz, O.; Pluschke, G.; Gertsch, J. (2012). “Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors”.
280
Journal of Biological Chemistry 287 (44): 36944–36967. doi:10.1074/jbc.M112.382481. PMC 3481297. PMID 22952224.
Chapter 211
Virodhamine Virodhamine (O-arachidonoyl ethanolamine) is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. O-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine ed by an ester linkage, the opposite of the amide linkage found in anandamide. Based on this opposite orientation, the molecule was named virodhamine from the Sanskrit word virodha, which means opposition. It acts as an antagonist of the CB1 receptor and agonist of the CB2 receptor. Concentrations of virodhamine in the human hippocampus are similar to those of anandamide, but they are 2to 9-fold higher in peripheral tissues that express CB2 . Virodhamine lowers body temperature in mice, demonstrating cannabinoid activity in vivo.[1]
211.1 See also • Anandamide • Oleamide
211.2 References [1] Porter AC, Sauer JM, Knierman MD et al. (2002). “Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor”. J. Pharmacol. Exp. Ther. 301 (3): 1020– 4. doi:10.1124/jpet.301.3.1020. PMID 12023533. Retrieved 2007-10-31.
281
Chapter 212
HU-320 HU-320 is a drug related to cannabidiol, which has strong antiinflammatory and immunosuppressive properties while demonstrating no psychoactive effects.[1]
212.1 See also • HU-210 • HU-308 • HU-331
212.2 References [1] Sumariwalla PF, et al. (2004). “A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis”. Arthritis Rheum. 50 (3): 985–998. doi:10.1002/art.20050. PMID 15022343.
282
Chapter 213
HU-336 HU-336 is a strongly antiangiogenic compound, significantly inhibiting angiogenesis at concentrations as low as 300nM. It inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and antiangiogenic cytokines and their receptors. HU-336 is highly effective against tumor xenografts in nude mice.[1]
213.1 See also • HU-210 • HU-331 • HU-345
213.2 References [1] Natalya M. Kogan, et al. (2006). “A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells”. Molecular Pharmacology 70 (1): 51–59. doi:10.1124/mol.105.021089. PMID 16571653.
283
Chapter 214
HU-345 HU-345 (cannabinol quinone) is a drug that is able to inhibit aortic ring angiogenesis more potently than its parent compound cannabinol.[1][2]
214.1 See also • HU-210 • HU-336
214.2 References [1] Natalya M. Kogan, et al. (2006). “A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells”. Molecular Pharmacology 70 (1): 51–59. doi:10.1124/mol.105.021089. PMID 16571653. [2] US patent 0092584, Mechoulam R, Kogan NM, Rabinowitz R, Schlesinger M, “Therapeutic Use of Quinonoid Derivatives of Cannabinoids”, granted 2011-04-21
284
Chapter 215
Raphael Mechoulam Raphael Mechoulam (Hebrew: ( )רפאל משולםborn 1930) is an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of Jerusalem in Israel. Mechoulam is best known for his work (together with Y. Gaoni) in the isolation, structure elucidation and total synthesis of Δ9 -tetrahydrocannabinol, the main active principle of cannabis and for the isolation and the identification of the endogenous cannabinoids anandamide from the brain and 2-arachidonoyl glycerol (2-AG) from peripheral organs together with his students, postdocs and collaborators.
215.2 Research Raphael Mechoulam’s major scientific interest is the chemistry and pharmacology of cannabinoids. He and his research group succeeded in the total synthesis of the major plant cannabinoids Δ9 -tetrahydrocannabinol, cannabidiol, cannabigerol and various others. Another research project initiated by him led to the isolation of the first described endocannabinoid anandamide which was isolated and characterized by two of his postdoctoral researchers, Lumír Ondřej Hanuš and William Devane. Another endogenous cannabinoid, 2-AG, was soon discovered by Shimon Ben-Shabat, one of his PhD students. He published more than 350 scientific articles.
215.1 Biography 215.3 References Raphael Mechoulam was born in Sofia, Bulgaria on November 5, 1930. His father was a physician and head of a local hospital, while his mother “who had studied in Berlin, enjoyed the life of a well-to-do Jewish family”. He attended an “American Grade School” until his parents were forced to leave their hometown because of antisemitic laws and his father was subsequently sent to a concentration camp, from which he survived. After the communist takeover of hitherto pro-German Bulgaria in 1944 he studied chemical engineering, which he “disliked.” In 1949 his family immigrated to Israel where he later studied chemistry. He gained his first research experience in the Israeli Army working on insecticides.[2]
[1] http://www.nndb.com/people/699/000210069/ [2] Conversation with Raphael Mechoulam, Addiction (Wiley) 102 (6), 2007: 887–893, doi:10.1111/j.13600443.2007.01795.x, PMID 17523982 [3] Michael Denman (2007), “MECHOULAM, RAPHAEL”, Encyclopaedia Judaica 13 (2nd ed.), Thomson Gale, pp. 711–712
215.4 Podcasts
He received his M.Sc. in biochemistry from the Hebrew University of Jerusalem (1952), and his Ph.D. at the Weizmann Institute, Reḥovot (1958), with a thesis on the chemistry of steroids. After postdoctoral studies at the Rockefeller Institute, New York (1959–60), he was on the scientific staff of the Weizmann Institute (1960–65), before moving to the Hebrew University of Jerusalem, where he became professor (1972) and Lionel Jacobson Professor of Medicinal Chemistry from 1975. He was rector (1979–82) and pro-rector (1983–85). In 1994 he was elected a member of the Israel Academy of Sciences. His honors include the Kolthof Prize in chemistry from the Haifa Technion (1994) and the Israel Prize in chemistry (2000).[3] 285
• A podcast (open access) of an interview with Raphael Mechoulam, recorded by Steve Alexander for the British Journal of Pharmacology on the occasion of his 80th Birthday in November 2010.
Chapter 216
John W. Huffman John William Huffman (born 1932) is a professor emeritus of organic chemistry at Clemson University who first synthesised many novel cannabinoids.[1] His research, funded by the National Institute on Drug Abuse, was focused on making a drug to target endocannabinoid receptors in the body.[2]
216.2 See also • List of JWH cannabinoids
216.3 References
Beginning in 1984, Huffman and his team of researchers began developing cannabinoid compounds to aid in research of multiple sclerosis, HIV/AIDS, and chemotherapy. Over the course of twenty years, Huffman and his team developed 450 synthetic cannabinoid compounds which were used to test the effect of cannabinoid receptors in the brain and other organs. Ultimately, the cannabinoid research provided understanding of diseases and information for medication development. In the late 2000s, two of Huffman’s cannabinoid compounds began being sold in as marijuana alternatives known as K2 and Spice. “I figured once it got started in it was going to spread. I'm concerned that it could hurt people,” Huffman said. “I think this was something that was more or less inevitable. It bothers me that people are so stupid as to use this stuff”. Huffman may have developed these compounds for scientific research, but now he gets blamed for its abuse. As JWH-018 is more potent and easy to make, Huffman believes it is a more widely used synthetic cannabinoid of the JWH series.[3]
216.1 Law enforcement More than half a dozen countries have banned herbal blends containing synthetic cannabinoids since 2008. Many countries also consider banning these mixtures. In the US, the states of Kansas, Georgia, Alabama, Tennessee, Missouri, Louisiana, Mississippi, Arkansas, and New York banned K2, herbal incense. JWH-018 is currently banned by controlled substances act. [3] Law enforcement officials in Canada asked Huffman to serve as a consultant and expert witness. He received numerous media queries and requests for analytical help from law enforcement officials.[3] 286
[1] “Clemson University :: Department of Chemistry”. Clemson.edu. Retrieved 2010-08-24. [2] Brownstein, Joseph (March 17, 2010), K2 Giving People Another Dangerous Way to Get High, ABC News [3] Wang, Linda (June 28, 2010). “C&EN Talks With John W. Huffman”. Chemical & Engineering News 88 (26): 43. Retrieved October 8, 2011.
Chapter 217
JWH-007 JWH-007 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It was the most active of the first group of N-alkyl naphoylindoles discovered by the team led by John W Huffman, several years after the family was initially described with the discovery of the N-morpholinylethyl compounds pravadoline (WIN 48,098), WIN 55,225 (JWH-200) and WIN 55,212-2 by the Sterling Winthrop group.[1] Several other N-alkyl substituents were found to be active by Huffman’s team including the n-butyl, n-hexyl, 2-heptyl and cyclohexylethyl groups,[2] but it was subsequently determined that the 2-methyl group on the indole ring is not required for CB1 binding, and tends to increase affinity for CB2 instead.[3][4] Consequently the 2-desmethyl derivative of JWH-007, JWH-018 has slightly higher binding affinity for CB1 , with an optimum binding of 9.00nM at CB1 and 2.94nM at CB2 , and JWH-007 displayed optimum binding of 9.50nM at CB1 and 2.94nM at CB2 .[5]
217.3 References
217.1 Law Sweden: JWH-007 was banned in Sweden on 1 October 2010 as a hazardous good harmful to health, after being identified as an ingredient in “herbal” synthetic cannabis products.[6][7] Poland: JWH-007 is illegal in Poland since 08.06.2010 on the basis of 'Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii' published in Dz.U. 2011 nr 105 poz. 614[8]
217.2 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073 287
[1] Compton, D. R., et al. (1992). “Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol”. The Journal of Pharmacology and Experimental Therapeutics 263 (3): 1118–1126. PMID 1335057. [2] Huffman JW, Dong D. Design, Synthesis and Pharmacology of Cannabimimetic Indoles. Bioorganic and Medicinal Chemistry Letters. 1994;4(4):563-566. [3] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455. [4] Huffman, J. W.; Padgett, L. W. (2005). “Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes”. Current medicinal chemistry 12 (12): 1395–1411. doi:10.2174/0929867054020864. PMID 15974991. [5] Aung, M. M., et al. (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding”. Drug and alcohol dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [6] Swedish Code of Statutes Regulation (2010:1086). [7] Swedish Code of Statutes Regulation (2010:1086). (pdf) [8] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". ISAP. Retrieved 12 June 2011.
Chapter 218
Naphthoylindole JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM678[1] is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2 . It produces effects in animals similar to those of THC, a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products such as “legal cannabis herbal incense blends” which in some countries are sold legally as “incense”, labeled “not for human consumption”.[2][3][4][5][6]
218.2.1 Pharmacokinetics JWH-018 istered to rats resulted in the excretion of an indole-N-desalkyl metabolite as well as several hydroxylated metabolites in urine. The highest signals were observed for the hydroxylated N-desalkyl metabolites. Hydroxylation took place on the side chain and in both aromatic systems, the naphthalene and the indole rings, as could be shown by mass shift of the corresponding fragments and by MS3 experiments.[13] Human metabolites were similar although most metabolism took place on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with glucuronide.[14]
218.1 History John W. Huffman, an organic chemist at Clemson University, synthesized analogues and metabolites of Δ9 tetrahydrocannabinol (THC), the principal active component of cannabis. JWH-018 is one of these analogues, with studies showing an affinity for the cannabinoid (CB1 ) receptor five times greater than that of THC. Cannabinoid receptors are found in mammalian brain and spleen tissue; however, the structural details of the active sites are currently unknown.[7][8] On December 15, 2008, it was reported by the German pharmaceutical company THC Pharm that JWH-018 was found as one of the active components in at least three versions of the herbal blend Spice, which has been sold as an incense in a number of countries around the world since 2002.[9][10][11] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[12]
218.3 Usage At least one case of JWH-018 dependence has been reported by the media.[2] The consumed JWH-018 daily for eight months. Withdrawal symptoms were similar to those experienced as a result of cannabis dependence. JWH-018 has been shown to cause profound changes in CB1 receptor density following istration, causing desensitization to its effects more rapidly than related cannabinoids.[6] On October 15, 2011, Anderson County coroner Greg Shore attributed the death of a South Carolina college basketball player to “drug toxicity and organ failure” caused by JWH-018.[15] An email dated Nov 4, 2011 concerning the case was finally released by the city of Anderson S.C. on Dec 16, 2011 under the Freedom of Information Act after multiple requests by media to see the information had been denied.[16]
Compared to THC, which is a partial agonist at CB1 receptors, JWH-018 (and many of its analogues) are full agonists. THC has been shown to inhibit GABA receptor neurotransmission in the brain via several pathways.[17][18] JWH-018 may cause intense anxiety, ag218.2 Pharmacology itation, and, in rare cases (generally with non-regular JWH s), has been assumed to have been the cause of JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotranscannabinoid receptors, with a reported binding affinity of mission more effectively than THC. Cannabinoid recep9.00 ± 5.00 nM at CB1 and 2.94 ± 2.65 nM at CB2 .[3] tor full agonists may present serious dangers to the 288
218.6. SYNTHESIS
289
when used to excess.[19] Various physical and psychological adverse effects have been reported from JWH-018 use. One study reported psychotic relapses and anxiety symptoms in welltreated patients with mental illness following JWH-018 inhalation.[20] Due to concerns about the potential of JWH-018 and other synthetic cannabinoids to cause psychosis in vulnerable individuals, it has been recommended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51] nesses (like a past or family history of psychosis) not use these substances.[21]
218.6 Synthesis 218.7 See also
218.4 Detection in biological fluids JWH-018 usage is readily detected in urine using “spice” screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and carboxyl metabolites.[22] JWH-018 will not be detected by older methods employed for detecting THC and other cannabis terpenoids. Determination of the parent drug in serum or its metabolites in urine has been accomplished by GC-MS or LC-MS. Serum JWH-018 concentrations are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolite is a compound that is monohydroxylated on the omega minus one carbon atom of the alkyl side chain. A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of 6 s of the drug at concentrations of 6–50 μg/L, primarily as a glucuronide conjugate.[23][24][25][26][27][28][29][30][31]
218.5 Legal status
• AM-2201 • BB-22 (drug) • JWH-073 • JWH-250 • JWH-200 • PB-22 • SDB-001
218.8 References [1] “Department of Justice :: Drug Enforcement istration”. 2011-03-01. Retrieved 2011-03-02. [2] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal Phenomena and Dependence Syndrome After the Consumption of “Spice Gold"". Dtsch Arztebl Int 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [3] Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [4] US patent 6900236, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200505-31 [5] US patent 7241799, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200707-10
JWH-018 powder as it was commonly sold online
[6] Atwood, B.K., et al., “JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB1 receptor agonist.” British Journal of Pharmacology, Vol. 160, No. 3. 585-593. 2010.
290
CHAPTER 218. NAPHTHOYLINDOLE
[7] “Clemson University :: Department of Chemistry”. Clemson.edu. Retrieved 2010-08-23. [8] “Drugs Forum”. Drugs Forum. Retrieved 2010-08-23. [9] Gefährlicher Kick mit Spice (German) [10] Erstmals Bestandteile nachgewiesen (German)
der
Modedroge
“Spice”
[11] Spice enthält chemischen Wirkstoff (German) [12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L, Beuerle T (30 October 2009). “Spice: A never ending story?". Forensic Science International (Forensic Science International) 191 (1): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [13] T. Kraemer, et al. Studies on the metabolism of JWH018 and of a homologue of 47,497, pharmacologically active ingredients of different misused incense (“Spice”) using GC-MS and LC-MSn techniques (Institute of Legal Medicine, Saarland University, 66421 Homburg, http://www.gtfch.org/cms/images/ stories/media/tk/tk76_2/abstractsvortraege.pdf [14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010). “Detection of JWH-018 metabolites in smoking mixture post-istration urine”. Forensic Science International 200 (1–3): 141–7. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [15] wyff4.com, Coroner: Synthetic Pot Killed College Athlete, posted 10/14/11, accessed 12/22/11, http://www. wyff4.com/news/29497549/detail.html, [16] Mayo, Nikie, “City Releases Email in Lamar Jacks Case”, independentmail.com, posted Dec 16, 2011, accessed 12/22/11, http://www.independentmail.com/news/2011/ dec/16/city-releases-email-lamar-jack-case/ [17] Laaris N, Good CH, Lupica CR (July–August 2010). "Δ9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus”. Neuropharmacology 59 (1–2): 121–127. doi:10.1016/j.neuropharm.2010.04.013. PMC 2882293. PMID 20417220. [18] Hoffman AF, Lupica CR (2000-04-01). “Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus”. The Journal of Neuroscience 20 (7): 2470–2479. ISSN 0270-6474. PMID 10729327. Retrieved 2011-07-26. [19] European Monitoring Centre for Drugs and Drug Addiction. “Understanding the Spice Phenomenon.” 2009. ISBN 978-92-9168-411-3. [20] Every-Palmer, S. Synthetic cannabinoid use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011. [Epub ahead of print]. [21] Every-Palmer S (2010). “WARNING: LEGAL SYNTHETIC CANNABINOID-RECEPTOR AGONISTS SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS IN VULNERABLE INDIVIDUALS”. Addiction 105: doi:10.1111/j.1360-0443.2010.03119.x. 1859–1860. PMID 20840203.
[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/ content/37/5/284.abstract, https://www.caymanchem. com/app/template/Product.vm/catalog/580210; http://www.randoxtoxicology.com/Products/Elisa-p-50, http://tulipbiolabs.com/our-product-areas/ synthetic-cannabinoids and others. [23] Möller I, et al. Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls. Drug Test. Anal. Sep 24, 2010. [Epub ahead of print] [24] Teske J, et al. Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatography-tandem mass spectrometry. J Chrom. B 878: 2659-2663, 2010. [25] Auwärter V, Dresen S, Weinmann W, Müller M, Pütz M, Ferreirós N (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. Free version [26] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal phenomena and dependence syndrome after the consumption of “spice gold"". Deutsches Arzteblatt international 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). “Detection of JWH-018 metabolites in smoking mixture postistration urine”. Forensic Science International 200 (1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [28] Beuck S, Möller I, Thomas A, Klose A, Schlörer N, Schänzer W, Thevis M (August 2011). “Structure characterisation of urinary metabolites of the cannabimimetic JWH-018 using chemically synthesised reference material for the of LC-MS/MS-based drug testing”. Anal Bioanal Chem 401 (2): 493–505. doi:10.1007/s00216-011-4931-5. PMID 21455647. [29] Moran CL, Le VH, Chimalakonda KC, Smedley AL, Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski PJ, Wessinger WD, Fantegrossi WE, Prather PL, James LP, Radominska-Pandya A, Moran JH (June 2011). “Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine”. Anal. Chem. 83 (11): 4228–36. doi:10.1021/ac2005636. PMID 21506519. [30] Logan BK, et al. Identification of primary JWH018 and JWH-073 metabolites in human urine. NMS Labs Technical Bulletin, May 25, 2011. http://toxwiki.wikispaces.com/file/view/JWH_ metabolites_Technical_Bulletin_Final_v1.1.pdf [31] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 10th edition, Biomedical Publications, Seal Beach, CA, 2014, p. 1863. [32]
218.9. EXTERNAL LINKS
291
[33] “Controlled Drugs and Substances Act”. Laws.justice.gc.ca. 2010-08-16. Retrieved 201008-23. [34] *** Tiedote/Valtioneuvoston viestintäyksikkö: VALTIONEUVOSTON YLEISISTUNTO 1.3.2012 *** (Finnish) [35] “EMCDDA | Drug profile: Synthetic cannabinoids and 'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved 2010-08-23. [36] http://www.afssaps.fr/var/afssaps_site/storage/original/ application/d23d05edc58479d91c803b496017f073.pdf [37] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19. Januar 2009, S. 49–50. [38] Many head shop products banned - Irish Times. [39] http://www.politicheantidroga.it/ comunicazione/comunicati/2010/luglio/spice, -n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian) [40] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are [41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465. html [42]
(2 July 2009). “1 ‘5- - ’ . Retrieved 18 February 2010.
".
[43] http://www.regeringen.se/sb/d/12102/a/130038 (Swedish) [44] “Illicit Drug Report of Turkey 2010”. Department of Anti-smuggling and Organised Crime. Retrieved 201205-03.(Turkish) [45] “Decision of the Council of Ministers, Enactment 2011/1310”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [46] “Attachment to Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [47] “Decision of the Council of Ministers, Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [48] Ford, Richard (2009-12-23). “Three legal highs banned after deaths linked to the drugs”. The Times (London). Retrieved 2010-05-07. [49] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [50]
[51] Appendino G, Minassi A, Taglialatela-Scafati O (2014). “Recreational drug discovery: natural products as lead structures for the synthesis of smart drugs”. Natural Product Reports 31 (7): 880–904. doi:10.1039/c4np00010b.
218.9 External links • JWH-018 Report Psychonaut Web Mapping Research Project • of legal high
Chapter 219
JWH-019 JWH-019 is an analgesic chemical from the naphthoylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is the N1-hexyl homologue of the more common synthetic cannabinoid compound JWH-018. Unlike the butyl homologue JWH-073, which is several times weaker than JWH-018, the hexyl homologue is only slightly less potent, although extending the chain one carbon longer to the heptyl homologue JWH-020 results in dramatic loss of activity. These results show that the optimum side chain length for CB1 binding in the naphthoylindole series is the five-carbon pentyl chain, shorter than in the classical cannabinoids where a seven-carbon heptyl chain produces the most potent compounds. This difference is thought to reflect a slightly different binding conformation adopted by the naphthoylindole compounds as compared to the classical cannabinoids, and may be useful in characterising the active site of the CB1 and CB2 receptors.[2][3][4]
219.2 See also • JWH-007 • JWH-018 • JWH-073 • JWH-200
219.3 References
219.1 Legal Status 219.1.1
Poland
[4] Ashton JC, Wright JL, Martland JM, Tyndall JD (2008). “Cannabinoid CB1 and CB2 receptor ligand specificity and the development of CB2-selective agonists”. Current Medicinal Chemistry 15 (14): 1428–43. doi:10.2174/092986708784567716. PMID 18537620.
Sweden
JWH-019 is illegal in Sweden
219.1.3
UK
[5] http://crimlaw.blogspot.com/2011/04/ no-more-synthetic-cannabinoid.html
JWH-019 is Class B in the United Kingdom.
219.1.4
[2] Aung MM, et al. (August 2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding”. Drug and Alcohol Dependence 60 (2): 133–40. doi:10.1016/S03768716(99)00152-0. PMID 10940540. [3] Poso A, Huffman JW (January 2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335–46. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473.
In Poland, JWH-019 is I-N (Poland)[1]
219.1.2
[1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 12 June 2011.
USA
JWH-019 is not controlled federally in the United States, however if intended for human consumption, possession or sales could possibly be prosecuted under the Federal Analog Act. JWH-019 is illegal in Virginia.[5] 292
Chapter 220
JWH-030 JWH-030 is a research chemical which is a cannabinoid receptor agonist.[1] It has analgesic effects and is used in scientific research.[2] It is a partial agonist at CB1 receptors, with a Ki of 87nM, making it roughly half the potency of THC.[3] It was discovered and named after Dr. John W. Huffman.
220.1 See also • JWH-147
220.2 References [1] Lainton JAH, Huffman JW, Martin BR, Compton DR. Tetrahedron Letters. 1995; 36:1401. [2] Pertwee RG, Griffin, G, Lainton JAH, Huffman JW. European Journal of Pharmacology. 1995; 284:241. [3] Griffin, G.; Atkinson, P. J.; Showalter, V. M.; Martin, B. R.; Abood, M. E. (1998). “Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5'O-(3-35Sthio)-triphosphate binding assay in rat cerebellar membranes”. The Journal of Pharmacology and Experimental Therapeutics 285 (2): 553–560. PMID 9580597.
293
Chapter 221
JWH-047 JWH-047 is a selective cannabinoid ligand, with a bindining affinity of Kᵢ = 0.9 nM for the CB2 subtype, and more than 65 times selectivity over the CB1 .[1]
221.1 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073
221.2 References [1] Aung MM, Griffin G, Huffman JW, Wu M-J, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
294
Chapter 222
JWH-048 JWH-048 is a selective cannabinoid ligand, with a bindining affinity of Kᵢ = 0.5 ± 0.1 nM for the CB2 subtype, and more than 22 times selectivity over the CB1 .[1]
222.1 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073
222.2 References [1] Aung MM, Griffin G, Huffman JW, Wu M-J, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
295
Chapter 223
JWH-073 JWH-073 is an analgesic chemical from the synthetic cannabis smoking blends. naphthoylindole family that acts as a partial agonist at both the CB1 and CB2 cannabinoid receptors. It is somewhat selective for the CB1 subtype, with affinity at this subtype approximately 5x the affinity at CB2 .[2] The abbreviation JWH stands for John W. Huffman, one of the inventors of the compound. On 20 April 2009, JWH-073 was claimed by researchers at the University of Freiburg to have been found in a “fertiliser” product called “Forest Humus”, along with another synthetic cannabinoid (C8)- 47,497.[3] These claims were confirmed in July 2009 when tests of Spice product, seized after the legal ban on JWH-018 had gone into effect in , were shown to contain the unregulated compound JWH-073 instead.[4]
223.1 Pharmacology JWH-073 has been shown to produce behavioral effects very similar to THC in animals.[5] Its effects are produced by binding and acting as an ago4'-Methyl-JWH-073 nist to the CB1 and CB2 cannabinoid receptors. The CB1 receptor is found in the brain. JWH-073 bind to CB1 with a higher affinity than THC, suggesting that taking more too soon after the initial dose could lead to diminished 223.3 Legal status effects. CB2 is found outside the brain, mostly in the immune system. The binding with CB2 receptors has been 223.3.1 United States shown to be similar between JWH-073 and THC.[5] A search in the literature yielded no published studies of See also: JWH-018 the effects of JWH-073 in humans, but these studies in The US DEA temporarily declared JWH-073 a schedule animals suggest with high probability that JWH-073 pro- I controlled substance on 1 March 2011 through 76 FR duces effects very similar to those of THC in humans.[5] 11075, and permanently instated the same schedule on 9 July 2012 in the Section 1152 of the Food and Drug istration Safety and Innovation Act.[7]
223.2 Derivatives
The 4'-methyl derivative of JWH-073 has been encountered as an ingredient of synthetic cannabis blends in and several other European countries since 2010.[6] The 4'-methoxy derivative JWH-080 is also known to be a potent cannabinoid agonist and has been banned in some countries, though it is unclear if it has also been used in
223.3.2 Australia See also: JWH-018 On 8 July 2011 the AUS government banned the sale of JWH-073.[8]
296
223.5. REFERENCES
297
[9] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are
1 g of JWH-073
223.3.3
New Zealand
On 8 May 2014 the New Zealand government banned the sale of JWH-073. [9]
223.4 See also • JWH-081 • JWH-018 • JWH-019 • HU-210
223.5 References [1] http://www.likumi.lv/doc.php?id=201101&from=off [2] Aung MM, et al. (August 2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding”. Drug Alcohol Depend 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [3] Forest Humus - Enthält synthetische Cannabinoide (in German) [4] Lindigkeit R, et al. (July 2009). “Spice: A never ending story?". Forensic Science International 191 (1–3): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [5] http://www.deadiversion.usdoj.gov/drugs_concern/ spice/spice_jwh073.html [6] EMCDDA Annual Report 2010 [7] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [8] http://www.tga.gov.au/pdf/scheduling/ scheduling-decisions-1107-final.pdf
Chapter 224
JWH-081 JWH-081 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors.[2] With a Kᵢ of 1.2nM it is fairly selective for the CB1 subtype, its affinity at this subtype approximately 10x the affinity at CB2 .[3] It was discovered by and named after Dr. John W. Huffman.
224.1 See also • JWH-018 • JWH-098 • JWH-164 • JWH-198 • JWH-210
224.2 References [1] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii (Dz.U. 2011 nr 105 poz. 614)". Internetowy System Aktów Prawnych. Retrieved 12 June 2011. [2] Aung MM, et al. Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding. Drug and Alcohol Dependence 2000; 60:133140. [3] Huffman JW, et al. Structure–activity relationships for 1alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists. Bioorganic and Medicinal Chemistry. 2005; 13:89-112.
298
Chapter 225
JWH-098 JWH-098 is a synthetic cannabinoid receptor agonist from the naphthoylindole family. It is the indole 2-methyl derivative of a closely related compound JWH-081, but has markedly different affinity for the CB1 and CB2 receptors. While JWH-081 is around 10x selective for CB1 over CB2 , in JWH-098 this is reversed, and it is around 4 times weaker than JWH-081 at CB1 while being six times more potent at CB2 , giving it a slight selectivity for CB2 overall. This makes JWH-098 a good example of how methylation of the indole 2-position in the naphthoylindole series tends to increase CB2 affinity, but often at the expense of CB1 binding.[1] JWH-098 is illegal in Russia,[2] Sweden,[3] and the UK,[4] although it is unclear whether it has any history of human use.
225.1 See also • JWH-007 • JWH-081
225.2 References [1] Huffman JW, et al. Structure–activity relationships for 1alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists. Bioorganic and Medicinal Chemistry. 2005; 13:89-112. PMID 15582455 [2] "Постановление от 31 декабря 2009 г. № 1186 О внесении изменений в некоторые постановления Правительства Российской Федерации по вопросам, связанным с оборотом наркотических средств". Government.ru. Retrieved 2010-09-09. [3] Svensk författningssamling [4] The Misuse of Drugs Act 1971 (Amendment) Order 2009
299
Chapter 226
JWH-116 JWH-116 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the indole 2-ethyl derivative of related compound JWH-018. The binding affinity of JWH-116 for the CB1 receptor is reported as Kᵢ = 52 ± 5 nM.[1]
226.1 See also • JWH-018 • JWH-081
226.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
300
Chapter 227
JWH-147 JWH-147 is an analgesic drug used in scientific research, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Ki of 11.0nM at CB1 vs 7.1nM at CB2 .[1] It was discovered and named after Dr. John W. Huffman. JWH-147 was banned in Sweden on 1 October 2010 as a hazardous good harmful to health, after being identified as an ingredient in “herbal” synthetic cannabis products.[2][3]
227.1 See also • JWH-030 • JWH-307
227.2 References [1] Huffman JW, Padgett LW, Isherwood ML, Wiley JL, Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New high affinity ligands for the cannabinoid CB1 and CB2 receptors. Bioorganic & Medicinal Chemistry Letters 2006; 16:5432-5435. [2] Swedish Code of Statutes Regulation (2010:1086). [3] Swedish Code of Statutes Regulation (2010:1086). (pdf)
301
Chapter 228
JWH-164 JWH-164 is a synthetic cannabinoid receptor agonist from the naphthoylindole family. It has approximately equal affinity for the CB1 and CB2 receptors, with a Kᵢ of 6.6nM at CB1 and 6.9nM at CB2 . JWH-164 is a positional isomer of the related compound JWH-081, but with a methoxy group at the 7-position of the naphthyl ring, rather than the 4-position as in JWH-081. Its potency is intermediate between that of JWH-081 and its ring unsubstituted derivative JWH-018, demonstrating that substitution of the naphthyl 7-position can also result in increased cannabinoid receptor binding affinity.[1][2]
228.1 References [1] Huffman JW, et al. Structure–activity relationships for 1alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists. Bioorganic and Medicinal Chemistry. 2005; 13:89-112. PMID 15582455 [2] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. PMID 15974991
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Chapter 229
Phenylacetylindole JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 1.75x selectivity for CB1 with a Kᵢ of 90nM ± 17 and 159nM ± 14 at CB2 . Similar to the related 2'-methoxy compound JWH-250, and the 2'-chloro compound JWH-203, JWH-167 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds.[1][2]
229.1 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
303
Chapter 230
JWH-175 JWH-175 is a drug from the naphthylmethylindole family which acts as a cannabinoid receptor agonist. It was invented by the scientist John W. Huffman and colleagues at Clemson University. JWH-175 is closely related to the widely used cannabinoid designer drug JWH-018, but with the ketone bridge replaced by a simpler methylene bridge. It is several times weaker than JWH-018, having a binding affinity at the CB1 receptor of 22nM, though some derivatives substituted at the 4-position of the naphthyl ring have potency more closely approaching that of the equivalent naphthoylindoles.[1] This makes JWH-175 considerably less potent than most synthetic cannabinoid drugs used in synthetic cannabis blends, and it is unclear if JWH-175 has ever been used for this purpose. However it has still been explicitly banned in several jurisdictions including Russia and some Australian states, in order to stop its potential use as an ingredient in such products.
230.1 See also • JWH-176 • JWH-184 • JWH-185
230.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411.
304
Chapter 231
JWH-184 JWH-184 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the carbonyl-reduced derivative of related compound JWH-122. The binding affinity of JWH-184 for the CB1 receptor is reported as Kᵢ = 23 ± 6 nM.[1]
231.1 See also • JWH-018 • JWH-122 • JWH-185
231.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
305
Chapter 232
JWH-185 JWH-185 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the carbonyl-reduced derivative of related compound JWH-081. The binding affinity of JWH-185 for the CB1 receptor is reported as Kᵢ = 17 ± 3 nM.[1]
232.1 See also • JWH-081 • JWH-184
232.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
306
Chapter 233
JWH-196 JWH-196 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the indole 2-methyl derivative of related compound JWH-175, and the carbonyl reduced analog of JWH-007. The binding affinity of JWH-196 for the CB1 receptor is reported as Kᵢ = 151 ± 18 nM.[1]
233.1 See also • JWH-007 • JWH-175
233.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
307
Chapter 234
JWH-203 JWH-203 (1-pentyl-3-(2-chlorophenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family that acts as a cannabinoid agonist with approximately equal affinity at both the CB1 and CB2 receptors, having a Kᵢ of 8.0nM at CB1 and 7.0nM at CB2 . It was originally discovered by, and named after, Dr. John W. Huffman, but has subsequently been sold without his permission as an ingredient of synthetic cannabis smoking blends.[2] Similar to the related 2'-methoxy compound JWH-250, the 2'-bromo compound JWH-249, and the 2'-methyl compound JWH-251, JWH-203 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds, and has the strongest in vitro binding affinity for the cannabinoid receptors of any compound in the phenylacetyl group.[3][4][5] Unexpectedly despite its weaker CB1 Kᵢ in vitro, the 2methylindole derivative JWH-204 is actually more potent than JWH-203 in animal tests for cannabinoid activity, though it is still weaker than JWH-249.[6]
234.1 See also JWH-204
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
[4] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
234.2 References [1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 17 June 2011.
[5] Bononi M, Belgi P, Tateo F (2011). “Analytical data for identification of the Cannabimimetic Phenylacetylindole JWH-203”. Journal of Analytical Toxicology 35 (6): 360– 3. doi:10.1093/anatox/35.6.360. PMID 21740693.
[2] “Analytical data for identification of the Cannabimimetic Phenylacetylindole JWH-203”. J Anal Toxicol 35 (6): 360–3. July 2011. doi:10.1093/anatox/35.6.360. PMID 21740693.
[6] “1-Pentyl-3-phenylacetylindoles and JWH-018 share in vivo cannabinoid profiles in mice”. Drug Alcohol Depend. November 2011. doi:10.1016/j.drugalcdep.2011.11.001. PMID 22127210.
[3] Huffman, JW, et al. (2005). “1-Pentyl-3phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
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Chapter 235
JWH-210 JWH-210 is an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both the CB1 and CB2 receptors, with Kᵢ values of 0.46nM at CB1 and 0.69nM at CB2 . It is one of the most potent 4-substituted naphthoyl derivatives in the naphthoylindole series, having a higher binding affinity (i.e. lower Kᵢ) at CB1 than both its 4-methyl and 4-n-propyl homologues JWH-122 (CB1 Kᵢ 0.69nM) and JWH-182 (CB1 Kᵢ 0.65nM) respectively, and than the 4-methoxy compound JWH-081 (CB1 Kᵢ 1.2nM).[2] It was discovered by and named after Dr. John W. Huffman. JWH-210 and JWH-122 were banned in Sweden on 1 October 2010 as hazardous goods harmful to health, after being identified as ingredients in “herbal” synthetic cannabis products.[3][4] The substances JWH-210, JWH-122 and JWH-203 were classified as illegal drugs by the Swedish government as of 1 September 2011.[5]
235.1 See also • JWH-081 • JWH-193 • JWH-398
235.2 References [1] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 12 June 2011. [2] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455. [3] Swedish Code of Statutes Regulation (2010:1086). [4] Swedish Code of Statutes Regulation (2010:1086). (pdf)
309
[5] LVFS 2011:8
Chapter 236
JWH-249 JWH-249 (1-pentyl-3-(2-bromophenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 2.4x selectivity for CB1 with a Kᵢ of 8.4nM ± 1.8 and 20nM ± 2 at CB2 . Similar to the related 2'-methoxy compound JWH-250, the 2'-chloro compound JWH-203, and the 2'-methyl compound JWH-251, JWH-249 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds. [1][2]
236.1 See also • AM-679
236.2 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
310
Chapter 237
JWH-250 JWH-250 or (1-pentyl-3-(2methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors, with a Kᵢ of 11nM at CB1 and 33nM at CB2 . Unlike many of the older JWH series compounds, this compound does not have a naphthalene ring, instead occupying this position with a 2'-methoxy-phenylacetyl group, making JWH-250 a representative member of a new class of cannabinoid ligands.[2] Other 2'substituted analogues such as the methyl, chloro and bromo compounds are also active and somewhat more potent.[3][4]
237.1 History JWH-250 was discovered by, and named after the researcher Dr. John W. Huffman. He created JWH250 and a number of other compounds to research the structure and function of the endocannabinoid system of mammals. Samples of JWH-250 were first identified in May 2009 by the German Federal Criminal Police, as an ingredient in new generation "herbal smoking blends" that had been released since the banning of the original ingredients (C8)- 47,497 and JWH-018.[5] An ELISA immunoassay technique for detecting JWH-250 in urine has been reported.[6]
237.2 References [1] Legal article in Latvian (www.likumi.lv) [2] Huffman, JW, et al. (2005). “1-Pentyl-3phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [3] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928. [4] The Cannabinoid Receptors. Edited by Patricia H Reggio. Humana Press 2009. ISBN 978-1-58829-712-9
311
[5] Understanding the ‘Spice’ phenomenon. EMCDDA, Lisbon, November 2009 [6] Arntson et al (2013) http://jat.oxfordjournals.org/ content/37/5/284.abstract
Chapter 238
JWH-251 JWH-251 (1-pentyl-3-(2-methylphenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 5x selectivity for CB1 with a Kᵢ of 29nM and 146nM at CB2 . Similar to the related 2'-methoxy compound JWH-250, the 2'-chloro compound JWH-203, and the 2'-bromo compound JWH-249, JWH-251 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds. [1][2]
238.1 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
312
Chapter 239
JWH-302 JWH-302 or (1-pentyl-3-(3methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist with moderate affinity at both the CB1 and CB2 receptors. It is a positional isomer of the more common drug JWH-250, though it is slightly less potent with a Kᵢ of 17nM at CB1 , compared to 11nM for JWH-250.[1][2] Because of their identical molecular weight and similar fragmentation patterns, JWH-302 and JWH-250 can be very difficult to distinguish by GC-MS testing.[3]
239.1 References [1] Huffman, JW. et al. (2005). “1-Pentyl-3phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928. [3] 'Herbal High' synthetic Cannabinoid composition, released by ESR July 2011
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JWH-307 JWH-307 is an analgesic drug used in scientific research, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Ki of 7.7nM at CB1 vs 3.3nM at CB2 .[1] It was discovered by, and named after, Dr. John W. Huffman. JWH-307 was detected as an ingredient in synthetic cannabis smoking blends in 2012, initially in .[2][3]
240.1 See also • JWH-147
240.2 References [1] Huffman JW, Padgett LW, Isherwood ML, Wiley JL, Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New high affinity ligands for the cannabinoid CB1 and CB2 receptors. Bioorganic & Medicinal Chemistry Letters 2006; 16:5432-5435. [2] Ernst, L.; Krüger, K.; Lindigkeit, R.; Schiebel, H. M.; Beuerle, T. (2012). “Synthetic cannabinoids in “spice-like” herbal blends: First appearance of JWH307 and recurrence of JWH-018 on the German market”. Forensic Science International 222 (1–3): 216–22. doi:10.1016/j.forsciint.2012.05.027. PMID 22748479. [3] Kneisel, S.; Auwärter, V. (2012). “Analysis of 30 synthetic cannabinoids in serum by liquid chromatographyelectrospray ionization tandem mass spectrometry after liquid-liquid extraction”. Journal of Mass Spectrometry 47 (7): 825–835. doi:10.1002/jms.3020. PMID 22791249.
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JWH-398 JWH-398 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It has mild selectivity for CB1 with a Kᵢ of 2.3nM and 2.8nM at CB2 .[2] It was identified by the EMCDDA as an ingredient in three separate "herbal incense" products purchased from online shops between February to June 2009.[3] It was discovered by, and named after, Dr. John W. Huffman.[4]
241.1 See also • JWH-122 • JWH-424
241.2 References [1] [2] Huffman JW (2009) Cannabimimetic indoles, pyrroles, and indenes: structure-activity relationships and receptor interactions. Cited in: The cannabinoid receptors, Reggio PH (Ed), Humana Press. ISBN 978-1-58829-712-9 doi:10.1007/978-1-59745-503-9 [3] Understanding the ‘Spice’ phenomenon. EMCDDA, Lisbon, November 2009 [4] John W. Huffman, et al. STRUCTURE-ACTIVITY RELATIONSHIPS AT THE CB1 AND CB2 RECEPTORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8HALOGEN SUBSTITUTED) INDOLES (2009) 19th Annual Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, Page 2.
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JWH-424 JWH-424 is a drug from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors, but with moderate selectivity for CB2 , having a Kᵢ of 5.44nM at CB2 vs 20.9nM at CB1 . The heavier 8-iodo analogue is even more CB2 selective, with its 2-methyl derivative having 40x selectivity for CB2 . However the 1-propyl homologues in this series showed much lower affinity at both receptors, reflecting a generally reduced affinity for the 8-substituted naphthoylindoles overall.[1][2]
242.1 See also • JWH-018 • JWH-398
242.2 References [1] Valerie Smith, John Huffman, Jenny Wiley and Billy Martin. EFFECTS OF HALOGEN SUBSTITUENTS UPON CB1 AND CB2 RECEPTOR AFFINITIES IN THE SERIES OF N-ALKYL-3-(8HALO-1-NAPTHOYL)INDOLES. (2007) 17th Annual Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, Page 72. [2] John W. Huffman, et al. STRUCTURE-ACTIVITY RELATIONSHIPS AT THE CB1 AND CB2 RECEPTORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8HALOGEN SUBSTITUTED) INDOLES (2009) 19th Annual Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, Page 2.
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Naphthoylindole JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM678[1] is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2 . It produces effects in animals similar to those of THC, a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products such as “legal cannabis herbal incense blends” which in some countries are sold legally as “incense”, labeled “not for human consumption”.[2][3][4][5][6]
243.2.1 Pharmacokinetics JWH-018 istered to rats resulted in the excretion of an indole-N-desalkyl metabolite as well as several hydroxylated metabolites in urine. The highest signals were observed for the hydroxylated N-desalkyl metabolites. Hydroxylation took place on the side chain and in both aromatic systems, the naphthalene and the indole rings, as could be shown by mass shift of the corresponding fragments and by MS3 experiments.[13] Human metabolites were similar although most metabolism took place on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with glucuronide.[14]
243.1 History John W. Huffman, an organic chemist at Clemson University, synthesized analogues and metabolites of Δ9 tetrahydrocannabinol (THC), the principal active component of cannabis. JWH-018 is one of these analogues, with studies showing an affinity for the cannabinoid (CB1 ) receptor five times greater than that of THC. Cannabinoid receptors are found in mammalian brain and spleen tissue; however, the structural details of the active sites are currently unknown.[7][8] On December 15, 2008, it was reported by the German pharmaceutical company THC Pharm that JWH-018 was found as one of the active components in at least three versions of the herbal blend Spice, which has been sold as an incense in a number of countries around the world since 2002.[9][10][11] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[12]
243.3 Usage At least one case of JWH-018 dependence has been reported by the media.[2] The consumed JWH-018 daily for eight months. Withdrawal symptoms were similar to those experienced as a result of cannabis dependence. JWH-018 has been shown to cause profound changes in CB1 receptor density following istration, causing desensitization to its effects more rapidly than related cannabinoids.[6] On October 15, 2011, Anderson County coroner Greg Shore attributed the death of a South Carolina college basketball player to “drug toxicity and organ failure” caused by JWH-018.[15] An email dated Nov 4, 2011 concerning the case was finally released by the city of Anderson S.C. on Dec 16, 2011 under the Freedom of Information Act after multiple requests by media to see the information had been denied.[16]
Compared to THC, which is a partial agonist at CB1 receptors, JWH-018 (and many of its analogues) are full agonists. THC has been shown to inhibit GABA receptor neurotransmission in the brain via several pathways.[17][18] JWH-018 may cause intense anxiety, ag243.2 Pharmacology itation, and, in rare cases (generally with non-regular JWH s), has been assumed to have been the cause of JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotranscannabinoid receptors, with a reported binding affinity of mission more effectively than THC. Cannabinoid recep9.00 ± 5.00 nM at CB1 and 2.94 ± 2.65 nM at CB2 .[3] tor full agonists may present serious dangers to the 317
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when used to excess.[19] Various physical and psychological adverse effects have been reported from JWH-018 use. One study reported psychotic relapses and anxiety symptoms in welltreated patients with mental illness following JWH-018 inhalation.[20] Due to concerns about the potential of JWH-018 and other synthetic cannabinoids to cause psychosis in vulnerable individuals, it has been recommended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51] nesses (like a past or family history of psychosis) not use these substances.[21]
243.6 Synthesis 243.7 See also
243.4 Detection in biological fluids JWH-018 usage is readily detected in urine using “spice” screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and carboxyl metabolites.[22] JWH-018 will not be detected by older methods employed for detecting THC and other cannabis terpenoids. Determination of the parent drug in serum or its metabolites in urine has been accomplished by GC-MS or LC-MS. Serum JWH-018 concentrations are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolite is a compound that is monohydroxylated on the omega minus one carbon atom of the alkyl side chain. A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of 6 s of the drug at concentrations of 6–50 μg/L, primarily as a glucuronide conjugate.[23][24][25][26][27][28][29][30][31]
243.5 Legal status
• AM-2201 • BB-22 (drug) • JWH-073 • JWH-250 • JWH-200 • PB-22 • SDB-001
243.8 References [1] “Department of Justice :: Drug Enforcement istration”. 2011-03-01. Retrieved 2011-03-02. [2] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal Phenomena and Dependence Syndrome After the Consumption of “Spice Gold"". Dtsch Arztebl Int 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [3] Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [4] US patent 6900236, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200505-31 [5] US patent 7241799, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200707-10
JWH-018 powder as it was commonly sold online
[6] Atwood, B.K., et al., “JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB1 receptor agonist.” British Journal of Pharmacology, Vol. 160, No. 3. 585-593. 2010.
243.8. REFERENCES
319
[7] “Clemson University :: Department of Chemistry”. Clemson.edu. Retrieved 2010-08-23. [8] “Drugs Forum”. Drugs Forum. Retrieved 2010-08-23. [9] Gefährlicher Kick mit Spice (German) [10] Erstmals Bestandteile nachgewiesen (German)
der
Modedroge
“Spice”
[11] Spice enthält chemischen Wirkstoff (German) [12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L, Beuerle T (30 October 2009). “Spice: A never ending story?". Forensic Science International (Forensic Science International) 191 (1): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [13] T. Kraemer, et al. Studies on the metabolism of JWH018 and of a homologue of 47,497, pharmacologically active ingredients of different misused incense (“Spice”) using GC-MS and LC-MSn techniques (Institute of Legal Medicine, Saarland University, 66421 Homburg, http://www.gtfch.org/cms/images/ stories/media/tk/tk76_2/abstractsvortraege.pdf [14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010). “Detection of JWH-018 metabolites in smoking mixture post-istration urine”. Forensic Science International 200 (1–3): 141–7. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [15] wyff4.com, Coroner: Synthetic Pot Killed College Athlete, posted 10/14/11, accessed 12/22/11, http://www. wyff4.com/news/29497549/detail.html, [16] Mayo, Nikie, “City Releases Email in Lamar Jacks Case”, independentmail.com, posted Dec 16, 2011, accessed 12/22/11, http://www.independentmail.com/news/2011/ dec/16/city-releases-email-lamar-jack-case/ [17] Laaris N, Good CH, Lupica CR (July–August 2010). "Δ9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus”. Neuropharmacology 59 (1–2): 121–127. doi:10.1016/j.neuropharm.2010.04.013. PMC 2882293. PMID 20417220. [18] Hoffman AF, Lupica CR (2000-04-01). “Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus”. The Journal of Neuroscience 20 (7): 2470–2479. ISSN 0270-6474. PMID 10729327. Retrieved 2011-07-26. [19] European Monitoring Centre for Drugs and Drug Addiction. “Understanding the Spice Phenomenon.” 2009. ISBN 978-92-9168-411-3. [20] Every-Palmer, S. Synthetic cannabinoid use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011. [Epub ahead of print]. [21] Every-Palmer S (2010). “WARNING: LEGAL SYNTHETIC CANNABINOID-RECEPTOR AGONISTS SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS IN VULNERABLE INDIVIDUALS”. Addiction 105: doi:10.1111/j.1360-0443.2010.03119.x. 1859–1860. PMID 20840203.
[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/ content/37/5/284.abstract, https://www.caymanchem. com/app/template/Product.vm/catalog/580210; http://www.randoxtoxicology.com/Products/Elisa-p-50, http://tulipbiolabs.com/our-product-areas/ synthetic-cannabinoids and others. [23] Möller I, et al. Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls. Drug Test. Anal. Sep 24, 2010. [Epub ahead of print] [24] Teske J, et al. Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatography-tandem mass spectrometry. J Chrom. B 878: 2659-2663, 2010. [25] Auwärter V, Dresen S, Weinmann W, Müller M, Pütz M, Ferreirós N (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. Free version [26] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal phenomena and dependence syndrome after the consumption of “spice gold"". Deutsches Arzteblatt international 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). “Detection of JWH-018 metabolites in smoking mixture postistration urine”. Forensic Science International 200 (1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [28] Beuck S, Möller I, Thomas A, Klose A, Schlörer N, Schänzer W, Thevis M (August 2011). “Structure characterisation of urinary metabolites of the cannabimimetic JWH-018 using chemically synthesised reference material for the of LC-MS/MS-based drug testing”. Anal Bioanal Chem 401 (2): 493–505. doi:10.1007/s00216-011-4931-5. PMID 21455647. [29] Moran CL, Le VH, Chimalakonda KC, Smedley AL, Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski PJ, Wessinger WD, Fantegrossi WE, Prather PL, James LP, Radominska-Pandya A, Moran JH (June 2011). “Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine”. Anal. Chem. 83 (11): 4228–36. doi:10.1021/ac2005636. PMID 21506519. [30] Logan BK, et al. Identification of primary JWH018 and JWH-073 metabolites in human urine. NMS Labs Technical Bulletin, May 25, 2011. http://toxwiki.wikispaces.com/file/view/JWH_ metabolites_Technical_Bulletin_Final_v1.1.pdf [31] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 10th edition, Biomedical Publications, Seal Beach, CA, 2014, p. 1863. [32]
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[33] “Controlled Drugs and Substances Act”. Laws.justice.gc.ca. 2010-08-16. Retrieved 201008-23. [34] *** Tiedote/Valtioneuvoston viestintäyksikkö: VALTIONEUVOSTON YLEISISTUNTO 1.3.2012 *** (Finnish) [35] “EMCDDA | Drug profile: Synthetic cannabinoids and 'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved 2010-08-23. [36] http://www.afssaps.fr/var/afssaps_site/storage/original/ application/d23d05edc58479d91c803b496017f073.pdf [37] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19. Januar 2009, S. 49–50. [38] Many head shop products banned - Irish Times. [39] http://www.politicheantidroga.it/ comunicazione/comunicati/2010/luglio/spice, -n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian) [40] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are [41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465. html [42]
(2 July 2009). “1 ‘5- - ’ . Retrieved 18 February 2010.
".
[43] http://www.regeringen.se/sb/d/12102/a/130038 (Swedish) [44] “Illicit Drug Report of Turkey 2010”. Department of Anti-smuggling and Organised Crime. Retrieved 201205-03.(Turkish) [45] “Decision of the Council of Ministers, Enactment 2011/1310”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [46] “Attachment to Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [47] “Decision of the Council of Ministers, Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [48] Ford, Richard (2009-12-23). “Three legal highs banned after deaths linked to the drugs”. The Times (London). Retrieved 2010-05-07. [49] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [50]
[51] Appendino G, Minassi A, Taglialatela-Scafati O (2014). “Recreational drug discovery: natural products as lead structures for the synthesis of smart drugs”. Natural Product Reports 31 (7): 880–904. doi:10.1039/c4np00010b.
243.9 External links • JWH-018 Report Psychonaut Web Mapping Research Project • of legal high
Chapter 244
Phenylacetylindole JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 1.75x selectivity for CB1 with a Kᵢ of 90nM ± 17 and 159nM ± 14 at CB2 . Similar to the related 2'-methoxy compound JWH-250, and the 2'-chloro compound JWH-203, JWH-167 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds.[1][2]
244.1 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
321
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RCS-8 RCS-8, or 1-(2-cyclohexylethyl)−3-(2methoxyphenylacetyl)indole, is a synthetic cannabinoid also known as SR-18 or BTM-8 that has been found as an ingredient of “herbal” synthetic cannabis blends. It can be described as an analogue of JWH-250 with the 1-pentyl group replaced by 1-(2-cyclohexylethyl), and can be expected to be less potent than JWH-250 (cf. JWH-007 and its cyclohexylethyl analogue).[1] Despite not having been reported in the scientific or patent literature as yet, reputed recreational use of RCS-8 in the United States has led to it being specifically listed in a proposed 2011 amendment to the Controlled Substances Act, aiming to add a number of synthetic drugs into Schedule I.[2]
245.1 See also • Cannabipiperidiethanone • JWH-250 • RCS-4
245.2 References [1] Huffman, J. W.; Dai, D.; Martin, B. R.; Compton, D. R. (1994). “Design, Synthesis and Pharmacology of Cannabimimetic Indoles”. Bioorganic & Medicinal Chemistry Letters 4 (4): 563. doi:10.1016/S0960894X(01)80155-4. [2] Synthetic Drug Control Act of 2011
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Intravenous Marijuana Syndrome Intravenous Marijuana Syndrome is a distinct shortterm clinical syndrome related to the intravenous injection of boiled cannabis broth, which had been filtered through a cotton cloth. The syndrome has at least 25 known cases in the English language literature, but all of them prior to 1983.[1] It is postulated that contamination, perhaps from the cotton used to strain the liquid of the broth or from particulate plant matter getting through the straining method, could be cause for the cases of illnesses.[1]
246.1 References [1] Daniel Brandenburg; Richard Wernick (July 1986). “Intravenous Marijuana Syndrome”. wjm 145 (1): 94–96. PMC 1306836. PMID 3489321. Retrieved 2008-06-21.
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Chapter 247
Mellow Yellow coffeeshop Mellow Yellow is the oldest cannabis coffee shop in Amsterdam. The coffee shop was founded in 1972 by Wernard Bruinin in Weesperzijde, Amsterdam, on the premises of a former bakery. The shop is named after "Mellow Yellow", a song by Donovan which describes the singer trying to become intoxicated through smoking the peel of banana.[1]
247.3 External links
The intent of the shop is to sell cannabis, despite this being illegal at the time of its creation.[1] Sales were originally disguised by drug dealers seated at the bar posing as customers. Mellow Yellow was unsuccessfully raided by police several times. Unpackaged cannabis, bought from wholesalers including drug lord Klaas Bruinsma, was hidden behind secret doors and shutters. In 1975, the concept was adopted by a shop named Russia situated on the same street as Mellow Yellow and was followed by another coffee shop called The Bulldog. Now there are 223[2] such coffee shops in Amsterdam. Bruining also runs Stichting Mediwiet (Medi Cannabis Foundation), a group that s the legalization of growing marijuana for medicinal uses.
247.1 Citations [1] “De eerste coffeeshop ter wereld” (in Dutch). November 2008. Retrieved December 2012. [2] “FAQ Coffeeshops in Amsterdam”. I Amsterdam. Retrieved 2013-03-24.
247.2 References • “Hasj” (in Dutch). Geschiedenis 24. • Schoof, Rob (1 May 2008). “De achterdeur van de coffeeshop” (in Dutch). NRC Handelsblad. • van Schaik, Nol (7 October 2009). “Dutch Cannabis Coffeeshop History”. 324
• Mellow Yellow Lounge • Stichting Mediwiet
Chapter 248
The Night Train Seizure The Night Train Drug Seizure was a 1978 seizure of 54 tons of marijuana by the United States Coast Guard off the southeastern coast of Florida which marked the beginning of Operation Stopgap, a United States federal law enforcement inter-agency drug interdiction operation focusing on interdicting drugs from Colombian cartels and other illicit Central and South American drug sources.[1] The Night Train seizure was the largest single drug seizure in history at the time it occurred, and it remains one of the largest marijuana seizures made in the territorial waters of the United States.[2]
• List of United States Coast Guard cutters
Operation Stopgap was one of the first inter-agency law enforcement efforts focused on the interdiction of illegal drugs from Central and South America, and it featured personnel of the Coast Guard, DEA and US Federal Marshals Service working together,[3] as well as the resources of the Intelligence Section of the Drug Enforcement istration and Coast Guard Intelligence (CGI).[4]
• United States Coast Guard Legal Division
The Night Train was a 189 foot coastal cargo vessel that had become legendary in the law enforcement community and smuggling circles due to its repeated ability to elude US law enforcement for almost two years before they were finally captured off of West Palm Beach as the first seizure of Stopgap. Operation Stopgap was but the first of a number of highly successful inter-agency intelligence and interdiction operations[5] that led to a large number of successful seizures and prosecutions in the late 1970s and early 1980s, garnering the U.S. Coast Guard considerable press coverage during this period as seizure records continued to be broken.[6] Stopgap was also one of the earliest interdiction operations to effectively use satellite technology in the pursuit and interdiction of drug smugglers.[7]
• List of United States Coast Guard stations • Maritime Law Enforcement Academy • MARSEC • National Data Buoy Center • National Ice Center • Patrol Forces Southwest Asia
• United States Coast Guard officer rank insignia • United States Coast Guard Research & Development Center
248.2 References [1] Name Of Pot-Laden Ship Sounded Familiar To Coast Guard Miami News, December 11, 1977 [2] Marijuana Seizure Was Largest Haul On Record Lakeland (Florida) Ledger, April 20, 1978 [3] “The Battle Against Drugs Takes to the Seas: High Seas Drama When the Night Train was Seized by the Coast Guard.” U.S. News and World Report LXXXIV (Mar 27, 1978), pp. 69–71. [4] DEA and Coast Guard Could Almost Track Drug Ship By The Smell St. Petersburg Times, July 11, 1978 [5] Operation Stopgap The Spokesman Review, September 16, 1978 [6] Operation Stopgap Nails The Legendary Night Train, St. Petersburg Times, July 11, 1978
248.1 See also
[7] Satellites Aiding In Pot Seizures Sarasota Herald-Tribune, July 11, 1978
• Coast Guard Investigative Service • Go-fast boat • t Maritime Training Center • List of active United States military aircraft 325
Chapter 249
PSN-375,963 PSN-375,963 is a selective ligand for the suggested novel cannabinoid receptor GPR119.[1]
249.1 See also • AR-231,453 • PSN-632,408
249.2 References [1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C. (2006). “Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.”. Cell Metab. 3 (3): 167–175. doi:10.1016/j.cmet.2006.02.004. PMID 16517404.
326
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PSN-632,408 PSN-632,408 is a selective ligand for the suggested novel cannabinoid receptor GPR119.[1]
250.1 See also • AR-231,453 • PSN-375,963
250.2 References [1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C. (2006). “Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.”. Cell Metab. 3 (3): 167–175. doi:10.1016/j.cmet.2006.02.004. PMID 16517404.
327
Chapter 251
Soma Seeds Soma Seeds (also known as Soma’s Sacred Seeds) is an Amsterdam based medical cannabis seed company owned by Soma. The company became internationally famous after winning the 1999 High Times Cannabis Cup with Soma’s 'Reclining Buddha' strain in the Indica category;[1] in 2001, 2002, 2003 and 2004 with 'NYC Diesel' strain in the Sativa category,[2] in 2002 with 'Buddha’s Sister' strain in the Indica category [3] in 2004 with 'Amnesia Haze' in the best strain category [4] and in 2005 with 'Lavender' strain in the Indica category.[5]
251.1 References [1] Cannabis Cup winners 1999. [2] Cannabis Cup winners 2001. [3] Cannabis Cup winners 2002. [4] Cannabis Cup winners 2004. [5] Cannabis Cup winners 2005.
251.2 External links • http://www.somaseeds.nl/
328
Chapter 252
TM-38837 TM38837 is a new small molecule inverse agonist/antagonist of the CB1 cannabinoid receptor. It is being developed for the treatment of obesity and metabolic disorders by 7TM Pharma.[1] The company has announced phase I clinical trials. TM38837 is among the first of a new generation of cannabinoid receptor antagonist designed to avoid the central nervous system liabilities of the first generation CB1 receptor antagonists, for example rimonabant.[2]
252.1 See also • AM-6545
252.2 References [1] http://www.7tm.com [2] Hung, M. S.; Chang, C. P.; Li, T. C.; Yeh, T. K.; Song, J. S.; Lin, Y.; Wu, C. H.; Kuo, P. C.; Amancha, P. K.; Wong, Y. C.; Hsiao, W. C.; Chao, Y. S.; Shia, K. S. (2010). “Discovery of 1-(2,4-Dichlorophenyl)−4-ethyl5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen2-yl)-N-(piperidin-1-yl)−1H-pyrazole-3-carboxamide as a Potential Peripheral Cannabinoid-1 Receptor Inverse Agonist”. ChemMedChem 5 (9): 1439–1443. doi:10.1002/cmdc.201000246. PMID 20652930.
252.3 External links • www.7tm.com • Experimental obesity drug avoids brain effects that troubled predecessors
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252.4 Text and image sources, contributors, and licenses 252.4.1
Text
• Cannabinoid Source: http://en.wikipedia.org/wiki/Cannabinoid?oldid=630426170 Contributors: Bryan Derksen, Edward, Kwertii, JWSchmidt, Nnh, AnthonyQBachler, Hadal, Fuelbottle, Centrx, Karn, Bens, Jfdwolff, St3vo, Eequor, Christopherlin, OldakQuill, Ferre, Mearlon, Lazypplunite, Freakofnurture, Rich Farmbrough, Cacycle, Kwamikagami, Tgeller, Renice, Arcadian, Kaf, Alansohn, Eric Kvaalen, Howrealisreal, Axl, Mrholybrain, Ombudsman, Gene Nygaard, Natalya, Bobrayner, Qnonsense, Mpj17, WadeSimMiser, Mandarax, SqueakBox, BD2412, Mendaliv, Zachjones4, Rjwilmsi, HappyCamper, Fred Bradstadt, X1987x, Avocado, FlaBot, Margosbot, Jrtayloriv, Nosforit, Fborgnia, YurikBot, Mushin, Chris Capoccia, Gaius Cornelius, Zwobot, S. Neuman, Jeh, Ochiwar, Smaines, Saric, Itub, SmackBot, Unyoyega, Jrockley, Antrophica, Timotheus Canens, Jpvinall, Edgar181, David.Throop, Chris the speller, Bluebot, Droll, Deli nk, Ioscius, Roadnottaken, Radagast83, Drphilharmonic, J306, Provider uk, Ilyse Kazar, Rhetth, CmdrObot, Scoticus, ShelfSkewed, Meodipt, Kupirijo, Dougweller, Thijs!bot, Barticus88, RobArmstrong, Bendroz, Luke poa, Gharmon, Subvertc, Headbomb, Java13690, E. Ripley, Big Bird, Smartse, Astavats, Dougher, Ph.eyes, MudPhud, Probios, PhilKnight, Iownutopia, Cannabis, Hiplibrarianship, CliffC, Leyo, Lumir, J.delanoy, Pharaoh of the Wizards, Extransit, Nonantum, Jeepday, Mikael Häggström, Tanevala, Enix150, Funandtrvl, MenasimBot, Benrr101, LeaveSleaves, GeorgeLTirebiter, Glaman7, Carinabean1, Sapphic, Doc James, Ohiostandard, Nonsomniac, Scarian, Bradgon, Delighted eyes, ClueBot, Andrew Nutter, Drmies, Niceguyedc, Anon lynx, Phil Ian Manning, Vivio Testarossa, Panoramix303, Werson, Tonytross, RexxS, Akofalvi, Jytdog, Chemgirl131, Ost316, Vojtěch Dostál, WikiDao, Addbot, DOI bot, Jncraton, Wormantson, Jameskirby, Tide rolls, OlEnglish, Teles, Jarble, Gaberdine2, Luckas-bot, Yobot, Themfromspace, Clarechenoweth, Dmarquard, AnomieBOT, Götz, Rjanag, JackieBot, Materialscientist, Flaminhaz, Citation bot, Xqbot, Dagrun, GrouchoBot, Slowart, Ajax151, Shadowjams, Custoo, FrescoBot, Lothar von Richthofen, Maria mdv, Biker Biker, Pinethicket, CCIC, Abductive, Tea with toast, Trainwreckwebb, David Hedlund, Minimac, Algarcia85, RjwilmsiBot, Mungox, Alph Bot, EmausBot, Eekerz, SalviaFan, Nuujinn, Beeshoney, Zane Russell,, Tommy2010, Dcirovic, Doddy Wuid, Subtropical-man, MajorVariola, WickedSpice, Wayne Slam, Duncan169, DASHBotAV, Frozen Wind, ClueBot NG, Horoporo, Osterluzei, Mesoderm, HenryScow, Helpful Pixie Bot, BG19bot, Lewisly, Petrarchan47, Nikos 1993, Verified72, Drpainless, Viridis Veritas, Seannyboy219, Papier K, Kingofoviedo, Shisha-Tom, TheBaur, Stark1987, 32cllou, Mogism, Makecat-bot, Cerabot, Aachaos, Eyesnore, Wicked licks, Dymethylated, Meteor sandwich yum, Farmkid1958, Monkbot, Bosch1ltd rc development, Crazykatchic, Medgirl131, Jameshelsing, JuggaloI, SP1977 and Anonymous: 218 • Entourage effect Source: http://en.wikipedia.org/wiki/Entourage_effect?oldid=630508268 Contributors: Bearcat, Afterwriting, ZuluPapa5, Yobot, BG19bot and BattyBot • Synthetic cannabis Source: http://en.wikipedia.org/wiki/Synthetic_cannabis?oldid=629537150 Contributors: Frecklefoot, Deisenbe, Katana0182, Furrykef, Dale Arnett, Alan Liefting, DocWatson42, Everyking, St3vo, Neilc, Chowbok, Gadfium, Beland, Jokestress, Oknazevad, Cacycle, Cyclopia, Mr2001, Alansohn, Eleland, Ynhockey, Sciurinæ, BDD, KevinOKeeffe, SqueakBox, Rjwilmsi, XLerate, Krzysiu, Wgfcrafty, Diza, Therefore, Wavelength, Jimp, RadioFan, Grafen, Alpha 4615, BorgQueen, Fram, JDspeeder1, Paul Erik, SmackBot, KAtremer, Kintetsubuffalo, Edgar181, Ohnoitsjamie, Hmains, Cs-wolves, Chris the speller, Myxsoma, Thumperward, Cybercobra, Derek R Bullamore, Drphilharmonic, Salamurai, Curly Turkey, Ohconfucius, AThing, John, Minna Sora no Shita, IronGargoyle, SandyGeorgia, Skinsmoke, G patkar, MrDolomite, Valoem, Winston Spencer, J Milburn, JForget, Edward Vielmetti, CBM, Nczempin, Meodipt, Funnyfarmofdoom, Doctormatt, Crossmr, Kotiwalo, DumbBOT, FG Fox, Qwyrxian, N5iln, Turkeyphant, Matthew Proctor, Pfranson, Ssr, Shirt58, Smartse, DuncanHill, Adjwilley, Jheiv, Zendu, Umeboshi, Hiplibrarianship, BatteryIncluded, Esteroth12, Andytuba, Leyo, Edgeweyes, 2012Olympian, Malkuth1, Carolfrog, Danwoodard, AngryEoin, DadaNeem, Themoodyblue, Pdcook, 360aerial, Speciate, VolkovBot, Dave Andrew, Trex21, Philip Trueman, TXiKiBoT, Philaweb, Fxhomie, Clarince63, Ownthink, Smb1138, Anarchangel, Falcon8765, Living under a rock, Caltas, Psilonautika, Sokari, Soporaeternus, Sfan00 IMG, Tmtung, ClueBot, The Thing That Should Not Be, Drmies, PixelBot, John Nevard, Coinmanj, Lnelsonmd, Buckethed, XLinkBot, Psych0-007, Richard-of-Earth, WikiDao, MystBot, Addbot, Alex.mccarthy, MartinezMD, Debresser, Favonian, Exor674, 5 albert square, Tide rolls, Teles, MuZemike, Hartz, Hxck, Luckas-bot, Yobot, Preppysob99, Guy1890, AnomieBOT, Metalhead94, Götz, MovieImage, Csigabi, GB fan, ArthurBot, LilHelpa, Ryanjca, NFD9001, Tyrol5, Mlpearc, Ragityman, 931, GrouchoBot, Clark candace, Jezhotwells, A45b22chp, Antitak, Epiftw, Shadowjams, FrescoBot, Wikicool11, Mu Mind, Moloch09, Ttg53, Louperibot, Nirmos, SpacemanSpiff, Pinethicket, Elockid, HRoestBot, Calmer Waters, MastiBot, Theodore.Miller3, Tim1357, PiRSquared17, Tolvic, Benbullen, David Hedlund, Reaper Eternal, Seahorseruler, Diannaa, Phunlee, Fastilysock, Tbhotch, Tzores, RjwilmsiBot, Bento00, Surentity, DASHBot, WikitanvirBot, Nuujinn, Asred, Psychonaut2010, Minimac’s Clone, Renamed01302013, Tisane, Tommy2010, White Trillium, GreatSuccess101, OregonIronCo, Elektrik Shoos, AcidBurn211, Bxj, BGinOC, WickedSpice, Wayne Slam, Glennconti, Astara85, Voxcarnage, Norsci, KazekageTR, L Kensington, Mr. SpiceMan, Deathwishh, Akakeillo34, Lgarcia024, Killerprey23, Dominic Ragbottom, Joshgolf81, Sailsbystars, Tobeprecise, DeirdreNocturne, Limelitespice, Orange Suede Sofa, Stacks19, Keeper0fdahoes, Lagato123, Marioja1, Joey kandewit, Bentway, EdoBot, Quagameefi, AJ12Gamer, E. Fokker, Teaktl17, Redpanda44, ClueBot NG, SpikeTorontoR, Munda8163, Bkane16, AznBurger, Mr. Berty, Dchrguy, Kylesnage, Names are hard to think of, Helpful Pixie Bot, BG19bot, Oliveralbq, Justthinking25, Thirdeye616, Bodhisvaha5, BattyBot, Dereistic, BaeyerDrewson, ComfyKem, Yo222, Schenka, Exesop, Anrnusna, Monkbot, Medgirl131, Amanda Smalls and Anonymous: 432 • 4-HTMPIPO Source: http://en.wikipedia.org/wiki/4-HTMPIPO?oldid=628510777 Contributors: ChemNerd, Enix150, The chemistds, Ad Orientem, BaeyerDrewson and Mrbenzhao • 5F-PB-22 Source: http://en.wikipedia.org/wiki/5F-PB-22?oldid=622763569 Contributors: Meodipt, Anaxial, Yobot, Fraggle81, FrescoBot, The chemistds, BaeyerDrewson, KMAnomalocaris, Gigglepox and Anonymous: 7 • A-40174 Source: http://en.wikipedia.org/wiki/A-40174?oldid=546115716 Contributors: CheMoBot, BogBot, Dcirovic and NotWith
Edgar181, Beetstra, Meodipt, Addbot,
• A-41988 Source: http://en.wikipedia.org/wiki/A-41988?oldid=509594440 Contributors: Pegship, SmackBot, Edgar181, Nuklear, Beetstra, Meodipt, CheMoBot, حسن علي البط, BogBot and NotWith • A-796,260 Source: http://en.wikipedia.org/wiki/A-796,260?oldid=589910504 Contributors: Edgar181, Drphilharmonic, Beetstra, Meodipt, Smartse, Tanevala, Enix150, CheMoBot, Trappist the monk, The chemistds, Skoot13, Stark1987 and Anonymous: 1 • A-834,735 Source: http://en.wikipedia.org/wiki/A-834,735?oldid=589910514 Contributors: Drphilharmonic, Beetstra, Meodipt, Enix150, CheMoBot, FrescoBot, Trappist the monk, The chemistds, Skoot13, Shisha-Tom and Anonymous: 1 • A-836,339 Source: http://en.wikipedia.org/wiki/A-836,339?oldid=578815101 Contributors: Drphilharmonic, Meodipt, Smartse, Enix150, CheMoBot, Anypodetos, حسن علي البط, FrescoBot, BogBot, The chemistds, Stark1987 and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
331
• AB-001 Source: http://en.wikipedia.org/wiki/AB-001?oldid=619562530 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Smartse, Enix150, C6541, CheMoBot, Bamyers99, The chemistds, Skoot13, Stark1987, BaeyerDrewson and Anonymous: 2 • AB-005 Source: http://en.wikipedia.org/wiki/AB-005?oldid=600007387 Contributors: Yobot, SciRambar, Josve05a, BaeyerDrewson, Jimer and Anonymous: 2 • AB-CHMINACA Source: http://en.wikipedia.org/wiki/AB-CHMINACA?oldid=626078386 Contributors: Bearcat, Edgar181, Magioladitis, MrX, Medgirl131, Aethyta, Grandmalanfall, Jamesjbradshaw and Anonymous: 1 • AB-FUBINACA Source: http://en.wikipedia.org/wiki/AB-FUBINACA?oldid=616120128 Contributors: Meodipt, BaeyerDrewson and Anonymous: 4 • AB-PINACA Source: http://en.wikipedia.org/wiki/AB-PINACA?oldid=616218448 Contributors: Edgar181, Meodipt, The chemistds, BaeyerDrewson, Capsaicin and Anonymous: 2 • Abnormal cannabidiol Source: http://en.wikipedia.org/wiki/Abnormal_cannabidiol?oldid=589953504 Contributors: Rjwilmsi, Beetstra, Meodipt, Headbomb, Enix150, Benrr101, EoGuy, Addbot, Yobot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, Nirmos, BogBot, Trappist the monk, 564dude, Dcirovic, Cobaltcigs, DouglasMcHugh, The chemistds, Shisha-Tom, Metilisopropilisergamida and Anonymous: 1 • ADB-FUBINACA Source: http://en.wikipedia.org/wiki/ADB-FUBINACA?oldid=616218510 Contributors: HazyM, AnomieBOT, The chemistds, BaeyerDrewson and Anonymous: 5
Edgar181, Meodipt,
• ADB-PINACA Source: http://en.wikipedia.org/wiki/ADB-PINACA?oldid=618895825 Contributors: Edgar181 and BattyBot • ADBICA Source: http://en.wikipedia.org/wiki/ADBICA?oldid=595202165 Contributors: Meodipt, Yosefxp, Anypodetos, AnomieBOT, BaeyerDrewson and Anonymous: 1 • Ajulemic acid Source: http://en.wikipedia.org/wiki/Ajulemic_acid?oldid=618474671 Contributors: St3vo, Cacycle, Physchim62, Derek.cashman, ERobson, Nuklear, Drphilharmonic, Beetstra, Meodipt, Enix150, Benrr101, Panoramix303, Tictrotactro, Addbot, Yobot, PharmHU, CheMoBot, Anypodetos, Citation bot, حسن علي البط, Joyful rabbit, BogBot, Daviesje, Louisajb, Medgirl131 and Anonymous: 3 • AM-087 Source: http://en.wikipedia.org/wiki/AM-087?oldid=522175575 Contributors: Bearcat, Pegship, Drphilharmonic, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, The chemistds, Skoot13 and BaeyerDrewson • AM-1220 Source: http://en.wikipedia.org/wiki/AM-1220?oldid=544648977 Contributors: Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, BogBot, Jesse V., The chemistds, Skoot13, Destruktor5000, Fuse809 and Anonymous: 1 • AM-1221 Source: http://en.wikipedia.org/wiki/AM-1221?oldid=619562492 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, BogBot, Bamyers99, The chemistds, Skoot13 and Anonymous: 1 • AM-1235 Source: http://en.wikipedia.org/wiki/AM-1235?oldid=517510799 Contributors: CheMoBot, Harbinary, BogBot, Jesse V., The chemistds and Skoot13
Drphilharmonic, Meodipt, Enix150,
• AM-1241 Source: http://en.wikipedia.org/wiki/AM-1241?oldid=590554371 Contributors: Bearcat, Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Headbomb, Enix150, Addbot, C6541, CheMoBot, حسن علي البط, Harbinary, Citation bot 1, Nirmos, BogBot, RjwilmsiBot, Dcirovic, Skoot13, Purple Blanket, Destruktor5000, Shisha-Tom, BaeyerDrewson, Monkbot and Anonymous: 1 • AM-1248 Source: http://en.wikipedia.org/wiki/AM-1248?oldid=590552939 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Smartse, Enix150, Squids and Chips, C6541, CheMoBot, BogBot, Skoot13, Stark1987 and Monkbot • AM-1714 Source: http://en.wikipedia.org/wiki/AM-1714?oldid=557804331 Contributors: Meodipt • AM-2201 Source: http://en.wikipedia.org/wiki/AM-2201?oldid=624831207 Contributors: Jeffhos, Edgar181, Drphilharmonic, Meodipt, ChemNerd, Boghog, Enix150, SamChem7, Glossologist, Wikieditor12, DrakeUnlimited, Addbot, C6541, CheMoBot, AnomieBOT, Harbinary, SD5, FrescoBot, Biker Biker, BogBot, ItsZippy, Vrenator, Товарищ, Jesse V., ZéroBot, The chemistds, ClueBot NG, Ieponumos, D42kn355, Verified72, Ungodlyzilla, BaeyerDrewson, Ezymike, Yougotwarsh, Medgirl131 and Anonymous: 36 • AM-2232 Source: http://en.wikipedia.org/wiki/AM-2232?oldid=587699474 Contributors: Drphilharmonic, Meodipt, Toohool, C6541, CheMoBot, BogBot, The chemistds and Anonymous: 1 • AM-2233 Source: http://en.wikipedia.org/wiki/AM-2233?oldid=619646412 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Smartse, Enix150, C6541, CheMoBot, Citation bot, BogBot, GoingBatty, The chemistds, ClueBot NG, Skoot13, Stark1987, Monkbot and Anonymous: 2 • AM-2389 Source: http://en.wikipedia.org/wiki/AM-2389?oldid=577466486 Contributors: Meodipt, CheMoBot, Anypodetos, Jesse V., The chemistds, Skoot13 and Anonymous: 1 • AM-4030 Source: http://en.wikipedia.org/wiki/AM-4030?oldid=512515874 Contributors: Bearcat, St3vo, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Jesse V. • AM-411 Source: http://en.wikipedia.org/wiki/AM-411?oldid=517503332 Contributors: Bearcat, Pegship, Drphilharmonic, Paradoxsociety, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Skoot13 and Anonymous: 1 • AM-630 Source: http://en.wikipedia.org/wiki/AM-630?oldid=590552979 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Enix150, SamChem7, Addbot, C6541, CheMoBot, Lapuchca, BogBot, Yunshui, Dcirovic, Skoot13, Shisha-Tom, Monkbot and Anonymous: 1 • AM-6545 Source: http://en.wikipedia.org/wiki/AM-6545?oldid=605160648 Contributors: Wavelength, Meodipt, CheMoBot, Tea with toast, Hazard-SJ, The chemistds and ChrisGualtieri • AM-679 (cannabinoid) Source: http://en.wikipedia.org/wiki/AM-679_(cannabinoid)?oldid=590553001 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, BogBot, The chemistds, Skoot13 and Monkbot • AM-694 Source: http://en.wikipedia.org/wiki/AM-694?oldid=541208550 Contributors: Bearcat, Aardark, Rjwilmsi, Edgar181, Drphilharmonic, Beetstra, Meodipt, Enix150, Pdcook, ClueBot, C6541, Ettrig, CheMoBot, AnomieBOT, حسن علي البط, Harbinary, Biker Biker, BogBot, Jesse V., John of Reading, D42kn355, Verified72 and Anonymous: 7
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CHAPTER 252. TM-38837
• AM-855 Source: http://en.wikipedia.org/wiki/AM-855?oldid=590553033 Contributors: Bearcat, Chris Capoccia, Pegship, Edgar181, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Addihockey10 (automated) and Monkbot • AM-905 Source: http://en.wikipedia.org/wiki/AM-905?oldid=561228668 Contributors: Bearcat, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Addihockey10 (automated) • AM-906 Source: http://en.wikipedia.org/wiki/AM-906?oldid=587215378 Contributors: Bearcat, Pegship, Beetstra, Meodipt, Enix150, Panoramix303, CheMoBot, حسن علي البط, BogBot, Dcirovic and Skoot13 • AM-919 Source: http://en.wikipedia.org/wiki/AM-919?oldid=589343788 Contributors: Bearcat, Pegship, Beetstra, Meodipt, Mblumber, Enix150, CheMoBot, حسن علي البط, BogBot and Anonymous: 1 • AM-938 Source: http://en.wikipedia.org/wiki/AM-938?oldid=480558829 Contributors: Bearcat, Pegship, Meodipt, Enix150, Mentisock, CheMoBot, حسن علي البط, BogBot and The chemistds • AM404 Source: http://en.wikipedia.org/wiki/AM404?oldid=630846827 Contributors: Bearcat, Bk0, Rich Farmbrough, Xezbeth, WhiteTimberwolf, Rjwilmsi, Tavilis, Pegship, SmackBot, Edgar181, Deli nk, Beetstra, Ccroberts, Fvasconcellos, Cydebot, Probios, Magioladitis, Cgingold, ChemNerd, Boghog, The Right Honourable, Enix150, Chemgirl131, Addbot, DOI bot, Yobot, CheMoBot, حسن علي البط, Xasodfuih, Custoo, Kpstewart, Citation bot 1, Tea with toast, BogBot, Trappist the monk, Bushwakko, EmausBot, BG19bot, Monkbot, Medgirl131 and Anonymous: 12 • AMG-1 Source: http://en.wikipedia.org/wiki/AMG-1?oldid=599472934 Contributors: St3vo, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Dcirovic, The chemistds, Lugia2453 and Anonymous: 1 • AMG-3 Source: http://en.wikipedia.org/wiki/AMG-3?oldid=575104646 Contributors: Pegship, Beetstra, Meodipt, Kdaly100, Enix150, CheMoBot, حسن علي البط, BogBot, Jesse V., The chemistds and Anonymous: 1 • AMG-36 Source: http://en.wikipedia.org/wiki/AMG-36?oldid=517504824 Contributors: CheMoBot, حسن علي البط, BogBot and Skoot13
Pegship, Beetstra, Meodipt, Enix150,
• AMG-41 Source: http://en.wikipedia.org/wiki/AMG-41?oldid=570390555 Contributors: Pegship, GoodDay, Beetstra, Meodipt, Enix150, Panoramix303, CheMoBot, حسن علي البط, BogBot, Skoot13 and Anonymous: 1 • APINACA Source: http://en.wikipedia.org/wiki/APINACA?oldid=616218465 Contributors: Edgar181, Dl2000, Meodipt, Enix150, Ziggy Sawdust, Addbot, C6541, Yobot, AnomieBOT, Moscow Connection, EmausBot, ZéroBot, Soimort, Lionratz, The chemistds, AngusWOOF, Bcxfu75k, BaeyerDrewson, Yougotwarsh and Anonymous: 4 • AR-231,453 Source: http://en.wikipedia.org/wiki/AR-231,453?oldid=450845414 Contributors: Bearcat, Malcolma, Beetstra, Meodipt, Chemgirl131, CheMoBot, حسن علي البط, Citation bot 1, Nirmos, Tea with toast, BogBot, RjwilmsiBot and PotatoBot • Arachidonyl-2'-chloroethylamide Source: http://en.wikipedia.org/wiki/Arachidonyl-2'-chloroethylamide?oldid=592115240 Contributors: Rjwilmsi, Edgar181, Beetstra, CheMoBot, Citation bot, Tea with toast, 564dude and The chemistds • Arachidonylcyclopropylamide Source: http://en.wikipedia.org/wiki/Arachidonylcyclopropylamide?oldid=619280789 Contributors: Rjwilmsi, Edgar181, Beetstra, CheMoBot, Citation bot, Tea with toast, The chemistds and Skoot13 • N-Arachidonylglycine Source: http://en.wikipedia.org/wiki/N-Arachidonylglycine?oldid=630748266 Contributors: Edgar181, Citation bot, Trappist the monk, BG19bot, BattyBot, Kjkokesh, Anne Delong, Sanganik, HasteurBot, Monkbot, Medgirl131 and Anonymous: 2 • AZ-11713908 Source: http://en.wikipedia.org/wiki/AZ-11713908?oldid=590724305 Contributors: MZMcBride, Meodipt, Reedy Bot, CheMoBot, Hazard-SJ, The chemistds and Monkbot • BAY 38-7271 Source: http://en.wikipedia.org/wiki/BAY_38-7271?oldid=629306223 Contributors: Wimvandorst, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Jesse V., The chemistds, Louisajb, Qixingbao07, Jodosma, BethNaught and Anonymous: 3 • BAY 59-3074 Source: http://en.wikipedia.org/wiki/BAY_59-3074?oldid=577145491 Contributors: CheMoBot, Anypodetos, حسن علي البط, BogBot and The chemistds
Pegship, Meodipt, Enix150,
• BML-190 Source: http://en.wikipedia.org/wiki/BML-190?oldid=588166438 Contributors: Rjwilmsi, Pegship, Edgar181, Drphilharmonic, Meodipt, ChemNerd, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, Dcirovic, MikeyMouse10, The chemistds and Shisha-Tom • (C6)- 47,497 Source: http://en.wikipedia.org/wiki/(C6)-_47,497?oldid=570943973 Contributors: Edgar181, Meodipt, JanetteDoe and Nikos 1993 • (C9)- 47,497 Source: http://en.wikipedia.org/wiki/(C9)-_47,497?oldid=570943911 Contributors: Edgar181, Meodipt, Tikuko, JanetteDoe and Nikos 1993 • Canbisol Source: http://en.wikipedia.org/wiki/Canbisol?oldid=618474701 Contributors: MZMcBride, Drphilharmonic, Meodipt, Reedy Bot, Enix150, CheMoBot, Anypodetos, FrescoBot, BogBot, Peryeat, The chemistds, Louisajb, Skoot13, Monkbot, Medgirl131 and Anonymous: 1 • Cannabichromene Source: http://en.wikipedia.org/wiki/Cannabichromene?oldid=627279471 Contributors: Chris Capoccia, Welsh, SmackBot, Edgar181, Jon513, Chrylis, Beetstra, VolkovBot, MenasimBot, Benrr101, Chem-awb, Mild Bill Hiccup, Plasmic Physics, Addbot, LaaknorBot, CheMoBot, Metalhead94, Citation bot, حسن علي البط, Custoo, A8UDI, RjwilmsiBot, EmausBot, Dcirovic, The chemistds, Louisajb, Nikos 1993, NotWith, Oneultralamewhiteboy and Anonymous: 1 • Cannabicyclohexanol Source: http://en.wikipedia.org/wiki/Cannabicyclohexanol?oldid=618475852 Contributors: Rich Farmbrough, EncMstr, Meodipt, Bobber0001, Boing! said Zebedee, Addbot, MartinezMD, CheMoBot, Biker Biker, BogBot, Dcirovic, ZéroBot, The chemistds, ClueBot NG, Diogenes2000, Skoot13, Robcrowl, Nikos 1993, Verified72, Monkbot, Medgirl131 and Anonymous: 4 • Cannabicyclol Source: http://en.wikipedia.org/wiki/Cannabicyclol?oldid=562446736 Contributors: Cheyinka, JIP, Pumeleon, Pegship, SmackBot, Edgar181, Beetstra, Leyo, Secretservgy, Panoramix303, Chemgirl131, Addbot, Mai-tai-guy, CheMoBot, Anypodetos, حسن علي البط, BenzolBot, Mcrosenstein, BogBot, Nikos 1993 and Anonymous: 5
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
333
• Cannabidiol Source: http://en.wikipedia.org/wiki/Cannabidiol?oldid=630847328 Contributors: Bryan Derksen, MadSurgeon, Andrevan, Selket, Phil Boswell, Robbot, St3vo, Vanished 1234567890, Ary29, Alexrexpvt, Rich Farmbrough, Cacycle, Zaslav, Kwamikagami, Causa sui, Tgeller, Renice, Viriditas, Eric Kvaalen, Benjah-bmm27, Howrealisreal, Thoric, Animated Cascade, Ceyockey, Lofor, Rjwilmsi, Heah, FlaBot, A scientist, Margosbot, SouthernNights, Shao, Physchim62, WriterHound, ThunderPeel2001, Nick, Revaaron, ASmartKid, SmackBot, Alex Ex, Ohnoitsjamie, HartzR, Elixir0219, Zachorious, Frantik, Ioscius, BullRangifer, Drphilharmonic, DMacks, Acdx, Fireemblem555, Gobonobo, Ckatz, Smith609, Beetstra, SandyGeorgia, DeLarge, MessedRobot, ShelfSkewed, Meodipt, Linuxrocks123, Cydebot, Supposed, Mrt50, DumbBOT, Alaibot, Thijs!bot, CopperKettle, Subvertc, Headbomb, Nashmaximus, SummerPhD, Smartse, 18hands, Badgerbear, NLuchs, Noobeditor, Cadsuane Melaidhrin, ChemNerd, Fconaway, Enix150, Funandtrvl, Meiskam, Sergivs-en, MenasimBot, Wikieditor12, Benrr101, LetTheSunshineIn, Cheryladay, Gamesguru2, Vvevo, Yintan, Alexbrn, Danelo, Eplebel, Literaturegeek, Leodmacleod, Panoramix303, Chemgirl131, Dthomsen8, Addbot, C6541, DOI bot, Hermógenes Teixeira Pinto Filho, SamatBot, Pigoutultra, Lightbot, Yobot, CheMoBot, Anypodetos, AnomieBOT, Götz, Royote, Jtmorgan, Citation bot, LilHelpa, Zad68, حسن علي البط, Harbinary, O0Alea0o, P-kun80, Custoo, Citation bot 1, Nirmos, DrM!KEY, A8UDI, Codwiki, Sucrase, Tea with toast, Oldmaneinstein, BogBot, David Hedlund, Gtziavelis, Reach Out to the Truth, RjwilmsiBot, Dustin 3choes, Kefirmonger, Dcirovic, AManWithNoPlan, Eagleye54321, Allethrin, Ehsan soltani, Bayhemp, Rachman321, Louisajb, ClueBot NG, Vjiced, BakuninGoldmanKropotkin, Osterluzei, Soleil mouse, TeXnocrat, Redmitrow, Shabadahabada, Eeroth, Helpful Pixie Bot, Busician, BG19bot, Petrarchan47, Nikos 1993, Exercisephys, MrBill3, NotWith, 123957a, Fuse809, BattyBot, TheBaur, ChrisGualtieri, Qxukhgiels, FoCuSandLeArN, Webclient101, Will Sandberg, Steinsplitter, UseTheCommandLine, ComfyKem, ScoutKnot, Youtalkfunny, Tentinator, ArmbrustBot, Merff, Tired canadian, Tankbank420, Dave Underbridge, HeyItsAedan, JaconaFrere, Zouloum, MissSpade602, Logan Lynn Roberts, C.o.young, Monkbot, Mattdavid22, Silent Singularitarian, Wendywhatnot, Daveyboy9999, Jakens84, JackDemarco 420, Medgirl131, Tristonlarsen, Rowanbiggs, Aethyta, Shirt0ripper0, DystoniaPatient and Anonymous: 156 • Cannabidivarin Source: http://en.wikipedia.org/wiki/Cannabidivarin?oldid=599332824 Contributors: RedWolf, Jorge Stolfi, Foobar, Cacycle, Ceyockey, PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Frantik, Beetstra, Alaibot, Benrr101, GeorgeLTirebiter, Panoramix303, DumZiBoT, Chemgirl131, Addbot, CheMoBot, Anypodetos, Casforty, حسن علي البط, Nirmos, MastiBot, BogBot, EmausBot, Davesynth, Nikos 1993, NotWith, BattyBot and Anonymous: 2 • Cannabigerol Source: http://en.wikipedia.org/wiki/Cannabigerol?oldid=618473245 Contributors: Renice, Cheyinka, Rjwilmsi, Pegship, Edgar181, Beetstra, ChemNerd, Benrr101, Secretservgy, Chem-awb, Panoramix303, Chemgirl131, Addbot, Tide rolls, CheMoBot, Anypodetos, Metalhead94, Citation bot, حسن علي البط, Custoo, Nirmos, MastiBot, Tea with toast, BogBot, PotatoBot, Louisajb, MerlIwBot, Nikos 1993, NotWith, Shisha-Tom, Sedind, Monkbot, Medgirl131 and Anonymous: 3 • Cannabinoidergic Source: http://en.wikipedia.org/wiki/Cannabinoidergic?oldid=630539739 Contributors: Rjwilmsi, Bhny, Fram, Wilhelmina Will, Addbot, The Elves Of Dunsimore, Sunilaggarwal7, CitationCleanerBot, Monkbot and Medgirl131 • Cannabinol Source: http://en.wikipedia.org/wiki/Cannabinol?oldid=618473196 Contributors: Robbot, Cacycle, Pacula, Howrealisreal, Ceyockey, Rjwilmsi, FlaBot, Physchim62, Pegship, SmackBot, Eskimbot, Frymaster, Edgar181, Lieutenant Colonel Frank Slade, Beetstra, Saxbryn, Cydebot, Rifleman 82, Absentis, Alaibot, Subvertc, VolkovBot, MenasimBot, THC Loadee, Benrr101, Chem-awb, Anthonyvidal, Eeekster, Panoramix303, Stevem848, Chemgirl131, Addbot, DOI bot, LaaknorBot, Wormantson, Luckas-bot, Ptbotgourou, Fraggle81, CheMoBot, Anypodetos, Götz, حسن علي البط, P-kun80, Custoo, Micasta, Citation bot 1, A8UDI, RedBot, MastiBot, BogBot, PotatoBot, Peryeat, Osterluzei, Jonfarrimond, Bemopa, Nikos 1993, NotWith, ArmbrustBot, MissSpade602, Monkbot, Sentaloc, Medgirl131 and Anonymous: 15 • Cannabivarin Source: http://en.wikipedia.org/wiki/Cannabivarin?oldid=599333620 Contributors: Jorge Stolfi, Cacycle, Aude, Ceyockey, PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Beetstra, Saxbryn, Alaibot, Benrr101, Chem-awb, Panoramix303, Addbot, CheMoBot, Casforty, حسن علي البط, FrescoBot, EmausBot, Dcirovic, HiW-Bot, Nikos 1993 and Anonymous: 1 • Caryophyllene Source: http://en.wikipedia.org/wiki/Caryophyllene?oldid=622304553 Contributors: Mboverload, Rich Farmbrough, Kwamikagami, Mendaliv, Rjwilmsi, WriterHound, Chris Capoccia, SmackBot, Edgar181, Sesquis, Mwtoews, DMacks, Beetstra, Timothykinney, Meodipt, Cydebot, Calvero JP, Deflective, NEUROtiker, ChemNerd, Arsenal1508, TimofKingsland, Chem-awb, Sensonet, Alexbot, Panoramix303, Addbot, DOI bot, Fothergill Volkensniff IV, LaaknorBot, Luckas-bot, Yobot, CheMoBot, Citation bot, Xqbot, حسن علي البط, Itineranttrader, Andromeas, Custoo, FrescoBot, Citation bot 1, Sorneguer, EmausBot, Dcirovic, NotWith, Bcary, DarafshBot, Mogism, ArmbrustBot, Monkbot, RohdeN and Anonymous: 14 • CB-13 Source: http://en.wikipedia.org/wiki/CB-13?oldid=590870232 Contributors: Meodipt, Enix150, Yobot, CheMoBot, حسن علي البط, BogBot, Hazard-SJ, BaeyerDrewson, Monkbot and Anonymous: 1 • CBS-0550 Source: http://en.wikipedia.org/wiki/CBS-0550?oldid=570619983 Contributors: Meodipt, The chemistds and Skoot13 • 47,497 Source: http://en.wikipedia.org/wiki/_47,497?oldid=610061328 Contributors: Cacycle, Alansohn, Poul818, Pegship, Cybercobra, Valenciano, Beetstra, Meodipt, Cydebot, Thijs!bot, Smartse, Enix150, Funandtrvl, TXiKiBoT, ClueBot, Addbot, C6541, MartinezMD, Ryanjca, حسن علي البط, Custoo, DrilBot, Biker Biker, BogBot, Akerans, LoverOfTheWord, Louisajb, ClueBot NG, Skoot13, Nikos 1993, Verified72, Woo 24, Monkbot and Anonymous: 26 • 55,244 Source: http://en.wikipedia.org/wiki/_55,244?oldid=561022757 Contributors: Rjwilmsi, Pegship, Edgar181, Meodipt, Rhadamante, Enix150, Funandtrvl, CheMoBot, حسن علي البط, BogBot and Anonymous: 1 • 55,940 Source: http://en.wikipedia.org/wiki/_55,940?oldid=618472345 Contributors: DropDeadGorgias, Ktotam, St3vo, Sam Hocevar, Cacycle, Flying Hamster, Ceyockey, Galaxiaad, Pol098, Rjwilmsi, Heah, Physchim62, Muijzo, Kajerm, SmackBot, GoldenXuniversity, Hmains, Tsca.bot, Simonster, Rory096, Saxbryn, Ccroberts, Meodipt, Cydebot, CDrecche, Alaibot, MattTweedell, Astavats, Floaterfluss, Tanevala, Enix150, Funandtrvl, Jonakimmen, Psych0-007, Wertyg, Modern Shaman, Addbot, C6541, Chempedia, AnomieBOT, Citation bot, حسن علي البط, Harbinary, Custoo, FrescoBot, BogBot, RjwilmsiBot, PotatoBot, Louisajb, Skoot13, Yukileoo, Delphine Psychoyos, Medgirl131 and Anonymous: 27 • Dexanabinol Source: http://en.wikipedia.org/wiki/Dexanabinol?oldid=602665690 Contributors: Drphilharmonic, Beetstra, Meodipt, Rod57, Enix150, Panoramix303, Addbot, CheMoBot, Anypodetos, حسن علي البط, Citation bot 1, HRoestBot, Tea with toast, BogBot, The chemistds, ClueBot NG, Skoot13, Monkbot, Madtay and Anonymous: 3 • Dimethylheptylpyran Source: http://en.wikipedia.org/wiki/Dimethylheptylpyran?oldid=629287274 Contributors: Bkell, St3vo, GregorB, Rjwilmsi, Pegship, Chris the speller, Beetstra, Meodipt, Astavats, Funandtrvl, Wikieditor12, Panoramix303, Chemgirl131, C6541, CheMoBot, Anypodetos, Rifter0x0000, Metalhead94, Materialscientist, Citation bot, حسن علي البط, Harbinary, BogBot, Lotje, Dcirovic, K kisses, Daviesje, Nikos 1993, Testem, ChrisGualtieri, Medgirl131 and Anonymous: 7
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• Docosatetraenoylethanolamide Source: http://en.wikipedia.org/wiki/Docosatetraenoylethanolamide?oldid=479428373 Contributors: Edgar181, Beetstra, Cydebot, CheMoBot, Citation bot, Erik9bot, Kpstewart, Citation bot 1, Tea with toast, The chemistds and Anonymous: 1 • Drinabant Source: http://en.wikipedia.org/wiki/Drinabant?oldid=608365837 Contributors: Woohookitty, Rjwilmsi, Edgar181, Meodipt, Chemgirl131, Yobot, A412 and Anonymous: 1 • EAM-2201 Source: http://en.wikipedia.org/wiki/EAM-2201?oldid=602234811 Contributors: Dl2000, Meodipt, Magioladitis, Destruktor5000, D42kn355 and Anonymous: 3 • Endocannabinoid reuptake inhibitor Source: http://en.wikipedia.org/wiki/Endocannabinoid_reuptake_inhibitor?oldid=630847750 Contributors: Firsfron, De728631, Mild Bill Hiccup, SchreiberBike, Custoo, Rideer13, AvicAWB, SaetaSolea, Beedublu, Jpgunner13, Sbuinformation, Medgirl131 and Anonymous: 3 • Endocannabinoid system Source: http://en.wikipedia.org/wiki/Endocannabinoid_system?oldid=630033669 Contributors: Nagelfar, Rich Farmbrough, Lycurgus, Jpgordon, C4 Diesel, Rjwilmsi, Chris Capoccia, Tavilis, Trovatore, Pb30, Winter Light, Banus, SmackBot, Roadnottaken, Mini-Geek, Clicketyclack, Gobonobo, Kimdonndenman, Rhetth, Darthelmo, Inferiority, CopperKettle, Headbomb, Leon7, Nick Number, MarshBot, Thibbs, Marcuj, Nono64, Boghog, Colincbn, Tanevala, Enix150, DragonBot, BDov777, ZuluPapa5, Wnt, DumZiBoT, Chemgirl131, Mjpresson, Ost316, Vojtěch Dostál, Addbot, JayGSXR750, Yobot, Bunnyhop11, Jzlong, Wrightmj, AnomieBOT, Materialscientist, Citation bot, Drilnoth, The myoclonic jerk, Lothar von Richthofen, Citation bot 1, I dream of horses, Tea with toast, David Hedlund, Gtziavelis, virus, Lucas Thoms, Jlb92, ClueBot NG, Vjiced, Osterluzei, SaetaSolea, Bibcode Bot, Snow Blizzard, Glacialfox, Wyliea, BattyBot, Hoodjuice, Ramizein, Meteor sandwich yum, Monkbot, Medgirl131, Mrokiestar and Anonymous: 59 • Endocannabinoid transporters Source: http://en.wikipedia.org/wiki/Endocannabinoid_transporters?oldid=625857200 Contributors: Rjwilmsi, Wavelength, Vigyani, Yobot, Citation bot, Alvin Seville, GoingBatty, Sbuinformation, Anaffen21, Medgirl131 and Anonymous: 1 • GW-405,833 Source: http://en.wikipedia.org/wiki/GW-405,833?oldid=610061444 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Cydebot, Enix150, Addbot, CheMoBot, حسن علي البط, Harbinary, Custoo, BogBot, Dcirovic and Louisajb • GW-842,166X Source: http://en.wikipedia.org/wiki/GW-842,166X?oldid=591559628 Contributors: Meodipt, CheMoBot, BogBot, The chemistds, Louisajb and Monkbot • Hemopressin Source: http://en.wikipedia.org/wiki/Hemopressin?oldid=619651829 Contributors: Kielsky, Arcadian, Rjwilmsi, Meodipt, Boghog, Enix150, Ronhjones, CheMoBot, ScottMHoward, Jesse V., RjwilmsiBot, The chemistds, Monkbot, Medgirl131 and Anonymous: 5 • HU-210 Source: http://en.wikipedia.org/wiki/HU-210?oldid=618472397 Contributors: Fnielsen, Rich Farmbrough, Cacycle, ZayZayEM, SqueakBox, Heah, Margosbot, Physchim62, Fourdee, WriterHound, YurikBot, Gaius Cornelius, Daemon8666, Pegship, SmackBot, C.Löser, GoldenXuniversity, Edgar181, Nuklear, Cybercobra, Drphilharmonic, Ourai, Beetstra, Ccroberts, CmdrObot, Meodipt, Alaibot, Gharmon, Turkeyphant, Smartse, Hoffmeier, ThinkBlue, Enix150, Funandtrvl, VolkovBot, Fences and windows, Altzinn, SPECVLVMSINCERVS, Panoramix303, Addbot, DOI bot, Tide rolls, Alfie66, Luckas-bot, Yobot, CheMoBot, Metalhead94, Götz, Codc, حسن علي البط, Harbinary, FrescoBot, StrawberryCube, Biker Biker, Snazzra, Calmer Waters, JKChandler, BogBot, Gould363, SalviaFan, Nuujinn, Renamed01302013, Daviesje, Phenomenologyx, Louisajb, Doctorarcane, RealMortimir, Skoot13, SubDural12, Verified72, Hmainsbot1, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 51 • HU-243 Source: http://en.wikipedia.org/wiki/HU-243?oldid=536294331 Contributors: Meodipt • HU-308 Source: http://en.wikipedia.org/wiki/HU-308?oldid=610213643 Contributors: St3vo, Wimvandorst, FlaBot, Pegship, Nuklear, Drphilharmonic, Beetstra, Meodipt, Cydebot, Enix150, Panoramix303, Addbot, C6541, CheMoBot, حسن علي البط, Custoo, BogBot, Dcirovic, Jimer and Anonymous: 2 • HU-331 Source: http://en.wikipedia.org/wiki/HU-331?oldid=613064375 Contributors: BD2412, Drphilharmonic, Meodipt, R'n'B, Enix150, SchreiberBike, Addbot, CheMoBot, Anypodetos, KamikazeBot, MALLUS, The chemistds, Skoot13, NotWith and ChrisGualtieri • 11-Hydroxy-THC Source: http://en.wikipedia.org/wiki/11-Hydroxy-THC?oldid=620143359 Contributors: Yidele, Cacycle, Rjwilmsi, Derek.cashman, Edgar181, Beetstra, Suboptimal name, Meodipt, Isilanes, Equazcion, DorganBot, Danelo, Alexbot, Panoramix303, MystBot, Addbot, Yobot, CheMoBot, KamikazeBot, Citation bot, حسن علي البط, Harbinary, Citation bot 1, BogBot, Jynto, Medgirl131 and Anonymous: 3 • 9-nor-9β-Hydroxyhexahydrocannabinol Source: http://en.wikipedia.org/wiki/9-nor-9β-Hydroxyhexahydrocannabinol?oldid= 517509498 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150, Yobot, Citation bot, حسن علي البط, Skoot13 and Anonymous: 1 • Ibipinabant Source: http://en.wikipedia.org/wiki/Ibipinabant?oldid=618474939 Contributors: Rjwilmsi, Pegship, SmackBot, Meodipt, Enix150, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Citation bot, حسن علي البط, BogBot, Peryeat, The chemistds, Louisajb, Pashihiko, Vaccinationist, Medgirl131 and Anonymous: 2 • IDFP Source: http://en.wikipedia.org/wiki/IDFP?oldid=576656123 Contributors: Meodipt • 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene Source: http://en.wikipedia.org/wiki/ Cacycle, Deyyaz, Peg2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene?oldid=545325142 Contributors: ship, Edgar181, Meodipt, Nono64, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, EmausBot and Anonymous: 1 • JTE 7-31 Source: http://en.wikipedia.org/wiki/JTE_7-31?oldid=546233677 Contributors: Meodipt, Enix150, Addbot, CheMoBot, RevelationDirect, Skoot13 and AvocatoBot • JTE-907 Source: http://en.wikipedia.org/wiki/JTE-907?oldid=606454861 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt, Smartse, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, EmausBot, Skoot13, Stark1987, WildCation and Anonymous: 1 • JWH-015 Source: http://en.wikipedia.org/wiki/JWH-015?oldid=616440152 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt, Cydebot, Headbomb, Boghog, Enix150, Addbot, C6541, Queenmomcat, CheMoBot, Citation bot, حسن علي البط, Lapuchca, Custoo, Jonesey95, BogBot, Tisane, Dcirovic, Skoot13, Monkbot, WildCation and Anonymous: 3 • JWH-051 Source: http://en.wikipedia.org/wiki/JWH-051?oldid=606457301 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, Tisane, WildCation and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
335
• JWH-057 Source: http://en.wikipedia.org/wiki/JWH-057?oldid=606458240 Contributors: Bgwhite, Meodipt, Magioladitis, AnomieBOT, BaeyerDrewson and WildCation • JWH-120 Source: http://en.wikipedia.org/wiki/JWH-120?oldid=606478716 Contributors: Meodipt, BaeyerDrewson and WildCation • JWH-122 Source: http://en.wikipedia.org/wiki/JWH-122?oldid=560783506 Contributors: Bearcat, Edgar181, Beetstra, Meodipt, Katharineamy, Enix150, Cvf-ps, Addbot, C6541, Yobot, CheMoBot, A412, Diogenes2000, Skoot13, Snotbot, JamietwBot and Anonymous: 2 • JWH-133 Source: http://en.wikipedia.org/wiki/JWH-133?oldid=618472603 Contributors: St3vo, Arcadian, SmackBot, Zaphraud, Beetstra, Saxbryn, Ccroberts, CmdrObot, Meodipt, Cydebot, NewEnglandYankee, Tanevala, Enix150, Altzinn, Addbot, CheMoBot, حسن علي البط, Harbinary, Anonabyss, Custoo, BogBot, Tisane, Dcirovic, Frozen Wind, Rich Smith, Managermerrill, AwamerT, Drblizz, Medgirl131 and Anonymous: 16 • JWH-148 Source: http://en.wikipedia.org/wiki/JWH-148?oldid=606481972 Contributors: Meodipt, BaeyerDrewson and WildCation • JWH-149 Source: http://en.wikipedia.org/wiki/JWH-149?oldid=606483315 Contributors: Meodipt, C6541, BaeyerDrewson and WildCation • JWH-161 Source: http://en.wikipedia.org/wiki/JWH-161?oldid=606483553 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150, CheMoBot, حسن علي البط, FrescoBot, BogBot and WildCation • JWH-176 Source: http://en.wikipedia.org/wiki/JWH-176?oldid=606485810 Contributors: Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Tisane, Deathhell77 and WildCation • JWH-359 Source: http://en.wikipedia.org/wiki/JWH-359?oldid=502194790 Contributors: Rjwilmsi, Nuklear, Meodipt, Headbomb, Nono64, Enix150, CheMoBot, Grim23, حسن علي البط, FrescoBot, BogBot, Tisane, Rich Smith, Managermerrill and Anonymous: 4 • JZL184 Source: http://en.wikipedia.org/wiki/JZL184?oldid=591975737 Contributors: Wimvandorst, Roadnottaken, Beetstra, Meodipt, Enix150, Chem-awb, Addbot, CheMoBot, Anypodetos, Jzlong, حسن علي البط, P-kun80, Citation bot 1, Nirmos, EmausBot, PotatoBot, Monkbot and Anonymous: 3 • JZL195 Source: http://en.wikipedia.org/wiki/JZL195?oldid=546258079 Contributors: Enix150, Addbot, The Blade of the Northern Lights and Rezabot • KM-233 Source: http://en.wikipedia.org/wiki/KM-233?oldid=624180345 Contributors: BD2412, Meodipt, Dthomsen8, Yobot, Skoot13 and WildCation • L-759,633 Source: http://en.wikipedia.org/wiki/L-759,633?oldid=610061479 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt, Cydebot, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Custoo, Citation bot 1, BogBot, Dcirovic, Louisajb and Shisha-Tom • L-759,656 Source: http://en.wikipedia.org/wiki/L-759,656?oldid=545322433 Contributors: Pegship, Nuklear, Drphilharmonic, Meodipt, Enix150, ClueBot, Addbot, CheMoBot, حسن علي البط, BogBot, Dcirovic, Louisajb and Anonymous: 1 • LASSBio-881 Source: http://en.wikipedia.org/wiki/LASSBio-881?oldid=489676335 Contributors: Meodipt • LBP-1 (drug) Source: http://en.wikipedia.org/wiki/LBP-1_(drug)?oldid=587855670 Contributors: Meodipt, Hazard-SJ and ChrisGualtieri • Leelamine Source: http://en.wikipedia.org/wiki/Leelamine?oldid=618475826 Contributors: Magioladitis, Eeekster, Sekio and Medgirl131 • Levonantradol Source: http://en.wikipedia.org/wiki/Levonantradol?oldid=618472637 Contributors: Howrealisreal, Wouterstomp, Rjwilmsi, FlaBot, Pegship, Edgar181, Beetstra, Meodipt, Cydebot, Enix150, Funandtrvl, Sam Blacketer, Addbot, CheMoBot, Anypodetos, حسن علي البط, Harbinary, Custoo, BogBot, ZéroBot, Peryeat, Skoot13, BattyBot, Najenager, Monkbot, Medgirl131 and Anonymous: 1 • List of AM cannabinoids Source: http://en.wikipedia.org/wiki/List_of_AM_cannabinoids?oldid=604703358 Contributors: Bearcat, Chris the speller, Meodipt, Enix150, Citation bot, BattyBot, Monkbot and Anonymous: 5 • List of JWH cannabinoids Source: http://en.wikipedia.org/wiki/List_of_JWH_cannabinoids?oldid=607385076 Contributors: Rjwilmsi, Meodipt, Uruiamme, Enix150, The Thing That Should Not Be, Ironholds, Quebec99, RjwilmsiBot, Tisane, 4321acb, BG19bot, BaeyerDrewson and Anonymous: 3 • LY-2183240 Source: http://en.wikipedia.org/wiki/LY-2183240?oldid=630847383 Contributors: Meodipt, Addbot, Rezabot, Fylbecatulous, WildCation, Medgirl131 and Anonymous: 3 • LY-320,135 Source: http://en.wikipedia.org/wiki/LY-320,135?oldid=525861108 Contributors: Pegship, Meodipt, RXPhd, Yobot, CheMoBot, حسن علي البط, BogBot and Anonymous: 1 • MAM-2201 Source: http://en.wikipedia.org/wiki/MAM-2201?oldid=615014022 Contributors: Dl2000, Meodipt, C6541, AnomieBOT, Harbinary and WildCation • MDA-19 Source: http://en.wikipedia.org/wiki/MDA-19?oldid=517576564 Contributors: Drphilharmonic, Beetstra, Meodipt, CheMoBot and Skoot13 • Menabitan Source: http://en.wikipedia.org/wiki/Menabitan?oldid=621328559 Contributors: Rjwilmsi, Edgar181, Meodipt, Chemgirl131, Anypodetos, Braincricket, Monkbot and Medgirl131 • Methanandamide Source: http://en.wikipedia.org/wiki/Methanandamide?oldid=544106189 Contributors: Bearcat, St3vo, Wimvandorst, Stemonitis, Rjwilmsi, SmackBot, Edgar181, Bluebot, Beetstra, Cytocon, Waacstats, STBot, Nono64, Enix150, Plasmic Physics, Addbot, CheMoBot, Anypodetos, Citation bot, حسن علي البط, Erik9bot, Tea with toast, Skoot13, Amolbot and Anonymous: 4 • MK-9470 Source: http://en.wikipedia.org/wiki/MK-9470?oldid=612370825 Contributors: Rjwilmsi, Pegship, Edgar181, DMacks, CmdrObot, Meodipt, MSBOT, Boghog, Chem-awb, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, RedBot, Dcirovic and WildCation • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-methoxyindole-3-carboxamide Source: http://en.wikipedia.org/wiki/N-(S) Edgar181, A5b, Meodipt, -Fenchyl-1-(2-morpholinoethyl)$-$7-methoxyindole-3-carboxamide?oldid=592608780 Contributors: Smartse, Ben MacDui, Enix150, Denisarona, Addbot, CheMoBot, AnomieBOT, Citation bot, Xqbot, SDPatrolBot, Dcirovic, The chemistds, Skoot13, ScottSteiner, Vasiliy 100, Vasiliy 101, ChrisGualtieri, Monkbot and Anonymous: 1
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• Nabazenil Source: http://en.wikipedia.org/wiki/Nabazenil?oldid=628470027 Contributors: Meodipt, ChemNerd, CheMoBot, حسن علي البط, BogBot, Peryeat, Helpful Pixie Bot, WildCation and Medgirl131 • Nabilone Source: http://en.wikipedia.org/wiki/Nabilone?oldid=627639158 Contributors: Selket, IceKarma, St3vo, Cacycle, Arcadian, Kjkolb, E=MC^2, Rad Racer, Rjwilmsi, Heah, FlaBot, Ground Zero, Kerowyn, Bgwhite, Asacarny, Pegship, JRey, Andrew73, SmackBot, Edgar181, Zachorious, Cybercobra, Beetstra, CmdrObot, Meodipt, Guitarmankev1, Anthonyhcole, Alaibot, Tins128, Amontgomery, Gwern, AliaGemma, ChemNerd, Gojo002, Floaterfluss, Enix150, Funandtrvl, McM.bot, Dr.michael.benjamin, Flyer22, Alexbrn, Atdavies, Mlaffs, Zhile, Dr. Anymouse, Chemgirl131, Addbot, DOI bot, Earthguy69, Yobot, CheMoBot, Yngvadottir, AnomieBOT, Metalhead94, Citation bot, Jü, حسن علي البط, Harbinary, Apteekkarin poika, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot, ZéroBot, Peteb4, Louisajb, ClueBot NG, Skoot13, Petrarchan47, PhnomPencil, Scopolaminemethylnitrate, Fuse809, Crocodile100100, Monkbot, Medgirl131, SP1977 and Anonymous: 27 • Nabitan Source: http://en.wikipedia.org/wiki/Nabitan?oldid=618475710 Contributors: St3vo, Pegship, Edgar181, Beetstra, Meodipt, Leftfoot69, Funandtrvl, Addbot, Yobot, CheMoBot, Anypodetos, حسن علي البط, BogBot, Snubcube, NotWith and Medgirl131 • Nabiximols Source: http://en.wikipedia.org/wiki/Nabiximols?oldid=625135113 Contributors: Pfrishauf, Arm, Jfdwolff, Trevor MacInnis, Tribble, Pacula, Eleland, Oasisbob, GJeffery, SidP, Galaxiaad, Urod, Tokek, SqueakBox, Vegaswikian, Aspro, WriterHound, YurikBot, Shalmoo, Andrew73, Anarchist42, Poldavo, Uthbrian, Cybercobra, Beetstra, L'œuf, Yaris678, Anthonyhcole, Psilocin, Path2k6, DB1986, Jamieliz, McM.bot, Martha p, VVVBot, Fibo1123581321, Toddst1, Dala11a, Denisarona, Morton12, Maxxx55, Mjpresson, Addbot, C6541, DOI bot, Armyyo, Luckas-bot, Yobot, CheMoBot, Anypodetos, GrouchoBot, Fuz2y, Dpf90, The myoclonic jerk, RedBot, Tea with toast, EmausBot, ZéroBot, Norsci, Satellizer, Vjiced, TheNoBrainer, Fuse809, Ellomo, Sedind, Medgirl131 and Anonymous: 49 • Naboctate Source: http://en.wikipedia.org/wiki/Naboctate?oldid=618475582 Contributors: Meodipt, Kupirijo, ChemNerd, CheMoBot, حسن علي البط, BogBot, Peryeat, Helpful Pixie Bot and Medgirl131 • NESS-0327 Source: http://en.wikipedia.org/wiki/NESS-0327?oldid=557658516 Contributors: Pegship, SmackBot, Edgar181, Meodipt, Tanevala, Enix150, Yobot, CheMoBot, Rjanag, حسن علي البطand BogBot • NESS-040C5 Source: http://en.wikipedia.org/wiki/NESS-040C5?oldid=581293179 Contributors: Meodipt and Mrbenzhao • NMP-7 Source: http://en.wikipedia.org/wiki/NMP-7?oldid=574549912 Contributors: Meodipt and The chemistds • Nonabine Source: http://en.wikipedia.org/wiki/Nonabine?oldid=618472034 Contributors: Wimvandorst, Pegship, Edgar181, Beetstra, Meodipt, CheMoBot, Anypodetos, حسن علي البط, BogBot, PotatoBot, Peryeat, NotWith, Medgirl131 and Anonymous: 1 • 11-nor-9-Carboxy-THC Source: http://en.wikipedia.org/wiki/11-nor-9-Carboxy-THC?oldid=626249075 Contributors: Cacycle, Rjwilmsi, Edgar181, Beetstra, Meodipt, ChemNerd, Bobber0001, Addbot, Luckas-bot, Legobot II, CheMoBot, Citation bot, حسن علي البط, Harbinary, Custoo, Citation bot 1, A8UDI, BogBot, 564dude, Jynto, EmausBot, Shisha-Tom, Igramudi, Medgirl131 and Anonymous: 10 • O-1057 Source: http://en.wikipedia.org/wiki/O-1057?oldid=608378294 Contributors: Pegship, Closedmouth, Meodipt, Enix150, Panoramix303, CheMoBot, حسن علي البط, BogBot, Gunnanmon, Skoot13 and WildCation • O-1125 Source: http://en.wikipedia.org/wiki/O-1125?oldid=608380315 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and WildCation • O-1238 Source: http://en.wikipedia.org/wiki/O-1238?oldid=513487985 Contributors: Shoefly, Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Shisha-Tom • O-1269 Source: http://en.wikipedia.org/wiki/O-1269?oldid=538765444 Contributors: Meodipt • O-1602 Source: http://en.wikipedia.org/wiki/O-1602?oldid=546479215 Contributors: Meodipt • O-1812 Source: http://en.wikipedia.org/wiki/O-1812?oldid=607130796 Contributors: Drphilharmonic, Meodipt, Enix150, Plasmic Physics, CheMoBot, BogBot, Skoot13 and Monkbot • O-1871 Source: http://en.wikipedia.org/wiki/O-1871?oldid=563934779 Contributors: Meodipt • O-1918 Source: http://en.wikipedia.org/wiki/O-1918?oldid=546480992 Contributors: Meodipt • O-2050 Source: http://en.wikipedia.org/wiki/O-2050?oldid=473933807 Contributors: Meodipt • O-2113 Source: http://en.wikipedia.org/wiki/O-2113?oldid=517511788 Contributors: Meodipt, The chemistds and Skoot13 • O-2372 Source: http://en.wikipedia.org/wiki/O-2372?oldid=591901705 Contributors: Edgar181, Drphilharmonic, Meodipt, Enix150, CheMoBot, BogBot, Skoot13 and Anonymous: 1 • O-2545 Source: http://en.wikipedia.org/wiki/O-2545?oldid=517511924 Contributors: Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Gunnanmon, Skoot13 and Anonymous: 3 • O-2694 Source: http://en.wikipedia.org/wiki/O-2694?oldid=517511601 Contributors: Pegship, Drphilharmonic, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Skoot13 • O-774 Source: http://en.wikipedia.org/wiki/O-774?oldid=607131131 Contributors: Meodipt, Enix150, Anypodetos, The chemistds and Skoot13 • O-806 Source: http://en.wikipedia.org/wiki/O-806?oldid=448105477 Contributors: Pegship, Nuklear, Meodipt, Marek69, Enix150, CheMoBot, حسن علي البط, BogBot and The chemistds • O-823 Source: http://en.wikipedia.org/wiki/O-823?oldid=513577948 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, The chemistds and Shisha-Tom • Org 27569 Source: http://en.wikipedia.org/wiki/Org_27569?oldid=592717766 Contributors: Meodipt, Addbot, CheMoBot, BogBot, Dcirovic, The chemistds and Monkbot • Org 28312 Source: http://en.wikipedia.org/wiki/Org_28312?oldid=592716560 Contributors: Beetstra, Meodipt, Enix150, CheMoBot, BogBot, The chemistds and Monkbot • Org 28611 Source: http://en.wikipedia.org/wiki/Org_28611?oldid=592716578 Contributors: Beetstra, Meodipt, Enix150, CheMoBot, BogBot, The chemistds and Monkbot
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• Otenabant Source: http://en.wikipedia.org/wiki/Otenabant?oldid=618474885 Contributors: Pegship, SmackBot, Meodipt, Chemgirl131, CheMoBot, Anypodetos, Rjanag, حسن علي البط, Harbinary, Custoo, Citation bot 1, Jonesey95, BogBot, RjwilmsiBot, Peryeat, Louisajb, Pashihiko, Skoot13, WildCation and Medgirl131 • Parahexyl Source: http://en.wikipedia.org/wiki/Parahexyl?oldid=618474777 Contributors: SqueakBox, Pegship, Beetstra, Meodipt, JaGa, Funandtrvl, Panoramix303, DumZiBoT, Addbot, DOI bot, CheMoBot, Anypodetos, Citation bot, حسن علي البط, BogBot, Nikos 1993, Medgirl131 and Anonymous: 5 • UR-144 Source: http://en.wikipedia.org/wiki/UR-144?oldid=627620534 Contributors: Discospinster, Wainblatrobert, MZMcBride, Vegaswikian, Edgar181, Myxsoma, Beetstra, Meodipt, Smartse, JamesBWatson, ChemNerd, Boghog, Reedy Bot, Enix150, Yikrazuul, Carriearchdale, C6541, , CheMoBot, AnomieBOT, SDPatrolBot, AManWithNoPlan, ClueBot NG, Skoot13, Frietjes, O.Koslowski, Ieponumos, Dipankan001, Vasiliy 100, Stark1987, ChrisGualtieri, BaeyerDrewson, Luxemoxie, Yougotwarsh, Rebrewind, Monkbot, Rusty Lugnuts and Anonymous: 22 • Perrottetinene Source: http://en.wikipedia.org/wiki/Perrottetinene?oldid=518915209 Contributors: Meodipt, Benrr101, CheMoBot, Anypodetos, حسن علي البط, BogBot and Anonymous: 2 • PF-03550096 Source: http://en.wikipedia.org/wiki/PF-03550096?oldid=618824275 Contributors: Meodipt, FreddysFun and WildCation • PF-514273 Source: http://en.wikipedia.org/wiki/PF-514273?oldid=583222914 Contributors: Meodipt, Anypodetos and The chemistds • PipISB Source: http://en.wikipedia.org/wiki/PipISB?oldid=538846629 Contributors: Meodipt • Pirnabine Source: http://en.wikipedia.org/wiki/Pirnabine?oldid=618818792 Contributors: Beetstra, Meodipt, CheMoBot, حسن علي البط, BogBot, WildCation and Medgirl131 • PSB-SB-1202 Source: http://en.wikipedia.org/wiki/PSB-SB-1202?oldid=575732178 Contributors: Meodipt, Fraggle81 and Mrbenzhao • PSB-SB-487 Source: http://en.wikipedia.org/wiki/PSB-SB-487?oldid=557656947 Contributors: Meodipt • QUCHIC Source: http://en.wikipedia.org/wiki/QUCHIC?oldid=617182468 Contributors: Meodipt, Yobot, SciRambar, The chemistds, BaeyerDrewson, Yougotwarsh and Anonymous: 7 • QUPIC Source: http://en.wikipedia.org/wiki/QUPIC?oldid=619859946 Contributors: Velella, Rjwilmsi, Meodipt, Enix150, Earcanal, Yobot, AnomieBOT, SciRambar, AManWithNoPlan, The chemistds, BG19bot, BaeyerDrewson, Dr J.Rozen, Yougotwarsh and Anonymous: 12 • Rimonabant Source: http://en.wikipedia.org/wiki/Rimonabant?oldid=628033220 Contributors: Kpjas, MadSurgeon, David spector, Tpbradbury, Francs2000, Schutz, ZimZalaBim, Obli, Fjarlq, St3vo, Geni, BozMo, Beland, Nowster, M1ss1ontomars2k4, Monkeyman, Rich Farmbrough, Cacycle, Peak Freak, Jtact, Remuel, Arcadian, Pacula, Wouterstomp, Malo, Versageek, Siafu, Scjessey, Eras-mus, SDC, Rjwilmsi, Darguz Parsilvan, Miserlou, Margosbot, Stevenfruitsmaak, Hydrargyrum, Janke, Semperf, Syldaril, Smaines, Yonidebest, Bdell555, Zzuuzz, Closedmouth, Colin, Kajerm, Jeffreymcmanus, SmackBot, Edgar181, Gilliam, Amatulic, Deli nk, Cormagh, JanesDaddy, Oltsw, KaiserbBot, Roadnottaken, JonHarder, Apexprim8, JHe, Cybercobra, Drphilharmonic, Lobster101, Simonster, Beetstra, Bwalters, Az1568, Linkspamremover, Fvasconcellos, DoctorFuQang, Cytocon, DrPiotroski, Give Peace A Chance, Ward3001, Thijs!bot, Sacxnz, Adjespers, Link Spam Remover, Mcscmd, AntiVandalBot, Yupik, Dextrovert, João Carvalho, Postlewaight, Astavats, Kgbveg, Rkwwkr, Krunalc, It2media, DietGurl, .anacondabot, OM, MaxPont, Jackboogie, Mtiffany71, Crazy-Chemist, Rettetast, Kkeane, Boghog, Mikael Häggström, Tanevala, Enix150, Danbearsea, TXiKiBoT, Celtus, Mikeaubert, GPryce, Nadsozinc, Eve Teschlemacher, Poterala, Oreiser, Le feu, Vcare, Lightmouse, Phillymutt, Sabne, Rimonabant, Sisalgs, ClueBot, Schaea, Osm agha, Carlo Banez, Panoramix303, Pharmankur, BlackHoleSon, DumZiBoT, Chemgirl131, Gazimoff, Addbot, DOI bot, SpBot, Shankkark, Nizil Shah, TALKO, CheMoBot, Anypodetos, AnomieBOT, Casforty, Rjanag, LilHelpa, Dagrun, Gigemag76, حسن علي البط, Custoo, Citation bot 1, Teenmd, Tea with toast, BogBot, David Hedlund, Peacedance, RjwilmsiBot, Yid, Dcirovic, ZéroBot, H3llBot, Timetraveler3.14, Peryeat, Skoot13, BG19bot, BattyBot, Vaccinationist, Monkbot, Medgirl131 and Anonymous: 108 • Rosonabant Source: http://en.wikipedia.org/wiki/Rosonabant?oldid=618474987 Contributors: Rjwilmsi, Edgar181, Chemgirl131, Anypodetos, BG19bot, Monkbot and Medgirl131 • S-444,823 Source: http://en.wikipedia.org/wiki/S-444,823?oldid=628622349 Contributors: Meodipt, Skoot13 and WildCation • SDB-001 Source: http://en.wikipedia.org/wiki/SDB-001?oldid=557806974 Contributors: Meodipt, Magioladitis, C6541, BaeyerDrewson and Anonymous: 2 • SDB-006 Source: http://en.wikipedia.org/wiki/SDB-006?oldid=585445393 Contributors: Meodipt, BaeyerDrewson, Mrbenzhao and Anonymous: 2 • SER-601 Source: http://en.wikipedia.org/wiki/SER-601?oldid=607679714 Contributors: Beetstra, Meodipt, Enix150, Davecrosby uk, CheMoBot, BogBot, The chemistds, Skoot13, Monkbot and Anonymous: 1 • Serinolamide A Source: http://en.wikipedia.org/wiki/Serinolamide_A?oldid=579444765 Contributors: Edgar181, Meodipt, John of Reading and RichardsonsRSC • SR-144,528 Source: http://en.wikipedia.org/wiki/SR-144,528?oldid=618472544 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Enix150, Addbot, CheMoBot, BogBot, Dcirovic, Louisajb, Skoot13, Monkbot and Medgirl131 • Stearoylethanolamide Source: http://en.wikipedia.org/wiki/Stearoylethanolamide?oldid=630989213 Contributors: Bearcat, Malcolma, Jatlas and Medgirl131 • STS-135 (drug) Source: http://en.wikipedia.org/wiki/STS-135_(drug)?oldid=628883259 Contributors: Edgar181, Meodipt, Jim1138, SciRambar, BaeyerDrewson, Yougotwarsh and Anonymous: 3 • Surinabant Source: http://en.wikipedia.org/wiki/Surinabant?oldid=618475012 Contributors: Edward, St3vo, Pegship, Beetstra, Meodipt, R'n'B, Enix150, Carlo Banez, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Dagrun, حسن علي البط, BogBot, PotatoBot, Peryeat, ChrisGualtieri and Medgirl131 • Taranabant Source: http://en.wikipedia.org/wiki/Taranabant?oldid=618475039 Contributors: St3vo, Woohookitty, OrphanBot, Meodipt, Magioladitis, ChemNerd, Enix150, Kizly, Carlo Banez, Panoramix303, Chemgirl131, Yobot, CheMoBot, Rjanag, Dagrun, حسن علي البط, P-kun80, BogBot, PotatoBot, Peryeat, Monkbot, Medgirl131 and Anonymous: 2 • Tedalinab Source: http://en.wikipedia.org/wiki/Tedalinab?oldid=491266810 Contributors: Meodipt
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• Tetrad test Source: http://en.wikipedia.org/wiki/Tetrad_test?oldid=443471240 Contributors: Chick Bowen, Roadnottaken, Jzlong, AloysiusLiliusBot, Aaron Kauppi and Anonymous: 1 • Tetrahydrocannabinol Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinol?oldid=630780019 Contributors: Damian Yerrick, AxelBoldt, Kpjas, Bryan Derksen, The Anome, Tarquin, Malcolm Farmer, SimonP, Pit, Gabbe, Chinju, Paul A, MichaelJanich, Mkweise, Ahoerstemeier, HarmonicSphere, TUF-KAT, JWSchmidt, Evercat, Iorsh, SaveThePoint, Andrevan, Furrykef, Gutsul, Robbot, Astronautics, Mirv, UtherSRG, Hif, DocWatson42, Nunh-huh, BenFrantzDale, Bradeos Graphon, Guanaco, St3vo, Eequor, Richard Myers, Andycjp, Geus, Sonjaaa, Ferre, Antandrus, HistoryBA, AlexanderWinston, OwenBlacker, Gene s, Bk0, Rlcantwell, Joyous!, Mearlon, Gerrit, Tonik, Idolcrash, Lynto008, Adashiel, Porges, Stevenmattern, Discospinster, Rich Farmbrough, Guanabot, Cacycle, Pie4all88, Bender235, Mykhal, Calair, Jensbn, Livajo, Cedders, Kwamikagami, Dennis Brown, Jpgordon, Jonathan Drain, Bobo192, Timon, Flying Hamster, Smalljim, Shenme, Viriditas, Mrdude, NotAbel, ZayZayEM, Giraffedata, Alansohn, Eleland, PopUpPirate, Eric Kvaalen, Atlant, Benjah-bmm27, Andrew Gray, Howrealisreal, Thoric, Ransack, Ynhockey, Hu, Velella, Keziah, Gene Nygaard, Netkinetic, Ceyockey, Japanese Searobin, Ron Ritzman, Mindmatrix, Lunar Jesters, Rajiv Varma, Kzollman, CiTrusD, GregorB, Jon Harald Søby, Palica, SqueakBox, Magister Mathematicae, Mendaliv, Canderson7, Sjö, Rjwilmsi, Londonbroil, Soakologist, Pabix, Heah, Rpinz, Nneonneo, DirkvdM, X1987x, FlaBot, Ground Zero, Mister Matt, AJR, Vayne, TheDJ, Wgfcrafty, Diza, Consumed Crustacean, Butros, WriterHound, Joseph11h, YurikBot, NTBot, Petiatil, Pacaro, Chris Capoccia, Ansell, Shaddack, NawlinWiki, Ytcracker, Johann Wolfgang, Belkov, ONEder Boy, Nad, Afiler, Xdenizen, Moe Epsilon, DeadEyeArrow, Bota47, BraneJ, Louieduvall, Max Schwarz, Mike Serfas, Zzuuzz, TheMadBaron, KGasso, Jolt76, BorgQueen, JRey, LeonardoRob0t, JLaTondre, CIreland, SmackBot, Mitchan, Brammers, Slashme, Anarchist42, Unyoyega, ParkerHiggins, Davewild, WookieInHeat, Jrockley, Jab843, Edgar181, HalfShadow, Gilliam, Ohnoitsjamie, Hmains, Shaggorama, Iain.dalton, Ksenon, Dolive21, Master of Puppets, GregRM, MalafayaBot, Domthedude001, SchfiftyThree, Zachorious, Mladifilozof, MaxSem, Muboshgu, Can't sleep, clown will eat me, Chlewbot, OrphanBot, Addshore, Bulbous, Cybercobra, T-borg, Drphilharmonic, DMacks, A5b, Lambiam, AThing, John, Jidanni, Gobonobo, Shlomke, Stwalkerster, Beetstra, Waggers, SandyGeorgia, Nialsh, Iridescent, Camb15, Newone, Igoldste, LadyofShalott, Nalco, Courcelles, Tawkerbot2, OS2Warp, Switchercat, CmdrObot, ArmyOfFluoride, Rikva, WeggeBot, T23c, Meodipt, Karmak, Cydebot, Rifleman 82, Gogo Dodo, D666D, A Softer Answer, Odie5533, Tawkerbot4, Carstensen, Codetiger, Dyakofborneo, Daven200520, Pinky sl, Epbr123, Legolas558, Loudsox, Bendroz, Yukichigai, Subvertc, Headbomb, Chrisdab, Rhrad, Matthew Proctor, Pfranson, Dawnseeker2000, Noclevername, Escarbot, Porqin, Exhilaration157, AntiVandalBot, The Obento Musubi, RobotG, DarkAudit, Smartse, GodGell, Spencer, Elaragirl, Deflective, MSBOT, Iownutopia, .anacondabot, Acroterion, Mattb112885, Bongwarrior, VoABot II, Jeff Dahl, JNW, JamesBWatson, Gold3nrul3, Balloonguy, Hiplibrarianship, Mreaster, Allstarecho, Tins128, Ajgregory, Pax:Vobiscum, MartinBot, By97aa, ChemNerd, Anaxial, Nono64, Leyo, Hairchrm, Fconaway, Lilac Soul, Tgeairn, J.delanoy, Bogey97, Boghog, Cocoaguy, Alwaysasking, Solidach, Afluegel, Mikael Häggström, L'Aquatique, Alphapeta, Plasticup, SJP, Enix150, Cometstyles, Bondo 6464, HazyM, Martial75, Halmstad, Signalhead, Gothbag, Deor, Hammersoft, VolkovBot, Rtdixon86, Philip Trueman, DoorsAjar, TXiKiBoT, A4bot, Qxz, Victimofleisure, Ph33rspace, Martin451, Wikieditor12, Tpk5010, Jsteinhoefel, Dvmedis, Vaubin, Nadsozinc, Falcon8765, Puusq, LetTheSunshineIn, Fischer.sebastian, Skepticignorant, Tbg connor, Peter Fleet, SieBot, Coffee, Da Joe, YourEyesOnly, Aswad87, Yintan, Agador, BrienIsSexy4, Flyer22, Alexbrn, Oneku201, Oxymoron83, Hello71, Poindexter Propellerhead, WacoJacko, La Parka Your Car, StaticGull, Mike2vil, DaDrought3, Dala11a, Mygerardromance, PerryTachett, Nn123645, 30SEC2, DRTllbrg, Chem-awb, Kanonkas, Tanvir Ahmmed, ClueBot, PipepBot, Anthonyvidal, The Thing That Should Not Be, Voxpuppet, MedialLateral, Yikrazuul, Drmies, Mild Bill Hiccup, Shinpah1, Redspades, Leodmacleod, Niceguyedc, Chiosu, Flubecabot, Excirial, Jusdafax, Ltnemo2000, John Nevard, Paymaun, Panoramix303, Jophis, Alchemist01010101, Cenarium, Iohannes Animosus, XeroX16, Williadb, BlackHoleSon, Thingg, Aitias, 7, Versus22, NJGW, BlueDevil, 0Chance, DumZiBoT, Skunkboy74, Chemgirl131, JS747, Ost316, SilvonenBot, NellieBly, NHJG, LikeHolyWater, Conversationalskills, Addbot, Piz d'Es-Cha, RH420, C6541, DOI bot, Tcncv, Eltone, Binary TSO, Ronhjones, Dnnisrdz, Skyezx, Protonk, Glass Sword, AndersBot, Roux, WikiDegausser, Sepulwiki, Adam Willenbrecht, Aldrich Hanssen, Pnpointer, Tide rolls, OlEnglish, Alfie66, Ben Ben, Drpickem, Slayer14666, Yobot, Andreasmperu, Ptbotgourou, CheMoBot, Whiskeydog, TestEditBot, Tempodivalse, Synchronism, Slowgenius, TheHighTree, AnomieBOT, Tryptofish, Metalhead94, Casforty, Götz, Choij, Message From Xenu, Modanung, Ulric1313, Bluerasberry, Mahmudmasri, Materialscientist, Citation bot, BlurTento, LilHelpa, Simultaneous movement, The Firewall, Apothecia, Jason.Singer, Capricorn42, Millahnna, Br77rino, حسن علي البط, Harbinary, Xxkeeenxx, Malbano17, Inferno, Lord of Penguins, Coretheapple, Cmerlin2, Anand droog, Shit Goes Here, Lapuchca, Crabjuicer, SassoBot, RomanHunt, Kyng, Tony12893, X172, C4andrei, Psychonaught, Neolith100, Evangelika, Ajax151, Custoo, Jatlas, Lothar von Richthofen, StaticVision, Vishnu2011, Ryan.rota, Laff able, Citation bot 1, Izzardthegizzard, Pinethicket, Jrew86, A8UDI, Jschnur, SpaceFlight89, Tea with toast, BogBot, Bioextra, Smatrese, DadOfBeanAndBug, MemphisUPEI, David Hedlund, Diannaa, 4ndyD, Suffusion of Yellow, Dungeonscaper, Gtziavelis, Dick blixen, Kanelbulle, DARTH SIDIOUS 2, Ashox D-Shay, Realizen, Moshasaurus, RjwilmsiBot, Ripchip Bot, FetchcommsAWB, Dizanl, Beyond My Ken, NerdyScienceDude, SeeKatethisisme, EmausBot, Franfran2010, Rbaselt, RA0808, 4meter4, Slightsmile, Tommy2010, John Cline, Jaydiem, ElationAviation, GZ-Bot, H3llBot, Cimmerian praetor, Dpdrums, L Kensington, Bayhemp, Tick avenger, DASHBotAV, Hetoi, Louisajb, ClueBot NG, Gaujo, Mini.knowledge.pea, Nielswillems26, FarmDee, Billyrubin2008, Skoot13, Hempknight121, Cj005257, Avagad2, Mesoderm, O.Koslowski, Widr, Helpful Pixie Bot, Psychonaut25, Bibcode Bot, Kenan133, DBigXray, BG19bot, Petrarchan47, Northamerica1000, Stuartteal, Spy12190, Nikos 1993, TheMan4000, Cbakker, Snow Blizzard, NotWith, Zujua, Wyliea, Zmbonvallat, Fuse809, TheBaur, LegacyWeapon, Indirectantagonist, EuroCarGT, 14jay69, Jeschjesch, Blazedbuddha, 00AgentBond93, Gareth CHEBI, Kilasic, Craigcrawford1988, CannaWikibiss, K-ronzagwarn, MidnightRequestLine, Babapcck, Rainyhemptree, JulianaPacheco, Camyoung54, ScoutKnot, Youtalkfunny, DavidLeighEllis, ArmbrustBot, PreCambrianBunny, Seppi333, Mjlphd, BOBBOBLEYBOBSON, Die Antwoorde, Korean181, Meteor sandwich yum, Lyschamb, Monkbot, 235N, Formerly 98, A915, Joshuabumbarger, Santavy2014, JoPhoenix, Fuzznerdees, Medgirl131, Amc98, GP10698 and Anonymous: 949 • Tetrahydrocannabinol-C4 Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinol-C4?oldid=618601612 Contributors: Cacycle, Natalya, BD2412, Pegship, Meodipt, Astavats, Benrr101, Mild Bill Hiccup, Phil Ian Manning, Chemgirl131, Yobot, CheMoBot, حسن علي البط, ZackRegit, BogBot, Nikos 1993, NotWith, Monkbot and Jakenowatzke • Tetrahydrocannabinolic acid Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinolic_acid?oldid=614212282 Contributors: Rjwilmsi, Meodipt, Wikieditor12, Benrr101, Götz, Jim1138, Monkbot and Anonymous: 4 • Tetrahydrocannabivarin Source: http://en.wikipedia.org/wiki/Tetrahydrocannabivarin?oldid=630568385 Contributors: William Avery, St3vo, Rich Farmbrough, Cacycle, Ceyockey, Amire80, Fred Bradstadt, Physchim62, WriterHound, YurikBot, Gaius Cornelius, Pegship, Edgar181, Naturalsol, Chris the speller, Fireemblem555, Smith609, Beetstra, Meodipt, Alaibot, Probios, VolkovBot, GeorgeLTirebiter, Chem-awb, Panoramix303, Burner0718, Chemgirl131, MystBot, Addbot, DOI bot, Wormantson, CheMoBot, Casforty, Obersachsebot, حسن علي البط, Custoo, Citation bot 1, UFO Reporter, MastiBot, BogBot, CrowzRSA, Jynto, ClueBot NG, Nikos 1993, NotWith, Sfgiants1995, Jakenowatzke, Medgirl131, Mplanine and Anonymous: 20 • THC-O-acetate Source: http://en.wikipedia.org/wiki/THC-O-acetate?oldid=586788432 Contributors: Cacycle, Pegship, SmackBot, Edgar181, Afasmit, Beetstra, Meodipt, JaGa, CheMoBot, حسن علي البط, BogBot, Helpful Pixie Bot, ChrisGualtieri and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
339
• THC-O-phosphate Source: http://en.wikipedia.org/wiki/THC-O-phosphate?oldid=447734263 Contributors: Koavf, Pegship, Edgar181, Beetstra, Meodipt, Alaibot, Mojo Hand, Greatmajor55, CheMoBot, حسن علي البطand BogBot • Tinabinol Source: http://en.wikipedia.org/wiki/Tinabinol?oldid=618475536 Contributors: Meodipt, OrenBochman, Chemgirl131, Anypodetos, Braincricket, BG19bot and Medgirl131 • URB602 Source: http://en.wikipedia.org/wiki/URB602?oldid=600974517 Contributors: Rjwilmsi, Edgar181, Beetstra, Smartse, MSBOT, Addbot, Yobot, CheMoBot, Citation bot, Tea with toast, The chemistds and Stark1987 • URB754 Source: http://en.wikipedia.org/wiki/URB754?oldid=618360159 Contributors: Arcadian, Fred Bradstadt, Itub, SmackBot, Bluebot, Roadnottaken, Bwduca, Beetstra, Smartse, Isilanes, Tanevala, Danelo, Chem-awb, Panoramix303, DOI bot, CheMoBot, حسن علي البط, P-kun80, RjwilmsiBot, GoingBatty, PotatoBot, Stark1987, Vaccinationist, Monkbot and Anonymous: 4 • VCHSR Source: http://en.wikipedia.org/wiki/VCHSR?oldid=600803681 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot and Anonymous: 1 • VDM-11 Source: http://en.wikipedia.org/wiki/VDM-11?oldid=630848440 Contributors: RussBot, Edgar181, CommonsDelinker, Enix150, Auntof6, Addbot, Yobot, CheMoBot, Rideer13, The chemistds, AvocatoBot, Medgirl131 and Anonymous: 2 • WIN 54,461 Source: http://en.wikipedia.org/wiki/WIN_54,461?oldid=593323168 Contributors: Drphilharmonic, Enix150, Anypodetos, BogBot, Skoot13 and Monkbot • WIN 55,212-2 Source: http://en.wikipedia.org/wiki/WIN_55,212-2?oldid=618472575 Contributors: GTBacchus, Howrealisreal, ^demon, Mandarax, Zachjones4, Fred Bradstadt, WriterHound, Pegship, SmackBot, Edgar181, Bluebot, Mirshafie, Phaedriel, Nuklear, Drphilharmonic, Saxbryn, Iridescent, Ccroberts, Meodipt, Cydebot, RelentlessRecusant, D666D, CopperKettle, Sony 1, Tanevala, Enix150, Funandtrvl, Altzinn, Panoramix303, Yuhong wang, Addbot, Maclia, Yobot, CheMoBot, حسن علي البط, Harbinary, Lapuchca, Custoo, FrescoBot, BogBot, RjwilmsiBot, Gould363, DASHBot, ZéroBot, Louisajb, Skoot13, Jeff.keyser, Fuse809, Testem, Gareth CHEBI, Medgirl131 and Anonymous: 12 • WIN 56,098 Source: http://en.wikipedia.org/wiki/WIN_56,098?oldid=605489228 Contributors: Enix150, Anypodetos, SwisterTwister, BogBot, Snotbot, Crosstemplejay, BattyBot and Monkbot • XLR-11 (drug) Source: http://en.wikipedia.org/wiki/XLR-11_(drug)?oldid=626107904 Contributors: Wainblatrobert, Dl2000, Meodipt, Boghog, Enix150, Balst32, CMBJ, Yobot, AnomieBOT, SciRambar, The chemistds, Skoot13, BattyBot, Testem, ChrisGualtieri, BaeyerDrewson, Epicgenius, KMAnomalocaris, Rebrewind, Monkbot and Anonymous: 5 • AM251 Source: http://en.wikipedia.org/wiki/AM251?oldid=544204589 Contributors: Bearcat, Circeus, Vanky, BorisTM, Rjwilmsi, Laminado, Beetstra, Ccroberts, Meodipt, Calvero JP, Astavats, Cgingold, Tanevala, Enix150, Panoramix303, Addbot, CheMoBot, Gongshow, Rjanag, حسن علي البط, BogBot, PotatoBot and Anonymous: 3 • Aminoalkylindole Source: http://en.wikipedia.org/wiki/Aminoalkylindole?oldid=582043905 Contributors: John Vandenberg, Smartse and AnomieBOT • Cannabipiperidiethanone Source: http://en.wikipedia.org/wiki/Cannabipiperidiethanone?oldid=618475932 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Addbot, Dcirovic, The chemistds, BaeyerDrewson, Medgirl131 and Anonymous: 1 • JWH-193 Source: http://en.wikipedia.org/wiki/JWH-193?oldid=606478297 Contributors: CheMoBot, BogBot, Skoot13, Monkbot and WildCation
Rjwilmsi, Meodipt, Enix150, C6541,
• JWH-198 Source: http://en.wikipedia.org/wiki/JWH-198?oldid=606597688 Contributors: CheMoBot, BogBot, Skoot13, Monkbot and WildCation
Rjwilmsi, Meodipt, Enix150, C6541,
• JWH-200 Source: http://en.wikipedia.org/wiki/JWH-200?oldid=606475531 Contributors: Rich Farmbrough, John Vandenberg, Velella, Rjwilmsi, Pegship, Edgar181, Drphilharmonic, Meodipt, Smartse, Enix150, Funandtrvl, Addbot, C6541, Favonian, CheMoBot, AnomieBOT, Citation bot, Grim23, حسن علي البط, BogBot, Unceasing, Tisane, HarDNox, SmokingNewton, Frozen Wind, Caponex, Silver Harshy, Managermerrill, Skoot13, Exercisephys, Fuse809, WildCation and Anonymous: 15 • Pravadoline Source: http://en.wikipedia.org/wiki/Pravadoline?oldid=607406644 Contributors: Rich Farmbrough, Wimvandorst, Natalya, Pegship, Drphilharmonic, Beetstra, Hu12, Meodipt, Enix150, Lamro, Panoramix303, CheMoBot, Anypodetos, Citation bot, حسن علي البط, Citation bot 1, Jonesey95, BogBot, Peryeat, S1lv3rblad3, Skoot13, Snotbot, Yukileoo, ChrisGualtieri and Anonymous: 2 • RCS-4 Source: http://en.wikipedia.org/wiki/RCS-4?oldid=525171484 Contributors: Aardark, XLerate, SmackBot, Shoy, Beetstra, Meodipt, Bobber0001, Enix150, C6541, CheMoBot, AnomieBOT, BogBot, Renamed01302013, The chemistds, ClueBot NG, Bped1985, VeiledReference, Pan Czy Pani and Anonymous: 2 • Anandamide Source: http://en.wikipedia.org/wiki/Anandamide?oldid=629335365 Contributors: MadSurgeon, Olivier, MartinHarper, Sugarfish, Robbot, Sanders muc, Fuelbottle, Unfree, Giftlite, SoCal, Mearlon, Rich Farmbrough, Cacycle, Van Flamm, Mjpieters, Bitplane, Mykhal, El C, Arcadian, Eritain, M7, Max rspct, Reaverdrop, Mahanga, Josh Parris, Rjwilmsi, Fred Bradstadt, FlaBot, Doc glasgow, RexNL, WriterHound, YurikBot, RobotE, Tavilis, El Cazangero, A314268, Joncolvin, Gamerider, Laminado, SmackBot, Saravask, AlexNordeen, Edgar181, Lennert B, Colonies Chris, Oatmeal batman, Roadnottaken, Drphilharmonic, Beetstra, Saxbryn, Chirality, Fvasconcellos, Mellery, Icek, Cydebot, Bendroz, Dream Focus, Trapezoidal, Belizefan3000, Lumir, .José, Boghog, Mikael Häggström, Pmallet, Tanevala, Enix150, DorganBot, VolkovBot, Chango369w, Cotard, Hertz1888, Djadvance, Chem-awb, Orbitalcombustion, ClueBot, Plastikspork, Redspades, Ltnemo2000, Nettacog, Yonskii, Chemgirl131, Dthomsen8, Addbot, DOI bot, Chempedia, Lightbot, Jarble, Gaberdine2, Yobot, Legobot II, CheMoBot, Götz, Citation bot, حسن علي البط, Jyffeh, GrouchoBot, Xasodfuih, Custoo, FrescoBot, Akshatrathi294, Tea with toast, BogBot, 564dude, RjwilmsiBot, Dcirovic, Tomásdearg92, Ronhirzmd, ClueBot NG, Gilderien, Vjiced, Skoot13, BG19bot, Lifeformnoho, Enomai, Valera123, Vjiced1, Anaffen21, JaconaFrere, Monkbot, Medgirl131 and Anonymous: 76 • N-Arachidonoyl dopamine Source: http://en.wikipedia.org/wiki/N-Arachidonoyl_dopamine?oldid=618471241 Contributors: St3vo, Rich Farmbrough, Rjwilmsi, Edgar181, Beetstra, Rhetth, Cydebot, ChemNerd, Enix150, Benrr101, ing4Taste, PookeyMaster, Chem-awb, Panoramix303, Chemgirl131, Addbot, DOI bot, CheMoBot, حسن علي البط, Custoo, Nirmos, Tea with toast, ZéroBot, The chemistds, Brainiacal, Monkbot, Medgirl131 and Anonymous: 3 • 2-Arachidonoylglycerol Source: http://en.wikipedia.org/wiki/2-Arachidonoylglycerol?oldid=618471104 Contributors: Rich Farmbrough, Rjwilmsi, WriterHound, Shaddack, El Cazangero, SmackBot, Edgar181, Roadnottaken, Beetstra, Rhetth, Cydebot, Astavats, Kilrothi, ChemNerd, Tanevala, Enix150, Michaël George, SieBot, Chem-awb, Drmies, Panoramix303, ChemSpiderMan, Chemgirl131, Addbot, K-MUS, DOI bot, Ginosbot, Yobot, CheMoBot, Jzlong, Citation bot, Xasodfuih, Custoo, Citation bot 1, RedBot, BogBot, CrowzRSA, 564dude, Dcirovic, ZéroBot, Helpful Pixie Bot, Shisha-Tom, Cotedesneiges, Austinpk, Jianhui67, Anaffen21, Monkbot, Medgirl131 and Anonymous: 15
340
CHAPTER 252. TM-38837
• 2-Arachidonyl glyceryl ether Source: http://en.wikipedia.org/wiki/2-Arachidonyl_glyceryl_ether?oldid=618471126 Contributors: St3vo, Rich Farmbrough, Physchim62, WriterHound, Slashme, Edgar181, Beetstra, Cydebot, Benrr101, Chem-awb, Panoramix303, ChemSpiderMan, Chemgirl131, Addbot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, CrowzRSA, Dcirovic, Cimmerian praetor, ChrisGualtieri, Gareth CHEBI, Medgirl131 and Anonymous: 5 • Oleamide Source: http://en.wikipedia.org/wiki/Oleamide?oldid=618471264 Contributors: AxelBoldt, Richard Taytor, Henrik, Rjwilmsi, WriterHound, SmackBot, Edgar181, Roadnottaken, Beetstra, Meodipt, Scouse123, ChemNerd, Ejhoekstra, TXiKiBoT, Benrr101, Living under a rock, Chem-awb, Yikrazuul, DumZiBoT, Chemgirl131, Addbot, DOI bot, CheMoBot, Neoligand, Citation bot, Custoo, Citation bot 1, Abductive, Tea with toast, BogBot, ZéroBot, Cimmerian praetor, Skoot13, Rezabot, Drpainless, Makecat-bot, Monkbot, Medgirl131 and Anonymous: 15 • RVD-Hpα Source: http://en.wikipedia.org/wiki/RVD-Hpα?oldid=618471413 Contributors: Meodipt, Magioladitis, Boghog, Yobot, Custoo, BG19bot, Medgirl131 and Anonymous: 1 • Virodhamine Source: http://en.wikipedia.org/wiki/Virodhamine?oldid=618471494 Contributors: Rich Farmbrough, Arcadian, Natalya, WriterHound, BlueZenith, Edgar181, David.Throop, Drphilharmonic, Beetstra, Rhetth, Cydebot, Enix150, Benrr101, Chem-awb, Plasmic Physics, Chemgirl131, Addbot, Luckas-bot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, ZéroBot, Medgirl131 and Anonymous: 1 • HU-320 Source: http://en.wikipedia.org/wiki/HU-320?oldid=517594060 Contributors: Rjwilmsi, Meodipt, Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13 • HU-336 Source: http://en.wikipedia.org/wiki/HU-336?oldid=580010784 Contributors: Rjwilmsi, Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13 • HU-345 Source: http://en.wikipedia.org/wiki/HU-345?oldid=580010824 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13 • Raphael Mechoulam Source: http://en.wikipedia.org/wiki/Raphael_Mechoulam?oldid=621871273 Contributors: GreatWhiteNortherner, Andycjp, WadeSimMiser, SqueakBox, Rjwilmsi, Bgwhite, RussBot, El Cazangero, Shuki, Mqzspa, Meodipt, Cydebot, Dougweller, J.delanoy, Enix150, Juliancolton, Tzahy, Panoramix303, Qwfp, Addbot, Lightbot, דוד55, Luckas-bot, Yobot, Amirobot, Davshul, Almabot, FrescoBot, Anti-Nationalist, ZéroBot, Cimmerian praetor, Vjiced, Drkup(IMJ), Cyberbot II, Jethro B, Reverend Mick man34, VIAFbot, Looppushh, Monkbot, Jonarnold1985 and Anonymous: 15 • John W. Huffman Source: http://en.wikipedia.org/wiki/John_W._Huffman?oldid=604651417 Contributors: Delirium, Wdfarmer, Dismas, Patken4, Stormbay, KGasso, SmackBot, Meodipt, Lugnuts, Spyder Monkey, Smartse, Trusilver, NewEnglandYankee, KudzuVine, Jackfork, Panoramix303, Addbot, Yobot, AVB, AnomieBOT, OlYeller21, Grim23, Sgravn, Gunnanmon, Tisane, ZéroBot, Andyman1125, Dagko, Allethrin, Frozen Wind, ClueBot NG, Skoot13, 4321acb, Nickt0963, Wiki magnet, Touchhole97 and Anonymous: 19 • JWH-007 Source: http://en.wikipedia.org/wiki/JWH-007?oldid=606455199 Contributors: Meodipt, Enix150, Ziggy Sawdust, C6541, CheMoBot, حسن علي البط, FrescoBot, BogBot, John of Reading, Tisane, Kabutop, Pan Czy Pani, D42kn355, NotWith and WildCation • JWH-018 Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch, Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser, Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilharmonic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT, Nirigihimu, Turkeyphant, Zefiel, Smartse, Theguy0000, MER-C, Grimelab, Iownutopia, JamesBWatson, Monosodious, Bradgib, ChemNerd, Leyo, Boghog, Malkuth1, Gutterkitty, Enix150, Pdcook, CardinalDan, Funandtrvl, Msrbl49, Fbifriday, Philip Trueman, Flux12n21, Flopster2, Wikieditor12, Jpaliano, Guldenat, Falcon8765, Living under a rock, Pjoef, Dlfreem, Dheau, Hobartimus, ClueBot, GorillaWarfare, Tomas e, Drmies, Yuubi, Auntof6, Ktr101, Alexbot, Dr.Koljan, Panoramix303, Sun Creator, Christopherbrian, XLinkBot, Fastily, ErgoSum88, ESO Fan, PurrfectPeach, Addbot, C6541, MartinezMD, Fieldday-sunday, Fluffernutter, LaaknorBot, DFS454, Favonian, Tide rolls, Wax025, Ben Ben, Legobot, Luckas-bot, Yobot, Legobot II, CheMoBot, Daddyrob81, Anypodetos, AnomieBOT, XLocal, Vinyl Ketone, Piano non troppo, Citation bot, GB fan, Intelati, OlYeller21, Δζ, Pontificalibus, Nasnema, Rhoodey, حسن علي البط, Harbinary, Shirik, Amaury, Psychonaught, Shadowjams, Custoo, FrescoBot, Nageh, RicHard-59, Metallica3790, Borguebabe, Weetoddid, Boylechem, Citation bot 1, Biker Biker, Calmer Waters, MastiBot, Sw1ngOnTheSp1ral, BogBot, CrowzRSA, Clickpop, David Hedlund, Tbhotch, RjwilmsiBot, Dustin 3choes, Jwh018, Rsharpe28, John of Reading, Gunnanmon, Katherine, Tisane, Clayman1976, Atropinesulfate, Tommy2010, Sraab2, Wikipelli, White Trillium, Fæ, Josve05a, James.dynamite, Hereforhomework2, H3llBot, Darkwire89, Drhjort, ALANON54, Wayne Slam, Ocaasi, OnePt618, Scema, PeterGriffinJK, Akacypress, Demetrius259, Corei7Maniac, Del nerius, Lagato123, Tjiseclipsed, ClamDip, HaydenBeck, W5NLbrian, Handsum53, DASHBotAV, Hetoi, Abnorml1, Louisajb, Mikhail Ryazanov, ClueBot NG, Agents of The Free, Easyzeh, Dualdj1, Tesacrynheart, EnvyCo, Diogenes2000, Skoot13, 4321acb, Jacobso4, Murraysymes, 1989Exley1989, Exercisephys, Verified72, Snow Blizzard, Boobs4fun, Justthinking25, Shisha-Tom, Fuse809, PhoenixPie, Kid squid, BattyBot, BaeyerDrewson, Rawrfaceace, KMAnomalocaris, Rebrewind, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 417 • JWH-019 Source: http://en.wikipedia.org/wiki/JWH-019?oldid=606455993 Contributors: Drphilharmonic, Meodipt, Leyo, Enix150, Alexbot, Addbot, C6541, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, Biker Biker, BogBot, Skoot13, Pan Czy Pani, Verified72, Shisha-Tom, Monkbot, WildCation and Anonymous: 2 • JWH-030 Source: http://en.wikipedia.org/wiki/JWH-030?oldid=628060353 Contributors: Wimvandorst, Pegship, Nuklear, Beetstra, Meodipt, Enix150, Funandtrvl, CheMoBot, حسن علي البط, BogBot, Tisane, Louisajb, WildCation and Anonymous: 4 • JWH-047 Source: http://en.wikipedia.org/wiki/JWH-047?oldid=540030725 Contributors: Rjwilmsi, RjwilmsiBot and BaeyerDrewson • JWH-048 Source: http://en.wikipedia.org/wiki/JWH-048?oldid=606457011 Contributors: Rjwilmsi, Wikieditor12, C6541, RjwilmsiBot, BaeyerDrewson and WildCation • JWH-073 Source: http://en.wikipedia.org/wiki/JWH-073?oldid=618472305 Contributors: Rich Farmbrough, Cacycle, LindsayH, Blaxthos, Grafen, Pegship, SmackBot, Cybercobra, Drphilharmonic, Meodipt, Cydebot, Marek69, Turkeyphant, Theguy0000, Iownutopia, Leyo, Enix150, Funandtrvl, X!, Krakaet, ClueBot, Panoramix303, Alibobar, Yoman82, ErgoSum88, Addbot, C6541, MartinezMD, Luckas-bot, Yobot, CheMoBot, XLocal, Piano non troppo, Addihockey10, OlYeller21, Grim23, حسن علي البط, Custoo, Weetoddid, Citation bot 1, Biker Biker, BogBot, Noraft, Tisane, Ocaasi, PeterGriffinJK, Darksp000n, Caponex, ClueBot NG, Dvsbmx, Skoot13, Exercisephys, Verified72, Cerabot, Woo 24, Monkbot, WildCation, Cbmacewan, Medgirl131 and Anonymous: 36
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
341
• JWH-081 Source: http://en.wikipedia.org/wiki/JWH-081?oldid=627566683 Contributors: Pegship, Beetstra, Meodipt, Turkeyphant, Terrek, Enix150, TopGun, Funandtrvl, Svick, Michał Sobkowski, Addbot, C6541, CheMoBot, Grim23, حسن علي البط, Biker Biker, BogBot, Tisane, ZéroBot, Frozen Wind, Caponex, ClueBot NG, Skoot13, Pan Czy Pani, Verified72, WildCation and Anonymous: 10 • JWH-098 Source: http://en.wikipedia.org/wiki/JWH-098?oldid=606459363 Contributors: Meodipt, Enix150, C6541, CheMoBot, حسن علي البط, BogBot, Skoot13 and WildCation • JWH-116 Source: http://en.wikipedia.org/wiki/JWH-116?oldid=608540716 Contributors: Rjwilmsi, C6541, BaeyerDrewson and WildCation • JWH-147 Source: http://en.wikipedia.org/wiki/JWH-147?oldid=606479371 Contributors: Pegship, Meodipt, Enix150, Yobot, CheMoBot, حسن علي البط, BogBot, Tisane, Destruktor5000, WildCation and Anonymous: 1 • JWH-164 Source: http://en.wikipedia.org/wiki/JWH-164?oldid=606483862 Contributors: Meodipt, Enix150, CheMoBot, حسن علي البط, FrescoBot, BogBot, Skoot13 and WildCation • JWH-167 Source: http://en.wikipedia.org/wiki/JWH-167?oldid=600826360 Contributors: Stephen, Rjwilmsi, Shoy, Beetstra, Boghog, Enix150, Jsfouche, C6541, Ben Ben, CheMoBot, Citation bot, EmausBot, The chemistds, Rezabot and Anonymous: 1 • JWH-175 Source: http://en.wikipedia.org/wiki/JWH-175?oldid=607110954 Contributors: Jorge Stolfi, Meodipt, Enix150, CheMoBot and WildCation • JWH-184 Source: http://en.wikipedia.org/wiki/JWH-184?oldid=608540728 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson • JWH-185 Source: http://en.wikipedia.org/wiki/JWH-185?oldid=608540720 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson • JWH-196 Source: http://en.wikipedia.org/wiki/JWH-196?oldid=608540711 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson • JWH-203 Source: http://en.wikipedia.org/wiki/JWH-203?oldid=607451648 Contributors: Rich Farmbrough, Rjwilmsi, Bazonka, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, Citation bot, Grim23, حسن علي البط, BogBot, Gunnanmon, Tisane, Caponex, Skoot13, Pan Czy Pani, Monkbot, WildCation and Anonymous: 3 • JWH-210 Source: http://en.wikipedia.org/wiki/JWH-210?oldid=625525612 Contributors: Mike Rosoft, KGasso, Edgar181, Meodipt, Christian75, DumbBOT, MER-C, Enix150, Addbot, C6541, Luckas-bot, CheMoBot, Anypodetos, Mdog228, Grim23, حسن علي البط, FrescoBot, BogBot, NotAnonymous0, Tisane, ZéroBot, DASHBotAV, Caponex, Tryptamines, Pan Czy Pani, WildCation and Anonymous: 16 • JWH-249 Source: http://en.wikipedia.org/wiki/JWH-249?oldid=600743349 Contributors: Rjwilmsi, Shoy, Beetstra, Meodipt, Enix150, Squids and Chips, Ben Ben, CheMoBot, Citation bot, BogBot and The chemistds • JWH-250 Source: http://en.wikipedia.org/wiki/JWH-250?oldid=606791115 Contributors: Mike Rosoft, Blaxthos, Rjwilmsi, WriterHound, KGasso, Edgar181, Drphilharmonic, Meodipt, Smartse, Salih, Enix150, Panoramix303, Chemgirl131, Addbot, C6541, Yobot, CheMoBot, Sarrus, XLocal, Citation bot, ArthurBot, OlYeller21, Grim23, حسن علي البط, Harbinary, Citation bot 1, BogBot, Tbhotch, EmausBot, Tisane, PotatoBot, Joseph3311, IGeMiNix, ChuispastonBot, DASHBotAV, Caponex, Louisajb, MelbourneStar, Skoot13, Names are hard to think of, Purple Blanket, Rebrewind, WildCation and Anonymous: 17 • JWH-251 Source: http://en.wikipedia.org/wiki/JWH-251?oldid=600909501 Contributors: Rjwilmsi, Bazonka, Beetstra, Meodipt, Enix150, Addbot, C6541, CheMoBot, Citation bot, The chemistds and AvocatoBot • JWH-302 Source: http://en.wikipedia.org/wiki/JWH-302?oldid=517587317 Contributors: Rjwilmsi, Beetstra, Meodipt, CheMoBot, BogBot, The chemistds and Skoot13 • JWH-307 Source: http://en.wikipedia.org/wiki/JWH-307?oldid=606472694 Contributors: Cacycle, NawlinWiki, Pegship, KGasso, Edgar181, Meodipt, Smartse, MER-C, Enix150, Addbot, CheMoBot, Sarrus, Grim23, حسن علي البط, Biker Biker, BogBot, Dinamikbot, Tbhotch, Tisane, Somerwind, Caponex, ClueBot NG, Verified72, WildCation and Anonymous: 14 • JWH-398 Source: http://en.wikipedia.org/wiki/JWH-398?oldid=622353964 Contributors: Rjwilmsi, Meodipt, Enix150, C6541, CheMoBot, Grim23, حسن علي البط, Harbinary, BogBot, Tisane, Skoot13, WildCation and Anonymous: 1 • JWH-424 Source: http://en.wikipedia.org/wiki/JWH-424?oldid=606469047 Contributors: Meodipt, Enix150, C6541, CheMoBot, Gongshow, FrescoBot, BogBot, Skoot13, BaeyerDrewson and WildCation • Naphthoylindole Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch, Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser, Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilharmonic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT, Nirigihimu, Turkeyphant, Zefiel, Smartse, Theguy0000, MER-C, Grimelab, Iownutopia, JamesBWatson, Monosodious, Bradgib, ChemNerd, Leyo, Boghog, Malkuth1, Gutterkitty, Enix150, Pdcook, CardinalDan, Funandtrvl, Msrbl49, Fbifriday, Philip Trueman, Flux12n21, Flopster2, Wikieditor12, Jpaliano, Guldenat, Falcon8765, Living under a rock, Pjoef, Dlfreem, Dheau, Hobartimus, ClueBot, GorillaWarfare, Tomas e, Drmies, Yuubi, Auntof6, Ktr101, Alexbot, Dr.Koljan, Panoramix303, Sun Creator, Christopherbrian, XLinkBot, Fastily, ErgoSum88, ESO Fan, PurrfectPeach, Addbot, C6541, MartinezMD, Fieldday-sunday, Fluffernutter, LaaknorBot, DFS454, Favonian, Tide rolls, Wax025, Ben Ben, Legobot, Luckas-bot, Yobot, Legobot II, CheMoBot, Daddyrob81, Anypodetos, AnomieBOT, XLocal, Vinyl Ketone, Piano non troppo, Citation bot, GB fan, Intelati, OlYeller21, Δζ, Pontificalibus, Nasnema, Rhoodey, حسن علي البط, Harbinary, Shirik, Amaury, Psychonaught, Shadowjams, Custoo, FrescoBot, Nageh, RicHard-59, Metallica3790, Borguebabe, Weetoddid, Boylechem, Citation bot 1, Biker Biker, Calmer Waters, MastiBot, Sw1ngOnTheSp1ral, BogBot, CrowzRSA, Clickpop, David Hedlund, Tbhotch, RjwilmsiBot, Dustin 3choes, Jwh018, Rsharpe28, John of Reading, Gunnanmon, Katherine, Tisane, Clayman1976, Atropinesulfate, Tommy2010, Sraab2, Wikipelli, White Trillium, Fæ, Josve05a, James.dynamite, Hereforhomework2, H3llBot, Darkwire89, Drhjort, ALANON54, Wayne Slam, Ocaasi, OnePt618, Scema, PeterGriffinJK, Akacypress, Demetrius259, Corei7Maniac, Del nerius, Lagato123, Tjiseclipsed, ClamDip, HaydenBeck, W5NLbrian, Handsum53, DASHBotAV, Hetoi, Abnorml1, Louisajb, Mikhail Ryazanov, ClueBot NG, Agents of The Free, Easyzeh, Dualdj1, Tesacrynheart, EnvyCo, Diogenes2000, Skoot13, 4321acb, Jacobso4, Murraysymes, 1989Exley1989, Exercisephys, Verified72, Snow Blizzard, Boobs4fun, Justthinking25, Shisha-Tom, Fuse809, PhoenixPie, Kid squid, BattyBot, BaeyerDrewson, Rawrfaceace, KMAnomalocaris, Rebrewind, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 417 • Phenylacetylindole Source: http://en.wikipedia.org/wiki/JWH-167?oldid=600826360 Contributors: Stephen, Rjwilmsi, Shoy, Beetstra, Boghog, Enix150, Jsfouche, C6541, Ben Ben, CheMoBot, Citation bot, EmausBot, The chemistds, Rezabot and Anonymous: 1
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• RCS-8 Source: http://en.wikipedia.org/wiki/RCS-8?oldid=568307281 Contributors: Shoy, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, AnomieBOT, BogBot, The chemistds, Bped1985 and BaeyerDrewson • Intravenous Marijuana Syndrome Source: http://en.wikipedia.org/wiki/Intravenous_Marijuana_Syndrome?oldid=619005877 Contributors: Nagelfar, ESkog, TheoClarke, GregorB, SqueakBox, Rjwilmsi, Wavelength, Kirix, Sadads, Slakr, Fences and windows, Another Believer, NJGW, Mjpresson, C6541, Anypodetos, ThaddeusB, Blueharvest26, Citation bot, Haeinous, Donner60, BG19bot, Darthgreg and Anonymous: 9 • Mellow Yellow coffeeshop Source: http://en.wikipedia.org/wiki/Mellow_Yellow_coffeeshop?oldid=606996853 Contributors: Rpyle731, SqueakBox, MrSativa, Katharineamy, Addbot, Diannaa, Ihakeycakeyabreak, Emayv, BattyBot, Mrt3366, Comatmebro, Mogism, Smokey McSmokealot, Tough brown zealot and Anonymous: 1 • The Night Train Seizure Source: http://en.wikipedia.org/wiki/The_Night_Train_Seizure?oldid=627809729 Contributors: Bearcat, ChrisCork, Slazenger, Katharineamy, Themoodyblue, Pjoef, Mcrabb23 and Ca2flbroker • PSN-375,963 Source: http://en.wikipedia.org/wiki/PSN-375,963?oldid=450845362 Contributors: Meodipt, Chemgirl131, CheMoBot, حسن علي البط, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot and PotatoBot • PSN-632,408 Source: http://en.wikipedia.org/wiki/PSN-632,408?oldid=450845292 Contributors: Meodipt, Chemgirl131, CheMoBot, حسن علي البط, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot and PotatoBot • Soma Seeds Source: http://en.wikipedia.org/wiki/Soma_Seeds?oldid=608038890 Contributors: Bearcat, Rpyle731, Alexf, Grafen, SmackBot, Berean Hunter, Guygoldman, Yobot, Hahamgaon, Soma Seeds, WeedFreak, Bakuto459, BitcoinSeeds and Anonymous: 1 • TM-38837 Source: http://en.wikipedia.org/wiki/TM-38837?oldid=608356887 Contributors: BD2412, Racklever, Meodipt, Enix150, Yobot, Custoo, The chemistds, Paul269, BG19bot, Vaccinationist and Anonymous: 1
252.4.2
Images
• File:(+)-(6aR,10aS)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/2/20/%28%2B%29-%286aR%2C10aS%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_shown%29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:(+)-(6aS,10aS)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/b/b1/%28%2B%29-%286aS%2C10aS%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_shown%29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:(+)-trans-cannabitriol.png Source: http://.wikimedia.org/wikipedia/commons/1/12/%28%2B%29-trans-cannabitriol.png License: CC-BY-SA-3.0 Contributors: Self-published work by Cacycle Original artist: Cacycle • File:(-)-trans-cannabitriol.png Source: http://.wikimedia.org/wikipedia/commons/a/a2/%28-%29-trans-cannabitriol.png License: CC-BY-SA-3.0 Contributors: Self-published work by Cacycle Original artist: Cacycle • File:(C6)-_47,497.png Source: http://.wikimedia.org/wikipedia/commons/d/d8/%28C6%29-_47%2C497.png License: Public domain Contributors: ChemSpider Original artist: ChemSpider • File:(C9)-_47,497.png Source: http://.wikimedia.org/wikipedia/commons/c/cb/%28C9%29-_47%2C497.png License: Public domain Contributors: ChemSpider Original artist: ChemSpider • File:(−)-(6aR,10aR)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/3/39/%28%E2%88%92%29-%286aR%2C10aR%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_ shown%29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:(−)-(6aS,10aR)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/1/1d/%28%E2%88%92%29-%286aS%2C10aR%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_shown% 29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:10-oxo-delta-6a(10a)-tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/f/f5/ 10-oxo-delta-6a%2810a%29-tetrahydrocannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:11-COOH-THC.svg Source: http://.wikimedia.org/wikipedia/commons/8/8d/11-COOH-THC.svg License: Public domain Contributors: Own work Original artist: Harbin • File:11-Hydroxy-THC-3D-balls.png Source: http://.wikimedia.org/wikipedia/commons/e/e3/11-Hydroxy-THC-3D-balls.png License: CC0 Contributors: This chemical image was created with Discovery Studio Visualizer. Original artist: Jynto (talk) • File:11-OH-THC.svg Source: http://.wikimedia.org/wikipedia/commons/6/6e/11-OH-THC.svg License: Public domain Contributors: Own work Original artist: Harbin • File:2-(6-Isopropenyl-3-methyl-1-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ CC0 wikipedia/commons/b/b4/2-%286-Isopropenyl-3-methyl-1-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-2-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/5/5d/2-%286-Isopropenyl-3-methyl-2-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-3-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/d/d2/2-%286-Isopropenyl-3-methyl-3-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-4-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/6/67/2-%286-Isopropenyl-3-methyl-4-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• File:2-(6-Isopropenyl-3-methyl-5-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/a/a2/2-%286-Isopropenyl-3-methyl-5-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-6-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/4/4c/2-%286-Isopropenyl-3-methyl-6-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methylenecyclohex-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/wikipedia/ commons/a/af/2-%286-Isopropenyl-3-methylenecyclohex-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-Arachidonyl_glyceryl_ether.svg Source: http://.wikimedia.org/wikipedia/commons/4/47/2-Arachidonyl_glyceryl_ether. svg License: Public domain Contributors: Own work Original artist: Benrr101 • File:2ag.svg Source: http://.wikimedia.org/wikipedia/commons/5/55/2ag.svg License: CC-BY-SA-3.0 Contributors: Own work in chemdraw/illustrator and originally from en.wikipedia; description page is/was here. 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• File:AM-6545_structure.png Source: http://.wikimedia.org/wikipedia/commons/c/c2/AM-6545_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:AM-679_structure.png Source: http://.wikimedia.org/wikipedia/commons/4/4c/AM-679_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:AM-855.svg Source: http://.wikimedia.org/wikipedia/commons/3/33/AM-855.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Panoramix303 • File:AM-905.svg Source: http://.wikimedia.org/wikipedia/commons/6/69/AM-905.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Panoramix303 • File:AM-906.svg Source: http://.wikimedia.org/wikipedia/commons/5/50/AM-906.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Panoramix303 • File:AM-919.png Source: http://.wikimedia.org/wikipedia/commons/a/a8/AM-919.png License: Public domain Contributors: Transferred from en.wikipedia by Ronhjones Original artist: Meodipt at en.wikipedia • File:AM-938.png Source: http://.wikimedia.org/wikipedia/commons/a/a6/AM-938.png License: Public domain Contributors: Transferred from en.wikipedia by Ronhjones Original artist: Meodipt at en.wikipedia • File:AM1220heterocycles.png Source: http://.wikimedia.org/wikipedia/commons/b/bd/AM1220heterocycles.png License: Public domain Contributors: Own work Original artist: Meodipt • File:AM2512d.png Source: http://.wikimedia.org/wikipedia/commons/e/e0/AM2512d.png License: Public domain Contributors: Own work Original artist: Ccroberts • File:AM2513d.png Source: http://.wikimedia.org/wikipedia/commons/b/b8/AM2513d.png License: Public domain Contributors: Own work Original artist: Ccroberts • File:AM404_skel.svg Source: http://.wikimedia.org/wikipedia/commons/b/ba/AM404_skel.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: WhiteTimberwolf, PNG version: Xasodfuih • File:AMG-1.png Source: http://.wikimedia.org/wikipedia/commons/5/5a/AMG-1.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Addihockey10 using CommonsHelper. 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Original artist: ? • File:Ambox_wikify.svg Source: http://.wikimedia.org/wikipedia/commons/e/e1/Ambox_wikify.svg License: Public domain Contributors: Own work Original artist: penubag • File:Anandamid.svg Source: http://.wikimedia.org/wikipedia/commons/1/1f/Anandamid.svg License: Public domain Contributors: Own work Original artist: NEUROtiker • File:Anandamide_skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/b/b7/Anandamide_skeletal.svg License: Public domain Contributors: Own work Original artist: Fvasconcellos 23:45, 27 May 2007 (UTC) • File:Arachidonyl-2-chloroethylamide.svg Source: http://.wikimedia.org/wikipedia/commons/a/ad/ Arachidonyl-2-chloroethylamide.svg License: Public domain Contributors: Own work Original artist: Ed (Edgar181) • File:Arachidonylcyclopropylamide.svg Source: http://.wikimedia.org/wikipedia/commons/c/c0/Arachidonylcyclopropylamide. svg License: Public domain Contributors: Own work Original artist: Ed (Edgar181)
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
345
• File:BAY38-7271.svg Source: http://.wikimedia.org/wikipedia/commons/f/f0/BAY38-7271.svg License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia. Later version(s) were ed by Edgar181 at en.wikipedia. • File:BAY59-3074.svg Source: http://.wikimedia.org/wikipedia/commons/d/da/BAY59-3074.svg License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia. Later version(s) were ed by Edgar181 at en.wikipedia. • File:BB-22.png Source: http://.wikimedia.org/wikipedia/commons/4/4b/BB-22.png License: Public domain Contributors: Own work Original artist: BaeyerDrewson • File:Beta-Caryophyllen.svg Source: http://.wikimedia.org/wikipedia/commons/b/b4/Beta-Caryophyllen.svg License: Public domain Contributors: Own work Original artist: NEUROtiker (talk) • File:C3-cannabielsoic_acid_B.png Source: http://.wikimedia.org/wikipedia/commons/b/b7/C3-cannabielsoic_acid_B.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:C3-cannabielsoin.png Source: http://.wikimedia.org/wikipedia/commons/3/37/C3-cannabielsoin.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:CB-13_structure.png Source: http://.wikimedia.org/wikipedia/commons/1/10/CB-13_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia • File:CBC-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/7/7a/CBC-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBC-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/0/08/CBC-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBD-3D-balls.png Source: http://.wikimedia.org/wikipedia/commons/e/e1/CBD-3D-balls.png License: Public domain Contributors: Own work Original artist: Ben Mills • File:CBD-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/2/26/CBD-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBD-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/d/dc/CBD-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBE-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/8/87/CBE-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBE-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/2/2c/CBE-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBG-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/8/87/CBG-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: Own work Original artist: Cacycle • File:CBG-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/6/67/CBG-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBL-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/d/d6/CBL-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBL-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/3/3b/CBL-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBN-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/2/2a/CBN-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBN-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/3/35/CBN-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBS-0550_structure.png Source: http://.wikimedia.org/wikipedia/commons/7/79/CBS-0550_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:CBT-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/4/4b/CBT-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBT-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/9/93/CBT-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:-47,497.svg Source: http://.wikimedia.org/wikipedia/commons/a/a0/-47%2C497.svg License: Public domain Contributors: Transferred from en.wikipedia Original artist: Original er was Meodipt at en.wikipedia • File:-55,244.svg Source: http://.wikimedia.org/wikipedia/commons/6/6d/-55%2C244.svg License: Public domain Contributors: Transferred from en.wikipedia Original artist: Original er was Meodipt at en.wikipedia • File:_55,940-2D-skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/d/d7/_55%2C940-2D-skeletal.svg License: Public domain Contributors: Own work Original artist: Harbin • File:Cannabichromanone-C3.png Source: http://.wikimedia.org/wikipedia/commons/5/58/Cannabichromanone-C3.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromanone.png Source: http://.wikimedia.org/wikipedia/commons/a/aa/Cannabichromanone.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromene-skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/0/0b/Cannabichromene-skeletal.svg License: Public domain Contributors: Own work Original artist: Benrr101
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• File:Cannabichromene.png Source: http://.wikimedia.org/wikipedia/commons/c/cd/Cannabichromene.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:Cannabichromenic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/a/af/Cannabichromenic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromevarine.png Source: http://.wikimedia.org/wikipedia/commons/3/34/Cannabichromevarine.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromevarinic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/4/4c/Cannabichromevarinic_acid_ A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicitran.png Source: http://.wikimedia.org/wikipedia/commons/8/83/Cannabicitran.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicoumaronone.png Source: http://.wikimedia.org/wikipedia/commons/8/8a/Cannabicoumaronone.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicyclohexanol.png Source: http://.wikimedia.org/wikipedia/commons/6/6c/Cannabicyclohexanol.png License: Public domain Contributors: Transferred from en.wikipedia Original artist: Meodipt at en.wikipedia • File:Cannabicyclol.png Source: http://.wikimedia.org/wikipedia/commons/4/49/Cannabicyclol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicyclolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/e/e9/Cannabicyclolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicyclovarin.png Source: http://.wikimedia.org/wikipedia/commons/0/01/Cannabicyclovarin.png License: CC-BYSA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol-C4.png Source: http://.wikimedia.org/wikipedia/commons/a/a7/Cannabidiol-C4.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol.png Source: http://.wikimedia.org/wikipedia/commons/3/3f/Cannabidiol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol.svg Source: http://.wikimedia.org/wikipedia/commons/9/9a/Cannabidiol.svg License: Public domain Contributors: Own work Original artist: Harbin • File:Cannabidiol3Dan.gif Source: http://.wikimedia.org/wikipedia/commons/4/44/Cannabidiol3Dan.gif License: CC-BY-SA3.0 Contributors: QuteMol Original artist: Fuse809 • File:Cannabidiol_momomethyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/5/54/Cannabidiol_momomethyl_ ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol_numbering.png Source: http://.wikimedia.org/wikipedia/commons/9/9f/Cannabidiol_numbering.png License: Public domain Contributors: SYNTHESIS OF DELTA-3-CANNABIDIOL AND THE DERIVED RIGID ANALOGS, 1987, p. 20 (37 in PDF file) Original artist: NAGARAJA, KODIHALLI NANJAPPA • File:Cannabidiolic_acid.png Source: http://.wikimedia.org/wikipedia/commons/d/d2/Cannabidiolic_acid.png License: CC-BYSA-3.0 Contributors: ? Original artist: ? • File:Cannabidiolic_acid_A_cannabitriol_ester.png Source: http://.wikimedia.org/wikipedia/commons/b/b8/Cannabidiolic_ acid_A_cannabitriol_ester.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiorcol.png Source: http://.wikimedia.org/wikipedia/commons/2/20/Cannabidiorcol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidivarin.png Source: http://.wikimedia.org/wikipedia/commons/4/40/Cannabidivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidivarin.svg Source: http://.wikimedia.org/wikipedia/commons/8/8a/Cannabidivarin.svg License: Public domain Contributors: Own work Original artist: Benrr101 • File:Cannabidivarinic_acid.png Source: http://.wikimedia.org/wikipedia/commons/5/55/Cannabidivarinic_acid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabielsoic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/2/22/Cannabielsoic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabielsoic_acid_B.png Source: http://.wikimedia.org/wikipedia/commons/9/90/Cannabielsoic_acid_B.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabielsoin.png Source: http://.wikimedia.org/wikipedia/commons/2/21/Cannabielsoin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabifuran.png Source: http://.wikimedia.org/wikipedia/commons/7/7f/Cannabifuran.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerol.png Source: http://.wikimedia.org/wikipedia/commons/b/bd/Cannabigerol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerol_monomethyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/6/6c/Cannabigerol_ monomethyl_ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/4/40/Cannabigerolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerolic_acid_A_monomethyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/9/9e/Cannabigerolic_ acid_A_monomethyl_ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ?
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
347
• File:Cannabigerovarin.png Source: http://.wikimedia.org/wikipedia/commons/2/20/Cannabigerovarin.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:Cannabigerovarinic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/6/63/Cannabigerovarinic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabiglendol-C3.png Source: http://.wikimedia.org/wikipedia/commons/2/23/Cannabiglendol-C3.png License: CC-BYSA-3.0 Contributors: ? Original artist: ? • File:Cannabinerolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/a/ae/Cannabinerolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinodiol.png Source: http://.wikimedia.org/wikipedia/commons/d/dd/Cannabinodiol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinodivarin.png Source: http://.wikimedia.org/wikipedia/commons/9/96/Cannabinodivarin.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:Cannabinol-C2.png Source: http://.wikimedia.org/wikipedia/commons/f/f0/Cannabinol-C2.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinol-C4.png Source: http://.wikimedia.org/wikipedia/commons/8/8d/Cannabinol-C4.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinol.png Source: http://.wikimedia.org/wikipedia/commons/1/1c/Cannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinol_methyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/d/d4/Cannabinol_methyl_ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/5/54/Cannabinolic_acid_A.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabiorcol.png Source: http://.wikimedia.org/wikipedia/commons/9/90/Cannabiorcol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabiripsol.png Source: http://.wikimedia.org/wikipedia/commons/e/ea/Cannabiripsol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabis_indica.jpg Source: http://.wikimedia.org/wikipedia/commons/7/77/Cannabis_indica.jpg License: FAL Contributors: 1. Ward, A Holmes, B (1985): Nabilone: a preliminary review of its pharmacological properties and therapeutic use. Drugs 30, 127-144. 2. Gagnon,B Bruera,E (1998): A review of the drug treatment of cachexia associated with cancer. Drugs 55, 675-688. 3. Nahas,G Sutin,K Bennett,WM (2000): Review of Marihuana and medicine. N Engl J Med 343, 514-515. 4. Tinklenberg,JR (1975): What a physician should know about marihuana. Rat Drug Ther 9/7, 1-6. 5. Grinspoon,L Bakalar,JB (1995): Marihuana as medicine. A plea for reconsideration. JAMA 273, 1875©1876. 6. Voth,EA Schwartz,RH (1997): Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 126, 791©798. 7. Merritt,JC Crawford,WJ Alexander,PC Anduze,AL Gelbart,SS (1980): Effect of marijuana on intraocular and blood pressure in glaucoma. Ophthalmology 87, 222©228. 8. Morris,K (1997): The cannabis remedy- wonder worker or evil weed? Lancet 350, 1828. Original artist: Axsadi Sánchez de Tagle • File:Cannabis_leaf.svg Source: http://.wikimedia.org/wikipedia/commons/a/a8/Cannabis_leaf.svg License: CC-BY-SA-3.0 Contributors: This vector image was created with Inkscape. Original artist: Oren neu dag • File:Cannabitetrol.png Source: http://.wikimedia.org/wikipedia/commons/b/b8/Cannabitetrol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabivarin.png Source: http://.wikimedia.org/wikipedia/commons/6/6f/Cannabivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabivarin.svg Source: http://.wikimedia.org/wikipedia/commons/9/97/Cannabivarin.svg License: Public domain Contributors: Own work Original artist: Benrr101 • File:Cis-cannabitriol.png Source: http://.wikimedia.org/wikipedia/commons/6/65/Cis-cannabitriol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cis-delta-9-tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/c/cc/ Cis-delta-9-tetrahydrocannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Commons-logo.svg Source: http://.wikimedia.org/wikipedia/en/4/4a/Commons-logo.svg License: ? Contributors: ? Original artist: ? • File:Dehydrocannabifuran.png Source: http://.wikimedia.org/wikipedia/commons/e/ec/Dehydrocannabifuran.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-7-cis-isotetrahydrocannabivarin.png Source: http://.wikimedia.org/wikipedia/commons/3/31/ Delta-7-cis-isotetrahydrocannabivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-7-trans-isotetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/c/ce/ Delta-7-trans-isotetrahydrocannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ?
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• File:Dibenzopyran_and_monoterpenoid_numbering_of_tetrahydrocannabinol.png Source: http://.wikimedia. org/wikipedia/commons/5/52/Dibenzopyran_and_monoterpenoid_numbering_of_tetrahydrocannabinol.png License: Public domain Contributors: Ronhjones (Talk) • File:Hu210_bns.png Source: http://.wikimedia.org/wikipedia/commons/7/7c/Hu210_bns.png License: CC0 Contributors: Own work Original artist: SubDural12 • File:Hydroxyhexahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/3/3e/Hydroxyhexahydrocannabinol. png License: Public domain Contributors: Transferred from en.wikipedia Original artist: Meodipt at en.wikipedia • File:IDFP_structure.png Source: http://.wikimedia.org/wikipedia/commons/6/6d/IDFP_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:IPMDHNPC.png Source: http://.wikimedia.org/wikipedia/commons/2/2b/IPMDHNPC.png License: Public domain Contributors: :Meodipt Original artist: :Meodipt • File:Ibipinabant.svg Source: http://.wikimedia.org/wikipedia/commons/4/43/Ibipinabant.svg License: Public domain Contributors: Own work Original artist: Vaccinationist • File:Imbox_content.png Source: http://.wikimedia.org/wikipedia/en/3/38/Imbox_content.png License: ? Contributors: Derived from Image:Information icon.svg Original artist: El T (original icon); David Levy (modified design); Penubag (modified color) • File:Iso-CBN-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/8/82/Iso-CBN-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Iso-CBN-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/e/e5/Iso-CBN-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:JMC2003_46_2110compound4b.png Source: http://.wikimedia.org/wikipedia/commons/5/57/JMC2003_46_ 2110compound4b.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JTE_7-31_molecular_structure.png Source: http://.wikimedia.org/wikipedia/commons/d/d6/JTE_7-31_molecular_ structure.png License: Public domain Contributors: Own work Original artist: Enix150 • File:JWH-018.jpg Source: http://.wikimedia.org/wikipedia/commons/7/7a/JWH-018.jpg License: Public domain Contributors: Own work Original artist: Psychonaught • File:JWH-018_synthesis.svg Source: http://.wikimedia.org/wikipedia/commons/9/96/JWH-018_synthesis.svg License: CC-BYSA-4.0 Contributors: Own work Original artist: Boghog • File:JWH-030.svg Source: http://.wikimedia.org/wikipedia/commons/1/16/JWH-030.svg License: Public domain Contributors: Own work Original artist: Harbinary • File:JWH-051.png Source: http://.wikimedia.org/wikipedia/commons/c/c7/JWH-051.png License: Public domain Contributors: :Meodipt Original artist: :Meodipt • File:JWH-133-2D-skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/a/ae/JWH-133-2D-skeletal.svg License: Public domain Contributors: Own work Original artist: Harbin • File:JWH-161_structure.png Source: http://.wikimedia.org/wikipedia/commons/0/09/JWH-161_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Meodipt. Original er was Meodipt at en.wikipedia • File:JWH-167_molecular_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/e6/JWH-167_molecular_ structure.png License: Public domain Contributors: Own work Original artist: Enix150
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• File:JWH-171.png Source: http://.wikimedia.org/wikipedia/commons/f/fc/JWH-171.png License: Public domain Contributors: :Meodipt Original artist: :Meodipt • File:JWH-175_structure.png Source: http://.wikimedia.org/wikipedia/commons/2/25/JWH-175_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-193_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/ec/JWH-193_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-198_structure.png Source: http://.wikimedia.org/wikipedia/commons/6/67/JWH-198_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-200.svg Source: http://.wikimedia.org/wikipedia/commons/f/fc/JWH-200.svg License: Public domain Contributors: Own work Original artist: Harbinary • File:JWH-204_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/e0/JWH-204_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-251_molecular_structure.png Source: http://.wikimedia.org/wikipedia/commons/3/3f/JWH-251_molecular_ structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-359_structure.png Source: http://.wikimedia.org/wikipedia/commons/c/c9/JWH-359_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. 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Original artist:
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
351
• File:Nabilone2D.svg Source: http://.wikimedia.org/wikipedia/commons/7/73/Nabilone2D.svg License: Public domain Contributors: MarvinSketch 6.0.0 Original artist: Fuse809 Fuse809 at en.wikipedia • File:Nabilone3Dan2.gif Source: http://.wikimedia.org/wikipedia/commons/0/04/Nabilone3Dan2.gif License: CC-BY-SA-3.0 Contributors: QuteMol Original artist: Fuse809 • File:Nabitan.svg Source: http://.wikimedia.org/wikipedia/commons/f/f5/Nabitan.svg License: Public domain Contributors: Own work Original artist: Snubcube ( talk) • File:Naboctate_structure.png Source: http://.wikimedia.org/wikipedia/commons/1/1a/Naboctate_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Meodipt. 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Original artist: Meodipt at en.wikipedia • File:O-1238.png Source: http://.wikimedia.org/wikipedia/commons/7/7d/O-1238.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Logan using CommonsHelper. 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Original artist: Meodipt at en.wikipedia. Later version(s) were ed by Edgar181 at en.wikipedia. • File:O-2694.png Source: http://.wikimedia.org/wikipedia/commons/0/0a/O-2694.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Logan using CommonsHelper. Original artist: Meodipt at en.wikipedia • File:O-774_structure.png Source: http://.wikimedia.org/wikipedia/commons/2/29/O-774_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:O-806.png Source: http://.wikimedia.org/wikipedia/commons/8/83/O-806.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Logan using CommonsHelper. Original artist: Meodipt at en.wikipedia • File:O-823.png Source: http://.wikimedia.org/wikipedia/commons/c/ca/O-823.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Logan using CommonsHelper. 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• File:Padlock-silver.svg Source: http://.wikimedia.org/wikipedia/commons/f/fc/Padlock-silver.svg License: ? Contributors: http: //openclipart.org/people/Anonymous/padlock_aj_ashton_01.svg Original artist: This image file was created by AJ Ashton. ed from English WP by :Eleassar. Converted by :AzaToth to a silver color. • File:Pancreatic_stellate_cell_cropped.png Source: cropped.png License: CC-BY-2.5 Contributors:
http://.wikimedia.org/wikipedia/commons/e/e0/Pancreatic_stellate_cell_
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252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
353
• File:Tetrahydrocannabinol.svg Source: http://.wikimedia.org/wikipedia/commons/4/4c/Tetrahydrocannabinol.svg License: Public domain Contributors: Own work Original artist: Yikrazuul • File:Tetrahydrocannabiorcol.png Source: http://.wikimedia.org/wikipedia/commons/8/85/Tetrahydrocannabiorcol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Text_document_with_red_question_mark.svg Source: http://.wikimedia.org/wikipedia/commons/a/a4/Text_document_ with_red_question_mark.svg License: Public domain Contributors: Created by bdesham with Inkscape; based upon Text-x-generic.svg from the Tango project. Original artist: Benjamin D. Esham (bdesham) • File:Thc.pdb.gif Source: http://.wikimedia.org/wikipedia/commons/7/77/Thc.pdb.gif License: Public domain Contributors: ? Original artist: ? • File:Trans-cannabitriol-C3.png Source: http://.wikimedia.org/wikipedia/commons/b/ba/Trans-cannabitriol-C3.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Trans-cannabitriol_ethyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/f/f1/Trans-cannabitriol_ethyl_ ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Trichomes_on_a_Cannabis_Sativa_Flower.jpg Source: http://.wikimedia.org/wikipedia/commons/4/46/Trichomes_on_ a_Cannabis_Sativa_Flower.jpg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Indirectantagonist • File:UR-12_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/e2/UR-12_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:URB754.svg Source: http://.wikimedia.org/wikipedia/commons/e/e0/URB754.svg License: Public domain Contributors: Own work Original artist: Isilanes • File:URB_602.svg Source: http://.wikimedia.org/wikipedia/commons/a/a3/URB_602.svg License: Public domain Contributors: Own work Original artist: Ed (Edgar181) • File:US-CoastGuard-Seal.svg Source: http://.wikimedia.org/wikipedia/commons/8/8d/US-CoastGuard-Seal.svg License: Public domain Contributors: Extracted from the cover of the PDF version of the March 2008 The Navy Reservist (direct PDF URL [1]). Original artist: U.S. Government • File:USCG-stub.PNG Source: http://.wikimedia.org/wikipedia/commons/2/27/USCG-stub.PNG License: Public domain Contributors: Own work Original artist: Bahamut0013 • File:Unbalanced_scales.svg Source: http://.wikimedia.org/wikipedia/commons/f/fe/Unbalanced_scales.svg License: Public domain Contributors: ? Original artist: ? • File:VDM-11.png Source: http://.wikimedia.org/wikipedia/commons/6/62/VDM-11.png License: Public domain Contributors: Own work Original artist: Edgar181 ( talk) • File:Virodhamine.svg Source: http://.wikimedia.org/wikipedia/commons/5/59/Virodhamine.svg License: Public domain Contributors: Own work Original artist: Benrr101 • File:WIN_55,212-2-2D-skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/1/18/WIN_55%2C212-2-2D-skeletal. svg License: Public domain Contributors: Own work Original artist: Harbin • File:White_widow.jpg Source: http://.wikimedia.org/wikipedia/commons/5/5a/White_widow.jpg License: CC-BY-2.0 Contributors: Flickr Original artist: Lenny Montana • File:X_mark.svg Source: http://.wikimedia.org/wikipedia/commons/a/a2/X_mark.svg License: Public domain Contributors: Own work Original artist: :Gmaxwell • File:Yes_check.svg Source: http://.wikimedia.org/wikipedia/en/f/fb/Yes_check.svg License: ? Contributors: ? Original artist: ?
252.4.3
Content license
• Creative Commons Attribution-Share Alike 3.0
Cannabinoid 1.1
1.2
3
Cannabinoid receptors
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.1.1
Cannabinoid receptor type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.1.2
Cannabinoid receptor type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2.1
Cannabis-derived cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2.2
Cannabinoids from other plants
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
1.2.3
Cannabis plant profile
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
1.2.4
Pharmacology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.2.5
Separation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.2.6
Natural occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.2.7
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
Endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.3.1
Types of endocannabinoid ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1.3.2
Function
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
1.4
Synthetic cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
1.5
Table of natural cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
1.6
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
1.7
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
1.8
Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.9
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
1.9.1
Cannabinoid information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
1.9.2
Cannabinoid research organizations
10
1.3
2
1
Phytocannabinoids
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Entourage effect
11
2.1
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
2.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
Synthetic cannabis
12
3.1
Misnomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
3.2
Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.2.1
Artificial cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.3
i
ii
CONTENTS 3.4
Drug testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5
Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5.1
Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5.2
South America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.3
Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.4
Australasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.5
North America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.6.1
Slang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.8
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.6
4
5
6
7
8
9
4-HTMPIPO
21
4.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5F-PB-22
22
5.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
5.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
A-40174
23
6.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
6.2
References
23
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-41988
24
7.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
7.2
References
24
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-796,260
25
8.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
8.2
References
25
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-834,735
26
9.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
9.2
References
26
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10 A-836,339 10.1 References
27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11 AB-001
27 28
11.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
11.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
12 AB-005 12.1 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29 29
CONTENTS
iii
12.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
12.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
13 AB-CHMINACA
30
13.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 AB-FUBINACA
30 31
14.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
14.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
15 AB-PINACA
32
15.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
15.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
16 Abnormal cannabidiol
33
16.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
16.2 References
33
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17 ADB-FUBINACA
35
17.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
17.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
18 ADB-PINACA
36
18.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
18.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
19 ADBICA
37
19.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
19.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
20 Ajulemic acid 20.1 References
38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21 AM-087
38 39
21.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
21.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
22 AM-1220
40
22.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
22.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
23 AM-1221
41
23.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
23.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
24 AM-1235
42
iv
CONTENTS 24.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.1.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
25 AM-1241
43
25.1 Effects in bone cancer model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
25.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
25.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
26 AM-1248
45
26.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
26.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
27 AM-1714
46
27.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
27.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
28 AM-2201
47
28.1 Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
29 AM-2232
48
29.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48
29.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48
30 AM-2233
49
30.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
30.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
31 AM-2389
50
31.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
31.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
32 AM-4030
51
32.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
32.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
33 AM-411 33.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52 52
CONTENTS
v
33.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 AM-630
52 53
34.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
34.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
35 AM-6545
54
35.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
35.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
36 AM-679 (cannabinoid)
55
36.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
36.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
37 AM-694
56
37.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
37.1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
37.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
37.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
38 AM-855
57
38.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 AM-905
57 58
39.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 AM-906
58 59
40.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
40.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
41 AM-919
60
41.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
41.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
42 AM-938
61
42.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
42.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
43 AM404
62
43.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
43.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
43.3 References
62
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44 AMG-1 44.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63 63
vi
CONTENTS
45 AMG-3
64
45.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 AMG-36
64 65
46.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 AMG-41
65 66
47.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 APINACA
66 67
48.1 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
48.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
48.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
49 AR-231,453
68
49.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
68
49.2 References
68
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50 Arachidonyl-2'-chloroethylamide 50.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Arachidonylcyclopropylamide 51.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 N-Arachidonylglycine
69 69 70 70 71
52.1 Synthesis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2 Research
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.1 Effects on the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.2 Effects on the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.3 Cell migration
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.4 Other targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
52.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
53 AZ-11713908
74
53.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
53.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
54 BAY 38-7271 54.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 BAY 59-3074 55.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 BML-190 56.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75 75 76 76 77 77
CONTENTS
vii
57 (C6)- 47,497
78
57.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 (C9)- 47,497
78 79
58.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Canbisol
79 80
59.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
80
59.2 References
80
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60 Cannabichromene
81
60.1 Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
81
60.2 References
81
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61 Cannabicyclohexanol
82
61.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
61.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
62 Cannabicyclol
83
62.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
62.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
63 Cannabidiol
84
63.1 Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.1 Antimicrobial actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.2 Neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.3 Psychotropic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.4 Dravet syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.2 CBD-enhanced cannabis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.3 Industrial hemp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.2 Pharmacokinetic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.3 Pharmaceutical preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.5 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.6 Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.6.1 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.7 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.8 US patent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87
63.10External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
64 Cannabidivarin 64.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90 90
viii
CONTENTS 64.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
64.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
65 Cannabigerol
91
65.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
91
65.2 References
91
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66 Cannabinoidergic
92
66.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
66.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
67 Cannabinol
93
67.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
67.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
67.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
68 Cannabivarin 68.1 References
94 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
68.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
68.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
69 Caryophyllene
95
69.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
69.2 Compendial status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
69.3 Notes and references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
70 CB-13
98
70.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
70.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
71 CBS-0550
99
71.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
99
71.2 References
99
72 47,497
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
100
72.1 Homologue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.3 Latvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.4 Lithuania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.5 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.6 Romania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 72.2.7 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
CONTENTS
ix
72.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 72.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 73 55,244
102
73.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 73.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 74 55,940
103
74.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 74.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 75 Dexanabinol
104
75.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 76 Dimethylheptylpyran
105
76.1 Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 76.2 Investigation as non-lethal incapacitating agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 76.3 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 76.4 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
77 Docosatetraenoylethanolamide
107
77.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 78 Drinabant
108
78.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 78.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
79 EAM-2201
109
79.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 79.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 79.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 79.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 80 Endocannabinoid reuptake inhibitor
110
80.1 Etymology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.3 Use in medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.4 Examples of eCBRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 80.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 81 Endocannabinoid system
112
81.1 Basic overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 81.1.1 Expression of receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 81.1.2 Endocannabinoid synthesis, release, and degradation . . . . . . . . . . . . . . . . . . . . . 112
x
CONTENTS 81.1.3 Binding and intracellular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 81.1.4 Binding and neuronal excitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 81.2 Functions of the endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.1 Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.2 Appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.3 Energy balance & metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 81.2.4 Stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 81.2.5 Immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 81.2.6 Female reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.7 Autonomic nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.8 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.9 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.2.10 Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.3 Experimental use of CB1 -/- phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 81.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 81.5 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 81.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
82 Endocannabinoid transporters 82.1 References 83 GW-405,833
120
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 121
83.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 84 GW-842,166X 84.1 References 85 Hemopressin
122 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 123
85.1 Role in diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 85.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 85.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 86 HU-210
124
86.1 Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.2.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.2.2 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.3 Other HU Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 86.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 86.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 87 HU-243
126
87.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
CONTENTS 87.2 References
xi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
88 HU-308
127
88.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 88.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 89 HU-331
128
89.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 89.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 89.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 90 11-Hydroxy-THC 90.1 References
130 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
91 9-nor-9β-Hydroxyhexahydrocannabinol
131
91.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 91.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
92 Ibipinabant
132
92.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 92.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 93 IDFP
133
93.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 93.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 94 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene
134
94.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 95 JTE 7-31
135
95.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 95.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 96 JTE-907
136
96.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 96.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 97 JWH-015
137
97.1 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 97.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 98 JWH-051
138
98.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 99 JWH-057
139
99.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
xii
CONTENTS 99.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
100JWH-120
140
100.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 100.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 101JWH-122
141
101.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 101.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 102JWH-133
142
102.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 102.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
102.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 103JWH-148
143
103.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 103.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 104JWH-149
144
104.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 104.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 105JWH-161
145
105.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 106JWH-176
146
106.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 106.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 107JWH-359
147
107.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 108JZL184
148
108.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 108.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 109JZL195
149
109.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 109.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 110KM-233
150
110.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 110.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 111L-759,633
151
CONTENTS
xiii
111.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 111.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 112L-759,656
152
112.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 112.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 113LASSBio-881
153
113.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 114LBP-1 (drug)
154
114.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 114.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
115Leelamine
155
115.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 115.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
116Levonantradol
156
116.1Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.2Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.3Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.4Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 116.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 116.6Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 116.7References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
117List of AM cannabinoids
158
117.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 117.2Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 117.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 118List of JWH cannabinoids
161
118.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 118.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 119LY-2183240
164
119.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 119.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 120LY-320,135
165
120.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 121MAM-2201
166
121.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
xiv
CONTENTS 121.1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 121.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
122MDA-19
167
122.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 122.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 123Menabitan
168
123.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 123.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
124Methanandamide
169
124.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 125MK-9470
170
125.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 126N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-methoxyindole-3-carboxamide
171
126.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 126.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 126.3Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 127Nabazenil 127.1References 128Nabilone
173 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 174
128.1Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 128.2Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 128.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 128.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 129Nabitan 129.1References 130Nabiximols
176 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 177
130.1Availability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 130.2Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.3Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.4Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 130.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 131Naboctate 131.1References
180 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
CONTENTS
xv
132NESS-0327
181
132.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 132.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 133NESS-040C5
182
133.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 133.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 134NMP-7
183
134.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 135Nonabine 135.1References
184 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
13611-nor-9-Carboxy-THC 136.1References 137O-1057
185
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 187
137.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 137.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 138O-1125
188
138.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 139O-1238
189
139.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 140O-1269
190
140.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 141O-1602
191
141.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 141.2References 142O-1812
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 192
142.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 142.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 143O-1871
193
143.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 143.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 144O-1918
194
144.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 144.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
xvi
CONTENTS
145O-2050
195
145.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 145.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 146O-2113
196
146.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 146.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 147O-2372
197
147.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 147.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 148O-2545
198
148.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 148.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 149O-2694
199
149.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 149.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 150O-774
200
150.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 150.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 151O-806
201
151.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 152O-823
202
152.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 153Org 27569 153.1References 154Org 28312
203 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 204
154.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 154.2References 155Org 28611
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 205
155.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 155.2References 156Otenabant
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 206
156.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 156.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 157Parahexyl
207
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xvii
157.1Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 157.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 157.3References 158UR-144
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 208
158.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.2History of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.3Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 158.6Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 159Perrottetinene 159.1References 160PF-03550096
210 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 211
160.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 160.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 161PF-514273
212
161.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 162PipISB
213
162.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 163Pirnabine 163.1References 164PSB-SB-1202
214 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 215
164.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 164.2References 165PSB-SB-487
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 216
165.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 165.2References 166QUCHIC
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 217
166.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 166.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 167QUPIC
218
167.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 167.2Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 167.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 167.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
xviii
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168Rimonabant
219
168.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 168.2Uses/potential uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 168.2.1 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 168.2.2 Smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.2.3 Addiction behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.2.4 Short-term memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.2.5 Blockage of cannabis effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.3Other effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.4Negative side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.5Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.6Brand names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 168.7References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 169Rosonabant
222
169.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 169.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
170S-444,823
223
170.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 170.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 171SDB-001
224
171.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 171.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 172SDB-006
225
172.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 172.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 173SER-601
226
173.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 173.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
174Serinolamide A
227
174.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 174.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 175SR-144,528
228
175.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 175.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 176Stearoylethanolamide
229
176.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
CONTENTS
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177STS-135 (drug)
230
177.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 177.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 177.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 178Surinabant
231
178.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 178.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 179Taranabant
232
179.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 179.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 180Tedalinab
233
180.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 180.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
181Tetrad test
234
181.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 182Tetrahydrocannabinol 182.1Effects
235
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.1.1 Appetite and taste
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.2Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.2.1 Discovery and structure identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.2.2 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.3Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 182.3.1 Multiple sclerosis symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.3.2 Neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.3.3 Other neurological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.3.4 Other studies in humans
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.4Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.4.1 Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 182.4.2 Cognitive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 182.4.3 Impact on psychosis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.4.4 Other potential long-term effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 182.4.5 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 182.5Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.5.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.6Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.7Chemical synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.8Marinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 182.8.1 Comparisons with medical marijuana
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
xx
CONTENTS 182.9Regulatory history
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
182.10See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 182.11References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
182.12Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 182.13External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 183Tetrahydrocannabinol-C4
246
183.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 183.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
184Tetrahydrocannabinolic acid
247
184.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 184.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
185Tetrahydrocannabivarin
249
185.1Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 185.2Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 185.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 185.4References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.5External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 186THC-O-acetate
250
186.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 187THC-O-phosphate 187.1References 188Tinabinol
251
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 252
188.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 188.2References 189URB602
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 253
189.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 190URB754
254
190.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 191VCHSR
255
191.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 192VDM-11
256
192.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 192.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 193WIN 54,461
257
193.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
CONTENTS 193.2References
xxi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
194WIN 55,212-2
258
194.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 194.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
194.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 195WIN 56,098
260
195.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 195.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
196XLR-11 (drug)
261
196.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.2Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.3Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 196.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 197AM251
263
197.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 197.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
198Aminoalkylindole
264
198.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 198.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 198.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 199Cannabipiperidiethanone
265
199.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 199.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 200JWH-193
266
200.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 200.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 201JWH-198
267
201.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 201.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 202JWH-200
268
202.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 202.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 203Pravadoline
269
203.1Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
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203.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 203.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 204RCS-4
270
204.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 204.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 204.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 205Anandamide
271
205.1History
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
205.2Physiological functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 205.3Synthesis and degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 205.4Medical benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 205.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 205.6References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 206N-Arachidonoyl dopamine
274
206.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 206.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
206.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 2072-Arachidonoylglycerol
275
207.1Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.2Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.4Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 207.6.1 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 207.6.2 General references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 2082-Arachidonyl glyceryl ether
277
208.1Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.2Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 208.5References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.6External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 209Oleamide
279
209.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 209.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
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210RVD-Hpα
280
210.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 211Virodhamine
281
211.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 211.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 212HU-320
282
212.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 212.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 213HU-336
283
213.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 213.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 214HU-345
284
214.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 214.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 215Raphael Mechoulam
285
215.1Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 215.2Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 215.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 215.4Podcasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 216John W. Huffman
286
216.1Law enforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 216.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 216.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 217JWH-007
287
217.1Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 217.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 217.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 218Naphthoylindole 218.1History
288
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 218.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 218.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 218.4Detection in biological fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 218.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 218.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 218.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
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218.8References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 219JWH-019
292
219.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.1 Poland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.2 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.3 UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.1.4 USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 219.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 220JWH-030
293
220.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 220.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 221JWH-047
294
221.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 221.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 222JWH-048
295
222.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 222.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 223JWH-073
296
223.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.2Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3.2 Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 223.3.3 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 223.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 223.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 224JWH-081
298
224.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 224.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 225JWH-098
299
225.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 225.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 226JWH-116
300
226.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
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226.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 227JWH-147
301
227.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 227.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 228JWH-164
302
228.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 229Phenylacetylindole
303
229.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 230JWH-175
304
230.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 230.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 231JWH-184
305
231.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 231.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 232JWH-185
306
232.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 232.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 233JWH-196
307
233.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 233.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 234JWH-203
308
234.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 234.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 235JWH-210
309
235.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 235.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 236JWH-249
310
236.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 236.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 237JWH-250
311
237.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 237.2References 238JWH-251
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 312
238.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
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239JWH-302
313
239.1References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
240JWH-307
314
240.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 240.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 241JWH-398
315
241.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 241.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 242JWH-424
316
242.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 242.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 243Naphthoylindole 243.1History
317
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 243.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 243.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 243.4Detection in biological fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 243.8References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 244Phenylacetylindole
321
244.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 245RCS-8
322
245.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 245.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 246Intravenous Marijuana Syndrome
323
246.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 247Mellow Yellow coffeeshop
324
247.1Citations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 247.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
247.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 248The Night Train Seizure
325
248.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 248.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
CONTENTS 249PSN-375,963
xxvii 326
249.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 249.2References 250PSN-632,408
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 327
250.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 250.2References 251Soma Seeds 251.1References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 328 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
251.2External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 252TM-38837
329
252.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 252.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
252.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 252.4Text and image sources, contributors, and licenses . . . . . . . . . . . . . . . . . . . . . . . . . . 330 252.4.1 Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 252.4.2 Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 252.4.3 Content license . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Chapter 1
Cannabinoid Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain. These receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals),[1] the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured chemically). The most notable cannabinoid is the phytocannabinoid ∆9 -tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis.[2][3] Cannabidiol (CBD) is another major constituent of the plant, representing up to 40% in extracts of the plant resin.[4] There are at least 85 different cannabinoids isolated from cannabis, exhibiting varied effects.[5]
including the hippocampus.[1] They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not the risk of respiratory or cardiovascular failure that can be produced by some drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
Synthetic cannabinoids encom a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5diarylpyrazoles, quinolines, and arylsulfonamides, as well as eicosanoids related to the endocannabinoids.[2]
CB2 receptors are predominantly found in the immune system, or immune-derived cells[8] with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.[9] CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.[8]
1.1.2 Cannabinoid receptor type 2 Main article: Cannabinoid receptor type 2
1.1 Cannabinoid receptors 1.2 Phytocannabinoids
Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2 ,[1] with mounting evidence of more.[6] The human brain has more cannabinoid receptors than any other G proteincoupled receptor (GPCR) type.[7]
1.1.1
1.2.1 Cannabis-derived cannabinoids The classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. At least 85 different cannabinoids have been isolated from the Cannabis plant[5] To the right, the main classes of cannabinoids from Cannabis are shown. The best studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).
Types
Cannabinoid receptor type 1
All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.[10] The classical cannabinoids are derived from their respective CB1 receptors are found primarily in the brain, more 2-carboxylic acids (2-COOH) by decarboxylation (catspecifically in the basal ganglia and in the limbic system, alyzed by heat, light, or alkaline conditions).[11] Main article: Cannabinoid receptor type 1
1
2
CHAPTER 1. CANNABINOID Tetrahydrocannabinol Tetrahydrocannabinol
Main
article:
Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta−9tetrahydrocannabinol (Δ9 -THC, THC) and delta−8tetrahydrocannabinol (Δ8 -THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. These two THCs produce the effects associated with cannabis by binding to the CB1 cannabinoid receptors in the brain. THC appears to ease moderate pain (analgesic) and to be neuroprotective, while also offering the potential to reduce neuroinflammation and to stimulate neurogenesis.[12] THC has approximately equal affinity for the CB1 and CB2 receptors.[13] The bracts surrounding a cluster of Cannabis sativa flowers are coated with cannabinoid-laden trichomes
Cannabidiol
Main article: Cannabidiol
Cannabidiol (CBD) is not psychoactive, and was thought not to affect the psychoactivity of THC.[14] However, recent evidence shows that smokers of cannabis with a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms.[15] This is ed by psychological tests, in which participants experience less intense psychotic-like effects when intravenous THC was co-istered with CBD (as measured with a PANSS test).[16] Cannabidiol has little affinity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists.[17] Recently it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[18] Cannabidiol has also been shown to act as a 5-HT₁A receptor agonist,[19] an action that is involved in its antidepressant,[20][21] anxiolytic,[21][22] and neuroprotective[23][24] effects.
Cannabis indica plant
• CBG (Cannabigerol) • CBC (Cannabichromene) • CBL (Cannabicyclol) • CBV (Cannabivarin) • THCV (Tetrahydrocannabivarin) • CBDV (Cannabidivarin) • CBCV (Cannabichromevarin) • CBGV (Cannabigerovarin) • CBGM (Cannabigerol Monomethyl Ether)
It appears to relieve convulsion, inflammation, anxiety, and nausea.[17] CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.[17] CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains. CBD apparently plays a role in preventing the short-term memory loss associated with THC in mammals. Some research suggests that the antipsychotic effects of cannabidiol potentially represent a novel mechanism in the treatment of schizophrenia.[25] Researchers at California Pacific Medical Center discovered CBD’s ability to “turn off” the activity of ID1, the gene responsible for metastasis in breast and other types of cancers, including the particularly aggressive triple negative breast cancer.[26][27][28] The researchers hope to start human trials soon.[29]
Cannabinol
Main article: Cannabinol
1.2. PHYTOCANNABINOIDS
3
Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB2 receptor is higher than for the CB1 receptor.[30] Cannabigerol
Main article: Cannabigerol
There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ9 -THC, while the minor form is called Δ8 THC. Under the alternate terpene numbering system, these same compounds are called Δ1 -THC and Δ6 -THC, respectively.
Length Most classical cannabinoids are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain attached to the aromatic ring. In THC, CBD, and CBN, this side-chain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3-carbon) chain. Cannabinoids with the propyl side-chain are named using the suffix varin, and are desarticle: ignated, for example, THCV, CBDV, or CBNV.
Cannabigerol (CBG) is non-psychotomimetic but still affects the overall effects of Cannabis. It acts as an α2 adrenergic receptor agonist, 5-HT₁A receptor antagonist, and CB1 receptor antagonist.[31] It also binds to the CB2 receptor.[31] Tetrahydrocannabivarin Tetrahydrocannabivarin
Main
Tetrahydrocannabivarin (THCV) is prevalent in cer- 1.2.2 Cannabinoids from other plants tain central Asian and southern African strains of Cannabis.[32][33] It is an antagonist of THC at CB1 recep- Phytocannabinoids are known to occur in several plant species besides cannabis. These include Echinacea tors and attenuates the psychoactive effects of THC.[34] purpurea, Echinacea angustifolia, Echinacea pallida, Acmella oleracea, Helichrysum umbraculigerum, and Cannabidivarin Main article: Cannabidivarin Radula marginata.[36] The best-known cannabinoids that are not derived from Cannabis are the lipophilic alka[36] At Although cannabidivarin (CBDV) is usually a minor mides (alkylamides) from Echinacea species. least 25 different alkylamides (dodeca-2E,4E,8Z,10E/Zconstituent of the cannabinoid profile, enhanced levels of CBDV have been reported in feral cannabis plants tetraenoic-acid-isobutylamides) have been identified, and them have shown affinities to the CB2 from the northwest Himalayas, and in hashish from some of[37][38] receptor. In Echinacea species, cannabinoids are [33][35] Nepal. found throughout the plant structure, but are most concentrated in the roots and flowers.[39][40] Yangonin found in the Kava plant is a ligand on the CB1 receptor.[41] Cannabichromene Main article: Cannabichromene Tea (Camellia sinensis) catechins have an affinity for human cannabinoid receptors.[42] A widespread dietary Cannabichromene (CBC) is non-psychoactive and does cannabinoid, beta-caryophyllene, a component from the not affect the psychoactivity of THC.[14] More comessential oil of cannabis and other medicinal plants, has mon in tropical cannabis varieties. Effects include antialso been identified as a selective agonist of peripheral inflammatory and analgesic. CB2 -receptors, in vivo.[43] Biosynthesis Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBGA. Next, CBGA is independently converted to either CBG, THCA, CBDA or CBCA by four separate synthase, FAD-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the propyl homologues (THCVA, CBDVA and CBCVA), there is a similar pathway that is based on CBGVA from divarinolic acid instead of olivetolic acid.
Most of the phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents.
1.2.3 Cannabis plant profile
Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant’s cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (comDouble bond position In addition, each of the com- monly called hemp) are bred such that they are low in psypounds above may be in different forms depending on the choactive chemicals like THC. Strains used in medicine position of the double bond in the alicyclic carbon ring. are often bred for high CBD content, and strains used for
4
CHAPTER 1. CANNABINOID
recreational purposes are usually bred for high THC con- 1.2.6 Natural occurrence tent or for a specific chemical balance. Quantitative analysis of a plant’s cannabinoid profile is of- Main article: Medical_cannabis § Difference between ten determined by gas chromatography (GC), or more re- C. indica and C. sativa liably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, and, unlike GC methods, can differentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.
Cannabis indica may have a CBD:THC ratio 4–5 times that of Cannabis sativa.
1.2.7 History Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964.
Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural pre1.2.4 Pharmacology cursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant Cannabinoids can be istered by smoking, vaporizfrom the precursor CBG. ing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, especially by cytochrome P450 mixed-function oxidases, 1.3 Endocannabinoids mainly CYP 2C9. Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication. For more details on the roles and regulation of the endoSome is also stored in fat in addition to being metabo- cannabinoids, see Endocannabinoid system. lized in the liver. Δ9 -THC is metabolized to 11-hydroxy- Endocannabinoids are substances produced from within Δ9 -THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body several weeks after istration. These metabolites are the chemicals recognized by common antibody-based “drug tests"; in the case of THC or others, these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous blood alcohol levels), but an integration of past consumption over an approximately month-long window. This is because they are fat-soluble, lipophilic molecules that accumulate in fatty tissues.[44]
1.2.5
Separation
Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures (73 atmospheres or more), there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high-purity cannabinoids, chemical synthesis or semisynthesis is generally required.
Anandamide, an endogenous ligand of CB1 and CB2
the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand for the receptor.
1.3.1 Types of endocannabinoid ligands Arachidonoylethanolamine (Anandamide or AEA) Main article: Arachidonoylethanolamine In 1992, in Raphael Mechoulam's lab, the first such compound was identified as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit
1.3. ENDOCANNABINOIDS word for bliss and -amide. Anandamide is derived from arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to the central (CB1 ) and, to a lesser extent, peripheral (CB2 ) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor.[45] Anandamide is found in nearly all tissues in a wide range of animals.[46] Anandamide has also been found in plants, including small amounts in chocolate.[47] Two analogs of anandamide, 7,10,13,16docosatetraenoylethanolamide and homo-γlinolenoylethanolamine, have similar pharmacology. All of these are of a family of signalling lipids called N-acylethanolamines, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide, which possess anti-inflammatory and orexigenic effects, respectively. Many Nacylethanolamines have also been identified in plant seeds[48] and in molluscs.[49]
2-Arachidonoylglycerol (2-AG)
5 N-Arachidonoyl dopamine (NADA) Main article: N-Arachidonoyl dopamine Discovered in 2000, NADA preferentially binds to the CB1 receptor.[54] Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.[55][56]
Virodhamine (OAE) Main article: Virodhamine A fifth endocannabinoid, virodhamine, or Oarachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1 , it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.[57]
Main article: 2-Arachidonoylglycerol Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both.[45] 2-AG is present at significantly higher concentrations in the brain than anandamide,[50] and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo.[1] In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.[51]
2-Arachidonyl glyceryl ether (noladin ether) Main article: 2-Arachidonyl glyceryl ether
Lysophosphatidylinositol (LPI) Recent evidence has highlighted lysophosphatidylinositol as the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid.[58]
1.3.2 Function Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons. Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
In 2001, a third, ether-type endocannabinoid, 2arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain.[52] Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at “any appreciable amount” in the brains of several different mammalian species.[53] It binds to the CB1 cannabinoid receptor (Kᵢ = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and The endocannabinoid 2-AG has been found in bovine and human maternal milk.[59] only weakly to the CB2 receptor.[45]
6 Retrograde signal
CHAPTER 1. CANNABINOID • Dronabinol (Marinol), is Δ9 -tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on • Nabilone (Cesamet, Canemes), a synthetic cannabia ‘postsynaptic’ cell, where presynaptic and postsynaptic noid and an analog of Marinol. It is Schedule II undesignate the sending and receiving sides of a synapse, like Marinol, which is Schedule III respectively. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most • Sativex, a cannabinoid extract oral spray containing commonly travel ‘backward’ against the usual synaptic THC, CBD, and other cannabinoids used for neutransmitter flow. They are, in effect, released from the ropathic pain and spasticity in 22 countries includpostsynaptic cell and act on the presynaptic cell, where ing England, Canada and Spain. Sativex develops the target receptors are densely concentrated on axonal whole-plant cannabinoid medicines terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid re• Rimonabant (SR141716), a selective cannabinoid ceptors temporarily reduces the amount of conventional (CB1 ) receptor inverse agonist once used as an antineurotransmitter released. This endocannabinoid mediobesity drug under the proprietary name Acomplia. ated system permits the postsynaptic cell to control its It was also used for smoking cessation own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For Other notable synthetic cannabinoids include: instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the ex• JWH-018, a potent synthetic cannabinoid agonist citability of the endocannabinoid-releasing cell. On the discovered by Dr. John W. Huffman at Clemson converse, when release of the excitatory neurotransmitUniversity. It is being increasingly sold in legal ter glutamate is reduced, the net effect is a decrease in smoke blends collectively known as “spice”. Several the excitability of the endocannabinoid-releasing cell. countries and states have moved to ban it legally. Range Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
1.4 Synthetic cannabinoids Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids. Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.
• JWH-073 • -55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC. • Dimethylheptylpyran • HU-210, about 100 times as potent as THC[60] • HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II. • SR144528, a CB2 receptor antagonist • WIN 55,212-2, a potent cannabinoid receptor agonist • JWH-133, a potent selective CB2 receptor agonist • Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine • AM-2201, a potent cannabinoid receptor agonist
1.5 Table of natural cannabinoids
Medications containing natural or synthetic cannabinoids From es:Cannabinoide#Tabla de cannabinoides naturales. or cannabinoid analogs:
1.7. REFERENCES
1.6 See also • Cannabinoid receptor antagonist • Cancer and nausea
1.7 References
7
doi:10.1046/j.1432-1327.2001.02030.x/j.14321327.2001.02030.x.pdf;jsessionid=3E999436DFF039CE743A44B5D42533C PMID 11248677. (subscription required (help)). |first2= missing |last2= in Authors list (help); |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help) ICID: 55687 [11] Patentdocs. Patent application title: Controlled cannabis decarboxylation. US Patent application number: 20120046352. Retrieved 28 December, 2013
[1] Pacher, P.; Bátkai, S; Kunos, G (2006). “The Endocannabinoid System as an Emerging Target of Pharmacotherapy”. Pharmacological Reviews 58 (3): 389– 462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
[12] Campbell, V A; Gowran, A (2007). “Alzheimer’s disease; taking the edge off with cannabinoids?". British Journal of Pharmacology 152 (5): 655–62. doi:10.1038/sj.bjp.0707446. PMC 2190031. PMID 17828287.
[2] Lambert, Didier M.; Fowler, Christopher J. (2005). “The Endocannabinoid System: Drug Targets, Lead Compounds, and Potential Therapeutic Applications”. Journal of Medicinal Chemistry 48 (16): 5059–87. doi:10.1021/jm058183t. PMID 16078824.
[13] Huffman, J. (2000). “The Search for Selective Ligands for the CB2 Receptor”. Current Pharmaceutical Design 6 (13): 1323–37. doi:10.2174/1381612003399347. PMID 10903395.
[3] Pertwee, Roger, ed. (2005). Cannabinoids. SpringerVerlag. p. 2. ISBN 3-540-22565-X. [4] “Bulletin on Narcotics - 1962 Issue 3 - 004”. UNODC (United Nations Office of Drugs and Crime). 1962-0101. Retrieved 2014-01-15. [5] El-Alfy, Abir T.; Ivey, Kelly; Robinson, Keisha; Ahmed, Safwat; Radwan, Mohamed; Slade, Desmond; Khan, Ikhlas; Elsohly, Mahmoud; Ross, Samir (2010). “Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”. Pharmacology Biochemistry and Behavior 95 (4): 434– 42. doi:10.1016/j.pbb.2010.03.004. PMC 2866040. PMID 20332000. [6] Begg, Malcolm; Pacher, Pál; Batkai, Sándor; Oseihyiaman, Douglas; Offertaler, László; Mo, Fong Ming; Liu, Jie; Kunos, George (2005). “Evidence for novel cannabinoid receptors”. Pharmacology & Therapeutics 106 (2): 133–45. doi:10.1016/j.pharmthera.2004.11.005. PMID 15866316.
[14] Ilan, A. B.; Gevins, A.; Coleman, M.; Elsohly, M. A.; De Wit, H. (2005). “Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids”. Behavioural Pharmacology 16 (5– 6): 487–96. doi:10.1097/00008877-200509000-00023. PMID 16148455. [15] Morgan, C. J. A.; Curran, H. V. (2008). “Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis”. The British Journal of Psychiatry 192 (4): 306–7. doi:10.1192/bjp.bp.107.046649. PMID 18378995. [16] “Should I Smoke Dope?". British Broadcasting Corporation. Retrieved 2008-05-24. [17] Mechoulam, Raphael; Peters, Maximilian; MurilloRodriguez, Eric; Hanuš, Lumír O. (2007). “Cannabidiol – Recent Advances”. Chemistry & Biodiversity 4 (8): 1678– 92. doi:10.1002/cbdv.200790147. PMID 17712814.
[7] Boron, Walter F.; Boulpaep, Emile L., eds. (2009). Medical Physiology: A Cellular and Molecular Approach. Saunders. p. 331. ISBN 978-1-4160-3115-4.
[18] Ryberg, E; Larsson, N; Sjögren, S; Hjorth, S; Hermansson, N-O; Leonova, J; Elebring, T; Nilsson, K; Drmota, T; Greasley, P J (2009). “The orphan receptor GPR55 is a novel cannabinoid receptor”. British Journal of Pharmacology 152 (7): 1092–101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302.
[8] Pacher, P.; Mechoulam, R. (2011). “Is lipid signaling through cannabinoid 2 receptors part of a protective system?". Progress in Lipid Research 50 (2): 193– 211. doi:10.1016/j.plipres.2011.01.001. PMC 3062638. PMID 21295074.
[19] Russo, Ethan B.; Burnett, Andrea; Hall, Brian; Parker, Keith K. (2005). “Agonistic Properties of Cannabidiol at 5-HT1a Receptors”. Neurochemical Research 30 (8): 1037–43. doi:10.1007/s11064-005-6978-1. PMID 16258853.
[9] Núñez, Estefanía; Benito, Cristina; Pazos, M. Ruth; Barbachano, Antonio; Fajardo, Otto; González, Sara; Tolón, Rosa M.; Romero, Julián (2004). “Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: An immunohistochemical study”. Synapse 53 (4): 208–13. doi:10.1002/syn.20050. PMID 15266552.
[20] Zanelati, TV; Biojone, C; Moreira, FA; Guimarães, FS; Joca, SRL (2010). “Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors”. British Journal of Pharmacology 159 (1): 122–8. doi:10.1111/j.1476-5381.2009.00521.x. PMC 2823358. PMID 20002102.
[10] Zenk, H. (2001). “Biosynthesis of cannabinoids”. Eur. J. Biochem 268 (6): 1596–1604.
[21] Resstel, Leonardo B.M.; Tavares, Rodrigo F.; Lisboa, Sabrina F.S.; Joca, Sâmia R.L.; Corrêa, Fernando M.A.; Guimarães, Francisco S. (2009). “5-HT1Areceptors are
8
CHAPTER 1. CANNABINOID
involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats”. British Journal of Pharmacology 156 (1): 181–8. doi:10.1111/j.1476-5381.2008.00046.x. PMC 2697769. PMID 19133999. [22] Campos, Alline Cristina; Guimarães, Francisco Silveira (2008). “Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats”. Psychopharmacology 199 (2): 223–30. doi:10.1007/s00213-008-1168-x. PMID 18446323. [23] Mishima, K.; Khoutorova, K.; Zhao, K.; Vigdorchik, T.; Belayev, N.; Busto, K.; Magal, M.; Ginsberg, MD (2005). “Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine1A Receptor-Dependent Mechanism”. Stroke 36 (5): 1071– 6. doi:10.1161/01.STR.0000163083.59201.34. PMID 15845890. [24] Hayakawa, Kazuhide; Mishima, Kenichi; Nozako, Masanori; Ogata, Ayumi; Hazekawa, Mai; Liu, An-Xin; Fujioka, Masayuki; Abe, Kohji; Hasebe, Nobuyoshi; Egashira, Nobuaki; Iwasaki, Katsunori; Fujiwara, Michihiro (2007). “Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance”. Neuropharmacology 52 (4): 1079– 87. doi:10.1016/j.neuropharm.2006.11.005. PMID 17320118. [25] Leweke, F M; Piomelli, D; Pahlisch, F; Muhl, D; Gerth, C W; Hoyer, C; Klosterkötter, J; Hellmich, M; Koethe, D (2012). “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia”. Translational Psychiatry 2 (3): e94–. doi:10.1038/tp.2012.15. PMC 3316151. PMID 22832859. [26] “Pot compound seen as tool against cancer”. SFGate. [27] McAllister, S. D.; Christian, R. T.; Horowitz, M. P.; Garcia, A.; Desprez, P.-Y. (2007). “Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells”. Molecular Cancer Therapeutics 6 (11): 2921–7. doi:10.1158/1535-7163.MCT-07-0371. PMID 18025276. [28] Ligresti, A.; Moriello, AS; Starowicz, K; Matias, I; Pisanti, S; De Petrocellis, L; Laezza, C; Portella, G; Bifulco, M; Di Marzo, V (2006). “Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma”. Journal of Pharmacology and Experimental Therapeutics 318 (3): 1375–87. doi:10.1124/jpet.106.105247. PMID 16728591. [29] “Marijuana Compound Fights Cancer; Human Trials Next”. NBC Bay Area. [30] Mahadevan, Anu; Siegel, Craig; Martin, Billy R.; Abood, Mary E.; Beletskaya, Irina; Razdan, Raj K. (2000). “Novel Cannabinol Probes for CB1 and CB2 Cannabinoid Receptors”. Journal of Medicinal Chemistry 43 (20): 3778–85. doi:10.1021/jm0001572. PMID 11020293.
[31] Cascio, MG; Gauson, LA; Stevenson, LA; Ross, RA; Pertwee, RG (2010). “Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist”. British Journal of Pharmacology 159 (1): 129–41. doi:10.1111/j.1476-5381.2009.00515.x. PMC 2823359. PMID 20002104. [32] Baker, PB; Gough, TA; Taylor, BJ (1980). “Illicitly imported Cannabis products: Some physical and chemical features indicative of their origin”. Bulletin on narcotics 32 (2): 31–40. PMID 6907024. [33] Hillig, K. W.; Mahlberg, P. G. (2004). “A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae)". American Journal of Botany 91 (6): 966–75. doi:10.3732/ajb.91.6.966. PMID 21653452. [34] Thomas, Adèle; Stevenson, Lesley A; Wease, Kerrie N; Price, Martin R; Baillie, Gemma; Ross, Ruth A; Pertwee, Roger G (2005). “Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1and CB2receptor antagonist”. British Journal of Pharmacology 146 (7): 917–26. doi:10.1038/sj.bjp.0706414. PMC 1751228. PMID 16205722. [35] Merkus, Frans W. H. M. (1971). “Cannabivarin and Tetrahydrocannabivarin, Two New Constituents of Hashish”. Nature 232 (5312): 579–80. doi:10.1038/232579a0. PMID 4937510. [36] Bauer, Rudolf; Salo-Ahen, Karin; Bauer, Outi (2008). “CB Receptor Ligands from Plants”. Current Topics in Medicinal Chemistry 8 (3): 173–86. doi:10.2174/156802608783498023. PMID 18289087. [37] Bauer, R.; Remiger, P. (2007). “TLC and HPLC Analysis of Alkamides inEchinaceaDrugs1,2”. Planta Medica 55 (4): 367–71. doi:10.1055/s-2006-962030. PMID 17262436. [38] Raduner, S; Majewska, A; Chen, J; Xie, X; Hamon, J; Faller, B; Altmann, K; Gertsch, J (2006). “Alkylamides from Echinacea Are a New Class of Cannabinomimetics: CANNABINOID TYPE 2 RECEPTOR-DEPENDENT AND -INDEPENDENT IMMUNOMODULATORY EFFECTS” (PDF). J. Biol. Chem. 281 (20): 14192–14206. doi:10.1074/jbc.M601074200. PMID 16547349. [39] Perry, Nigel; Van Klink, John; Burgess, Elaine; Parmenter, Graeme (2007). “Alkamide Levels inEchinacea purpurea: A Rapid Analytical Method Revealing Differences among Roots, Rhizomes, Stems, Leaves and Flowers”. Planta Medica 63 (1): 58–62. doi:10.1055/s-2006957605. PMID 17252329. [40] He, X; Lin, L; Bernart, MW; Lian, L (1998). “Analysis of alkamides in roots and achenes of Echinacea purpurea by liquid chromatography–electrospray mass spectrometry”. Journal of Chromatography A 815 (2): 205–11. doi:10.1016/S0021-9673(98)00447-6. [41] Ligresti, A.; Villano, R.; Allarà, M.; Ujváry, I. N.; Di Marzo, V. (2012). “Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB1
1.8. FURTHER READING
receptor ligand”. Pharmacological Research 66 (2): 163– 169. doi:10.1016/j.phrs.2012.04.003. PMID 22525682. [42] Korte, G.; Dreiseitel, A.; Schreier, P.; Oehme, A.; Locher, S.; Geiger, S.; Heilmann, J.; Sand, P.G. (2010). “Tea catechins’ affinity for human cannabinoid receptors”. Phytomedicine 17 (1): 19–22. doi:10.1016/j.phymed.2009.10.001. PMID 19897346. [43] Gertsch, J; Leonti, M; Raduner, S; Racz, I; Chen, J; Xie, X; Altmann, K; Karsak, M; Zimmer, A (2008). “Beta-caryophyllene is a dietary cannabinoid”. PNAS 105 (26): 9099–9104. doi:10.1073/pnas.0803601105. PMC 2449371. PMID 18574142. [44] Ashton CH (February 2001). “Pharmacology and effects of cannabis: a brief review”. Br J Psychiatry 178 (2): 101–106. doi:10.1192/bjp.178.2.101. PMID 11157422. “Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4-5 days. They are then slowly released back into other body compartments, including the brain. They are then slowly released back into other body compartments, including the brain. Because of the sequestration in fat, the tissue elimination half-life of THC is about 7 days, and complete elimination of a single dose may take up to 30 days.”
9
[52] Hanuš, Lumír; Abu-Lafi, Saleh; Fride, Ester; Breuer, Aviva; Vogel, Zvi; Shalev, Deborah E.; Kustanovich, Irina; Mechoulam, Raphael (2001). “2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor”. Proceedings of the National Academy of Sciences 98 (7): 3662–5. doi:10.1073/pnas.061029898. PMC 31108. PMID 11259648. [53] Oka, Saori; Tsuchie, Akiko; Tokumura, Akira; Muramatsu, Mayumi; Suhara, Yoshitomo; Takayama, Hiroaki; Waku, Keizo; Sugiura, Takayuki (2003). “Etherlinked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species”. Journal of Neurochemistry 85 (6): 1374– 81. doi:10.1046/j.1471-4159.2003.01804.x. PMID 12787057. [54] Bisogno, Tiziana; Melck, Dominique; Bobrov, Mikhail Yu.; Gretskaya, Natalia M.; Bezuglov, Vladimir V.; De Petrocellis, Luciano; Di Marzo, Vincenzo (2000). “N-acyl-dopamines: Novel synthetic CB1 cannabinoidreceptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo”. Biochemical Journal 351 (3): 817–24. doi:10.1042/02646021:3510817. PMC 1221424. PMID 11042139.
[45] Grotenhermen, Franjo (2005). “Cannabinoids”. Current Drug Target -CNS & Neurological Disorders 4 (5): 507. doi:10.2174/156800705774322111.
[55] Bisogno, T; Ligresti, A; Dimarzo, V (2005). “The endocannabinoid signalling system: Biochemical aspects”. Pharmacology Biochemistry and Behavior 81 (2): 224– 38. doi:10.1016/j.pbb.2005.01.027. PMID 15935454.
[46] Martin, B.R.; Mechoulam, R.; Razdan, R.K. (1999). “Discovery and characterization of endogenous cannabinoids”. Life Sciences 65 (6–7): 573. doi:10.1016/S00243205(99)00281-7.
[56] Ralevic, Vera (2003). “Cannabinoid modulation of peripheral autonomic and sensory neurotransmission”. European Journal of Pharmacology 472 (1–2): 1–21. doi:10.1016/S0014-2999(03)01813-2. PMID 12860468.
[47] Di Tomaso, Emmanuelle; Beltramo, Massimiliano; Piomelli, Daniele (1996). “Brain cannabinoids in chocolate”. Nature 382 (6593): 677–8. doi:10.1038/382677a0. PMID 8751435.
[57] Porter, A. C.; Sauer, JM; Knierman, MD; Becker, GW; Berna, MJ; Bao, J; Nomikos, GG; Carter, P; Bymaster, FP; Leese, AB; Felder, CC (2002). “Characterization of a Novel Endocannabinoid, Virodhamine, with Antagonist Activity at the CB1 Receptor”. Journal of Pharmacology and Experimental Therapeutics 301 (3): 1020–4. doi:10.1124/jpet.301.3.1020. PMID 12023533.
[48] Chapman, K. D.; Venables, B; Markovic, R; Blair Jr, RW; Bettinger, C (1999). “N-Acylethanolamines in Seeds. Quantification of Molecular Species and Their Degradation upon Imbibition”. Plant Physiology 120 (4): 1157– 64. doi:10.1104/pp.120.4.1157. PMC 59349. PMID 10444099. [49] Sepe, Nunzio; De Petrocellis, Luciano; Montanaro, sca; Cimino, Guido; Di Marzo, Vincenzo (1998). “Bioactive long chain N-acylethanolamines in five species of edible bivalve molluscs”. Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism 1389 (2): 101–11. doi:10.1016/S0005-2760(97)00132-X. PMID 9461251. [50] Piomelli, Daniele; Schweitzer, Nephi; Piomelli, Paul (1997). “A second endogenous cannabinoid that modulates long-term potentiation”. Nature 388 (6644): 773–8. doi:10.1038/42015. PMID 9285589. [51] Savinainen, Juha R; Järvinen, Tomi; Laine, Krista; Laitinen, Jarmo T (2001). “Despite substantial degradation, 2arachidonoylglycerol is a potent full efficacy agonist mediating CB1receptor-dependent G-protein activation in rat cerebellar membranes”. British Journal of Pharmacology 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC 1572991. PMID 11588122.
[58] Piñeiro, Roberto; Falasca, Marco (2012). “Lysophosphatidylinositol signalling: New wine from an old bottle”. Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids 1821 (4): 694–705. doi:10.1016/j.bbalip.2012.01.009. PMID 22285325. [59] Fride, E; Bregman, T; Kirkham, TC (2005). “Endocannabinoids and food intake: Newborn suckling and appetite regulation in adulthood”. Experimental biology and medicine 230 (4): 225–34. PMID 15792943. [60] “More medicinal uses for marijuana”. Marijuana.org. October 18, 2005. Archived from the original on 200512-21. Retrieved 2014-01-15.
1.8 Further reading • De Meijer, EP; Bagatta, M; Carboni, A; Crucitti, P; Moliterni, VM; Ranalli, P et al. (2003). “The inheritance of chemical phenotype in Cannabis sativa L”.
10
CHAPTER 1. CANNABINOID Genetics 163 (1): 335–46. PMC 1462421. PMID 12586720.
• Devane, W.; Hanus, L; Breuer, A; Pertwee, R.; Stevenson, L.; Griffin, G et al. (1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science 258 (5090): 1946– 9. doi:10.1126/science.1470919. PMID 1470919. • Elsohly, Mahmoud A.; Slade, Desmond (2005). “Chemical constituents of marijuana: The complex mixture of natural cannabinoids”. Life Sciences 78 (5): 539–48. doi:10.1016/j.lfs.2005.09.011. PMID 16199061.
• Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.; Rehnelt, J.; Martín, M. et al. (2008). “Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain”. Journal of Neuroscience 28 (46): 12125–35. doi:10.1523/JNEUROSCI.3400-08.2008. PMC 3844839. PMID 19005077. • Turner, C. E.; Mole, M. L.; Hanus, L.; Elsohly, H. N. (1981). “Constituents of Cannabis sativa. XIX. Isolation and Structure Elucidation of Cannabiglendol, A Novel Cannabinoid from an Indian Variant”. Journal of Natural Products 44 (1): 27–33. doi:10.1021/np50013a005.
• Hanus, Lumir; Gopher, Asher; Almog, Shlomo; Mechoulam, Raphael (1993). “Two new unsaturated fatty acid ethanolamides in brain 1.9 that bind to the cannabinoid receptor”. Journal of Medicinal Chemistry 36 (20): 3032–4. 1.9.1 doi:10.1021/jm00072a026. PMID 8411021. • Hanus, L (1987). “Biogenesis of cannabinoid substances in the plant”. Acta Universitatis Palackianae Olomucensis Facultatis Medicae 116: 47–53. PMID 2962461. • Hanuš, L.; Krejčí, Z. (1975). “Isolation of two new cannabinoid acids from Cannabis sativa L. of Czechoslovak origin”. Acta Univ. Olomuc., Fac. Med 74: 161–166. • Hanuš, L.; Krejčí, Z.; Hruban, L. (1975). “Isolation of cannabidiolic acid from Turkish variety of cannabis cultivated for fibre”. Acta Univ. Olomuc., Fac. Med 74: 167–172.
External links Cannabinoid information
• Bela Szabo: Pharmacology of Cannabinoid Receptors BIOTREND Reviews No. 02, February 2008 • Marijuana and Medicine – Assessing the Science Base (Institute of Medicine) – 1999 at National Academies Press • House of Lords Report – Cannabis (United Kingdom) – 1998 at Parliament of the United Kingdom • Cannabis: A Health Perspective and Research Agenda – 1997 at World Health Organization • Chemical Ecology of Cannabis (J. Intl. Hemp Assn. - 1994)
• Köfalvi, Attila, ed. (2008). “Cannabinoids and the Brain”. doi:10.1007/978-0-387-74349-3. ISBN 978-0-387-74348-6.
• THC (tetrahydrocannabinol) accumulation in glands of Cannabis (Cannabaceae)
• Nicoll, Roger A.; Alger, Bradley E. (2004). “The Brain’s Own Marijuana”. Scientific American 291 (6): 68–75. doi:10.1038/scientificamerican120468. PMID 15597982.
• Therapeutic Potential in Spotlight at Cannabinoid Researchers’ Meeting at California Cannabis Research Medical Group
• Non-psychotropic plant cannabinoids: new thera• Mechoulam, Raphael; Ben-Shabat, Shimon; Hanus, peutic opportunities from an ancient herb Lumir; Ligumsky, Moshe; Kaminski, Norbert E.; Schatz, Anthony R. et al. (1995). “Identification of an endogenous 2-monoglyceride, present 1.9.2 Cannabinoid research organizations in canine gut, that binds to cannabinoid recep• International Cannabinoid Research Society tors”. Biochemical Pharmacology 50 (1): 83– 90. doi:10.1016/0006-2952(95)00109-D. PMID • The Canadian Consortium for the Investigation of 7605349. Cannabinoids
• Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.; Rehnelt, J.; Martín, M. et al. (2008). “Interferonis a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain”. Journal of Neuroscience 28 (46): 12136–45. doi:10.1523/JNEUROSCI.3402-08.2008. PMC 3844840. PMID 19005078.
Chapter 2
Entourage effect Entourage effect is a phrase that was introduced in cannabinoid science in 1998 by S. Ben-Shabat, with Raphael Mechoulam, to represent a novel endogenous cannabinoid molecular regulation route. Biological activity assayed together with inactive compounds. References whole plant and whole person caregiver synergy treatments over isolated compound pharmacological dosages.[1][2][3][4][5][6][7][8]
2.1 External links • Dr. Sanjay Gupta: Medical marijuana and 'the entourage effect'
2.2 References [1] Lee, Martin A. (Sep 13, 2013). Smoke Signals: A Social History of Marijuana-Medical, Recreational and Scientific. Scribner. p. 465. ISBN 978-1439102619. [2] Ben-Shabat, Shimon (July 17, 1998). “An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity”. European Journal of Pharmacology 353 (1): 23–31. doi:10.1016/S0014-2999(98)00392-6. [3] Andersson, Karl-Erik (Feb 4, 2011). Urinary Tract. eBook: Springer Science & Business Media. p. 438. [4] Newnes (March 5, 2010). Comprehensive Natural Products II: Chemistry and Biology:. eBook: Google. p. 220. [5] Guy, Geoffrey William (July 1, 2004). The Medicinal Uses of Cannabis and Cannabinoids (1st ed.). Pharmaceutical Press. p. 114. ISBN 978-0853695172. [6] Castle, David (May 27, 2004). Marijuana and Madness: Psychiatry and Neurobiology. eBook: Google. p. 8. [7] Russo, Ethan B (Aug 2011). “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”. Br J Pharmacol 163 (7): 1344–1364. doi:10.1111/j.1476-5381.2011.01238.x. [8] Gardner, Fred (2011). “Terpenoids, 'minor' cannabinoids contribute to 'entourage effect' of Cannabis-based medicines”. The Journal of Cannavis in Clinical Practice: 1.
11
Chapter 3
Synthetic cannabis its metabolites in human urine. The synthetic cannabinoids contained in synthetic cannabis products have been made illegal in many European countries. On November 24, 2010, the US Drug Enforcement istration announced it would use emergency powers to ban many synthetic cannabinoids within a month.[4] Prior to the announcement, several US states had already made them illegal under state law. In the US, as of March 1, 2011, five cannabinoids, JWH-018, JWH-073, 47,497, JWH-200, and cannabicyclohexanol have been placed on Schedule I of the Controlled Substances Act (and are therefore illegal to possess or use in the US); the Drug Enforcement istration claims that said action is “to avoid an imminent hazard to the public safety.”[5][6] In July 2012, the Synthetic Drug Abuse Prevention Act of A bag of Spice brand herbal incense 2012 was signed into law. It banned synthetic compounds commonly found in synthetic cannabis, placing them unCommercially known as Synthetic cannabis (synthetic der Schedule I of the Controlled Substances Act.[7] marijuana), or technically cannabinoid research chemicals, is any designer drug that mimics the effects of cannabis.[1] There are several psychoactive artificial cannabinoid families (eg AM-xxx, HU-xxx, JWHxxx, xx) that are used as designer drugs sprayed on herbs and sold as natural highs under brand names like K2[2] and Spice,[3] both of which are genericized trade- 3.1 Misnomer marks used for any synthetic cannabis product. Synthetic cannabis is often termed spice product. There is controversy about calling Spice and K2 synthetic When synthetic cannabis blends first went on sale in the cannabis. Synthetic marijuana is a misnomer accordearly 2000s, it was thought that they achieved an effect ing to Lewis Nelson, MD, a medical toxicologist at the through a mixture of natural herbs. Laboratory anal- NYU School of Medicine. “It’s really quite different, ysis in 2008 showed that this is not the case, and that and the effects are much more unpredictable. It’s danthey in fact contain synthetic cannabinoids that act on the gerous, and there is no quality control in what you are body in a similar way to cannabinoids naturally found in getting.”[8] Since the term synthetic does not apply to the cannabis, such as THC. A large and complex variety of plant but rather to the chemical that the plant contains synthetic cannabinoids, most often cannabicyclohexanol, (tetrahydrocannabinol), the term synthetic cannabinoid is JWH-018, JWH-073, or HU-210, are used in an attempt more appropriate.[9] Research on the safety of synthetic to avoid the laws that make cannabis illegal, making syn- cannabinoids is now becoming available. Initial studthetic cannabis a designer drug. It has been sold under ies are focused on the role of synthetic cannabinoids in various brand names, online, in head shops, and at some psychosis. Synthetic cannabis may precipitate psychosis gas stations. and in some cases it may be prolonged. Some studies sugIt is often marketed as "herbal incense"; however, some gest that synthetic cannabinoid intoxication is associated brands market their products as “herbal smoking blends”. with acute psychosis, worsening of previously stable psyIn either case, the products are usually smoked by s. chotic disorders, and it may trigger a chronic (long-term) Although synthetic cannabis does not produce positive re- psychotic disorder among vulnerable individuals such as sults in drug tests for cannabis, it is possible to detect those with a family history of mental illness.[10][11] 12
3.3. SAFETY
3.2 Ingredients Synthetic cannabis is claimed by the manufacturers to contain a mixture of traditionally used medicinal herbs, each of which producing mild effects, with the overall blend resulting in the cannabis-like intoxication produced by the product. Herbs listed on the packaging of Spice include Canavalia maritima (Coastal Jackbean), Nymphaea caerulea (Blue Egyptian water lily), Scutellaria nana (dwarf skullcap), Pedicularis densiflora (Indian warrior), Leonotis leonurus (lion’s tail), Zornia latifolia (maconha brava), Nelumbo nucifera (lotus), and Leonurus sibiricus (honeyweed). However, when the product was analyzed by laboratories in and elsewhere, it was found that many of the characteristic “fingerprint” molecules expected to be present from the claimed plant ingredients were not present. There were also large amounts of synthetic tocopherol present. This suggested that the actual ingredients might not be the same as those listed on the packet, and a German government risk assessment of the product conducted in November 2008 concluded that it was unclear as to what the actual plant ingredients were, where the synthetic tocopherol had come from, and whether the subjective cannabis-like effects were actually produced by any of the claimed plant ingredients or instead caused by a synthetic cannabinoid drug.
3.2.1
Artificial cannabinoids
In January 2009, researchers at the University of Freiburg in announced that an active substance in Spice was an undisclosed analogue of the synthetic cannabinoid 47,497.[12] Later that month, 47,497 along with its dimethylhexyl, dimethyloctyl and dimethylnonyl homologues, were added to the German controlled drug schedules.[13][14] In May the analogue of 47,497 was named cannabicyclohexanol.[15] In July 2010, it was announced that JWH-018 is one of the active components in at least three versions of Spice, which had been sold in a number of countries around the world since 2002, often marketed as incense.[16][17][18][19] Another potent synthetic cannabinoid, HU-210, has been reported to have been found in Spice seized by U.S. Customs and Border Protection.[20] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[21] Different ratios of JWH-018 and 47,497 and their analogues have been found in different brands of synthetic cannabis[22] and manufacturers constantly change the composition of their products.[23] The amount of JWH-018 in Spice has been found to vary from 0.2% to 3%.[24]
13 not produce classical cannabis intoxication effects. This includes substituted cathinone derived stimulant drugs such as 4-methylbuphedrone and 4-methyl-alpha-PPP, and psychedelic tryptamine derivatives such as 4-HODET.[25][26] In 2013 a designer opioid drug AH-7921 was detected in smoking blends in Japan, along with several novel cannabinoids and a cathinone analogue.[27] New Zealand An analysis of 41 different synthetic cannabis blends sold commercially in New Zealand, conducted by the Institute of Environmental Science and Research and released in July 2011, found 11 different synthetic cannabinoid ingredients used: including JWH-018, JWH-073, AM-694, AM-2201, RCS-4, RCS-4 butyl homologue, JWH-210, JWH-081, JWH-250 (or possibly JWH-302, isomer not determined), JWH-203, and JWH-122— with between one and five different active ingredients, though JWH-018 was present in 37 of the 41 blends tested. In two brands the benzodiazepine anxiolytic drug phenazepam was also found, which is classified as a prescription medicine in New Zealand, and so these brands were ordered to be removed from the market by emergency recall.[28][29] Since this time, a further 15 cannabinoid compounds have been detected as ingredients of synthetic cannabis blends in New Zealand and banned as temporary class drugs.[30] In 2013 another hypnotic medication, zaleplon was found to have been used as an active ingredient in a blend that had been sold in New Zealand during 2011-2012.[31]
3.3 Safety No official studies have been conducted on the effects of synthetic cannabinoids on humans (as is usually the case with known toxic and/or illegal compounds).[36] However, reports describing effects seen in patients seeking medical care after taking synthetic cannabinoids have been published. Compared to cannabis and its active cannabinoid THC, the adverse effects are often much more severe and can include hypertension, tachycardia, myocardial infarction,[37] agitation, vomiting, hallucinations, psychoses, seizures, convulsions[38] and panic attacks.[39][40][41][42][43] Among individuals who need emergency treatment after using synthetic cannabis, the most common symptoms are accelerated heartbeat, high blood pressure, nausea, blurred vision, hallucination and agitation.[44] Other symptoms included epileptic seizures, acute psychosis, and heart attacks.[44]
At least one death has been linked to overdose of synthetic cannabinoids[45] and in Colorado three deaths in September 2013 have been investigated for being linked to synthetic cannabinoids.[46] In December 2012, after two weeks of daily synthetic cannabis use, a 17-year old Other non-cannabinoid ingredients have also been found girl suffered multiple strokes and subsequent brain damin synthetic cannabis blends around the world, but they do age, leaving her blind and paralyzed.[47]
14
CHAPTER 3. SYNTHETIC CANNABIS
These more severe adverse effects in contrast to use of 3.5 Legal status marijuana are believed to stem from the fact that many of the synthetic cannabinoids are full agonists to the 3.5.1 Europe cannabinoid receptors, CB1R and CB2R, compared to THC which is only a partial agonist and thus not able Austria The Austrian Ministry of Health announced on to saturate and activate all of the receptor population no December 18, 2008 that Spice would be controlled [48] matter of dose and resulting concentration. It has also under Paragraph 78 of their drug law on the grounds been seen that phase 1 metabolism of JWH-018 results that it contains an active substance that affects the in at least nine monohydroxylated metabolites and with functions of the body, and the legality of JWH-018 at least three of the metabolites shown to have full agois under review.[55][56][57] nistic effect on CB1R which compared to metabolism of THC only results in one psychoactive monohydroxylated JWH-018, 47,497 and the C6, C8 and C9 metabolite. This may further explain the increased toxihomologues of 47,497 are illegal in city of synthetic cannabinoids compared to THC.[45] since January 22, 2009.[14][58] Professor John W. Huffman, who first synthesised many of the cannabinoids used in synthetic cannabis, is quoted Finland Spice blends are classified as a medicine in Finland, and, therefore, it is illegal to order them withas saying, “People who use it are idiots.”[36] “You don't out a prescription. In practice, it is not possible to know what it’s going to do to you.”[49] A who conget a prescription. sumed 3 g of Spice Gold every day for several months showed withdrawal symptoms, similar to those associated with withdrawing from the use of narcotics. Doc- JWH-018, 47,497 (and its homologues) and HU-210 were all made illegal in on February tors treating the also noted that his use of the [50] 24, 2009.[59] product showed signs associated with addiction. One case has been reported wherein a , who had previwith a variety ously suffered from cannabis-induced recurrent psychotic Ireland From June 2010, JWH-018, along [60] of other designer drugs, is illegal. episodes, suffered reactivation of his symptoms after using Spice. Psychiatrists treating him have suggested Latvia JWH-018, JWH-073, 47,497 (and its homothat the lack of an antipsychotic chemical, similar to logues) and HU-210 are all banned in Latvia as well cannabidiol found in natural cannabis, may make synas leonotis leonurus.[61] thetic cannabis more likely to induce psychosis than natural cannabis.[51] Poland JWH-018 and many of the herbs mentioned on the ingredient lists of Spice and similar preparaStudies are currently available which suggest an assotions were made illegal in May 2009. The bill was ciation between synthetic cannabinoids and psychosis. ed by Polish Sejm,[62][63] Polish Senat[64] and Physicians should be aware that the use of synthetic was signed by the President.[65] cannabinoids can be associated with psychosis and investigate possible use of synthetic cannabinoids in patients with inexplicable psychotic symptoms. In contrast Romania Spice was made illegal in Romania on February 15, 2010.[66] to most other recreational drugs, the dramatic psychotic state induced by use of synthetic cannabinoids has been reported in multiple cases to persist for several weeks, Russia On April 9, 2009, the Chief Medical Officer of the Russian Federation issued a resolution on reand in one case for seven months, after complete cessa[52] inforcing control over the sales of smoking blends. tion of drug use. Individuals with risk factors for psyThese blends, marketed under the trade names AMchotic disorders should be counseled against using syn[53] HI-CO, Dream, Spice (Gold, Diamond), Zoom, Exthetic cannabinoids. ses, Yucatán Fire and others, have been declared to contain Salvia divinorum, Hawaiian Wood Rose, and Blue Lotus, and are prohibited to be sold. These substances have been found to have “psychotropic, 3.4 Drug testing narcotic effects, contain poisonous components and represent potential threat for humans”. The resoluSpice does not cause a positive drug test for cannabis tion does not mention JWH-018 or other synthetic or other illegal drugs using GC-MS-screening with cannabinoids.[67] On January 14, 2010, the Russian library search, multi-target screening by LC-MS/MS, government issued a statement including 23 synor immunological screening procedures.[22][50] A study thetic cannabinoids found in smoking blends Hawaihas been conducted into the detection of metabolites of ian Rose and Blue Lotus on the list of prohibited JWH-018 in urine; the metabolites are mainly conjugates narcotic and psychotropic substances. Thus, all of with glucuronic acid and can be reliably detected by GC– these plants and compounds are now illegal in the MS/MS and LC–MS/MS.[54] Russian Federation.[68]
3.5. LEGAL STATUS Slovakia Spice is legal in Slovakia. The National AntiDrug Unit is considering adding it to the list of controlled substances.[69] The latest anti-drug law version (468/2009) valid since January 2010 still does not mention active compounds of Spice.[70]
15 ed on September 18, 2013 that bans entire families of synthetic drugs instead of only banning existing compounds that have been identified.[82][83] The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.[83]
Sweden 47,497-C6, 47,497-C7, 47,497-C8, 47,497-C9, JWH-018, JWH-073 and HU-210 it is claswere all made illegal in Sweden on September 15, New Zealand Spice is illegal in New Zealand, [84] sified as a Class C controlled drug. The New 2009. The bill was accepted on July 30, 2009 and Zealand Parliament ed a law in July 2013 ban[71] was put in effect on September 15, 2009. ning the sale of legal highs in dairies and supermarkets, but allowing some “low risk” drugs to continue Switzerland Spice has been banned in Switzerland.[72] to be sold through speciality licensed shops.[85] SynTurkey Spice a.k.a Bonzai added to the list of drugs thetic cannabinoids, as well as all other 'legal highs’ and psychotropic substances in 07.01.2011 by the were outlawed at midnight on 7 May 2014, after a law which numbered as 2011/1310 B.K.K. (Februlaw was ed a week prior by the New Zealand ary 13, 2011 and the Official Gazette No. 27845) government.[86] [73]
United Kingdom Spice was legal in the United King3.5.5 North America dom until December 2009, when it was classified as [74] a Class B drug. Canada
3.5.2
South America
Chile The Chilean Ministry of Health on April 24, 2009 declared the sale of synthetic cannabis to be illegal.[75]
Spice and specific forms of JWHxxx are not specifically prohibited in Canada, but synthetic cannabis is listed as a schedule II drug.[87][88] Health Canada is debating on the subject.[89][90] United States
3.5.3
Asia
See also: JWH-018 § United States South Korea South Korea officially added JWH-018, 47,497 and HU-210 to the controlled substance The case of David Mitchell Rozga, an American teenager list on July 1, 2009, effectively making these chem- from Indianola, Iowa, United States, brought internaicals illegal.[76] tional attention to K2. Rozga shot himself in the head Japan Japan has banned JWH-018, 47, 497, and ho- with a family owned hunting rifle in an apparent suicide in June 6, 2010. After news of Rozga’s death, it was remologues, and HU-210 since October 2009 ported by friends that they had smoked K2 with Rozga United Arab Emirates The United Arab Emirates had approximately one hour before his death. The nature of stated that Spice was an illegal substance and posses- his death and reports from numerous family , sion or intent to sell would be a jailable offense.[77] had led investigators to believe that it was likely Rozga was under the influence of a mind-altering substance, at the time of his death. The death of Rozga has been used 3.5.4 Australasia as a face of political lobbying against the continuation of K2, and other legal synthetic drugs, such as bath salts.[91] Australia On June 17, 2011, the Western Australian government banned all of the synthetic cannabi- Following the incident, an act to ban the use and distribunoids found in already existing products, including tion of the drug was proposed by the US Senator Chuck brands such as Kronic, Kalma, Voodoo, Kaos, and Grassley of Iowa as the David Mitchell Rozga Act. It was legislation by the United States Congress Mango Kush. Western Australia was the first state approved into [92] in June 2011. On July 10, 2012, President Barack in Australia to prohibit the sale of certain synthetic signed the Synthetic Drug Abuse Prevention Act Obama [78][79] On June 18, 2013, an interim cannabinoids. of 2012 into law. It banned synthetic compounds comban made a large list of product brands and synthetic monly found in synthetic marijuana, placing them under [80] substances illegal to sell anywhere in Australia. Schedule I of the Controlled Substances Act.[7] This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[81] Synthetic Prior to that, some compounds within synthetic cannabis cannabis remains illegal in NSW, where a bill was (HU-210) were scheduled in the USA under federal law,
16 while others (JWH-073) have been temporarily scheduled until final determination of their status can be made.[93][94][95][96] The Drug Enforcement istration (DEA) considers it to be a “drug of concern”,[97] citing "...a surge in emergency-room visits and calls to poison-control centers. Adverse health effects associated with its use include seizures, hallucinations, paranoid behavior, agitation, anxiety, nausea, vomiting, racing heartbeat, and elevated blood pressure.”[98][99] Several states independently ed acts making it illegal under state law, including Kansas in March 2010,[100] Georgia and Alabama in May 2010,[101][102] Tennessee and Missouri in July 2010,[103][104] Louisiana in August 2010, Mississippi in September 2010, and Iowa.[105] An emergency order was ed in Arkansas in July 2010 banning the sale of synthetic cannabis.[106] In October 2010, the Oregon Board of Pharmacy listed synthetic cannabinoid chemicals on its Schedule 1 of controlled substance, which means that the sale and possession of these substances is illegal under the Oregon Uniform Controlled Substances Act.[107] According to the National Conference of State Legislatures, several other states are also considering legislation, including New Jersey, New York, Florida, and Ohio.[104] Illinois ed a law on July 27, 2010 banning all synthetic cannabinoids that goes into effect January 1, 2011.[108] Michigan banned synthetic cannabinoids in October 2010,[109] and the South Dakota Legislature ed a ban on these products which was signed into law by Gov. Dennis Daugaard on February 23, 2012 (and which took immediate effect under an emergency clause of the state constitution).[110] Indiana banned synthetic cannabinoids in a law which became effective in March 2012.[111] North Carolina banned synthetic cannabis by a unanimous vote of the state senate, due to concerns that its contents and effects are reasonably similar to natural cannabis, and may cause equal effects in of psychological dependency.[112][113] Following cases in Japan involving the use of synthetic cannabis by Navy, Army and Marine Corps personnel resulted in the official banning of it,[114] a punitive general order issued on January 4, 2010 by the Commander Marine Corps Forces, Pacific prohibits the actual or attempted possession, use, sale, distribution or manufacture of synthetic cannabis as well as any derivative, analogue or variant of it.[115] On June 8, 2010, the U.S. Air Force issued a memorandum that banned the possession and use of Spice, or any other mood-altering substance except alcohol or tobacco, among its service .[116] On November 24, 2010, the DEA announced that it would make JWH-018, JWH-073, JWH-200, 47,497, and cannabicyclohexanol, which are often found in synthetic cannabis, illegal using emergency powers.[117] They will be placed in Schedule I of the Controlled Substances Act, within a month of the announcement, and the ban will last for at least a year.[118][119] The temporary ban, for at least a year, came into effect on
CHAPTER 3. SYNTHETIC CANNABIS March 1, 2011.[120] On October 20, 2011, the Louisiana State University football program announced that it had suspended three players, including star cornerback Tyrann Mathieu, who tested positive for synthetic cannabis.[121]
3.6 History According to the Psychonaut Web Mapping Research Project, synthetic cannabis products, sold under the brand name Spice, first appeared in Europe in 2004.[122] The brand “Spice” was released in 2004 by the now-dormant company The Psyche Deli in London, UK. In 2006 the brand gained popularity. According to the Financial Times, the assets of The Psyche Deli rose from £65,000 in 2006 to £899,000 in 2007.[123] The EMCDDA reported in 2009 that 'Spice' products were identified in 21 of the 30 participating countries. Because 'Spice' was the dominant brand until 2009, the competing brands that started to appear from 2008 on were also dubbed 'Spice'. Spice can, therefore, refer to both the brand 'Spice', as to all herbal blends with synthetic cannabinoids added. A survey of readers of Mixmag in the UK in 2009 found that one in eight respondents had used synthetic cannabis, compared to 85% who had used cannabis.[124]
3.6.1 Slang In addition to K2 and Spice, other street names include Black Mamba (Turnera diffusa), Bombay Blue, Genie, and Zohai.[7] According to Partnership at Drugfree.org, other names also include Bliss, Blaze, JWH −018, −073, −250, Yucatan Fire, Skunk, Moon Rocks[125] and Bonzai (esp. in Turkey)[73]
3.7 References [1] Roland Macher; Tod W. Burke, Ph.D, Stephen S. Owen, Ph.D. “Synthetic Marijuana”. FBI Law Enforcement Bulletin. Retrieved 22 July 2012. [2] Mary Carmichael (March 4, 2010). “K2: Scary Drug or Another Drug Scare?". Newsweek. Retrieved November 24, 2010. [3] “What’s the buzz?: Synthetic marijuana, K2, Spice, JWH018 : Terra Sigillata”. Scienceblogs.com. Retrieved November 24, 2010. [4] Grim, Ryan (November 24, 2010). “K2 Crackdown: DEA Using Emergency Powers To Ban Fake Pot”. The Huffington Post. Retrieved November 25, 2010. [5] Jeanne Meserve (February 28, 2011). “DEA imposes “emergency” ban to control synthetic marijuana”. CNN.
3.7. REFERENCES
[6] Citing Imminent Hazard to Public Safety, DEA Temporarily Places Synthetic Cannabinoids Into Schedule I [7] Vashi, Sonam (September 26, 2012). K2 Trend Not Slowing Down WebMD Medical News via KOKI-TV [8] http://www.npr.org/blogs/health/2012/03/30/ 149679528/new-york-bans-synthetic-marijuana [9] www.emed-journal.com Lapoint J, Nelson LS. Synthetic Cannabinoids: The Newest, Almost Illicit Drug of Abuse. Emergency Medicine 2011;43(2):26-28 [10] Cannabis, synthetic cannabinoids, and psychosis risk: What the evidence says [11] Synthetic Cannabis May Pose an Even Greater Psychosis Risk [12] 19, 2009.19/ Hauptwirkstoff von “Spice Girl” identifiziert. W was here. January 19, 2009 (German) [13] “Modedroge “Spice” ist verboten!" (in German). Bmg.bund.de. March 10, 2009. Retrieved August 24, 2010. [14] BGBl I Nr. 3 vom January 21, 2009, 22. BtMÄndV vom 19. Jan 2009, S. 49–50. [15] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda Y (May 2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1–3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892. [16] “Gefährlicher Kick mit Spice (German)". Fr-online.de. Retrieved August 24, 2010. [17] “Erstmals Bestandteile der Modedroge “Spice” nachgewiesen (German)". Haz.de. Retrieved August 24, 2010. [18] “Spice enthält chemischen Wirkstoff (German)". Badische-zeitung.de. Retrieved August 24, 2010. [19] Schifano, F.; Corazza, O.; Deluca, P.; Davey, Z.; Di Furia, L.; Farre', M.; Flesland, L.; Mannonen, M.; Pagani, S.; Peltoniemi, T.; Pezzolesi, C.; Scherbaum, N.; Siemann, H.; Skutle, A.; Torrens, M.; Van Der Kreeft, P. (2009). “Psychoactive drug or mystical incense? Overview of the online available information on Spice products”. International Journal of Culture and Mental Health 2 (2): 137. doi:10.1080/17542860903350888. [20] “Spice” – Plant material(s) laced with synthetic cannabinoids or cannabinoid mimicking compounds (U.S. Drug Enforcement istration) [21] Lindigkeit, Rainer; Boehme, A; Eiserloh, I; Luebbecke, M; Wiggermann, M; Ernst, L; Beuerle, T (October 30, 2009). “Spice: A never-ending story?". Forensic Science International 191 (1): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [22] Auwärter, V., et al. (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. Free version
17
[23] Emanuel, C. E. J.; Ellison, B.; Banks, C. E. (2010). “Spice up your life: screening the illegal components of ‘Spice’ herbal products”. Analytical Methods 2 (6): 614. doi:10.1039/c0ay00200c. [24] Stafford, Ned. Synthetic Cannabis Mimic Found in Herbal Incense. Royal Society of Chemistry: Chemistry World. January 15, 2009. Accessed: June 17, 2010 [25] Kikura-Hanajiri, R.; Uchiyama, N.; Goda, Y. (2011). “Survey of current trends in the abuse of psychotropic substances and plants in Japan”. Legal Medicine 13 (3): 109–115. doi:10.1016/j.legalmed.2011.02.003. PMID 21377397. [26] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [27] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [28] Whitworth, Chris (July 7, 2011). “Kronic ingredients secret to stop industry 'cowboys’". 3 News. Retrieved November 16, 2011. [29] 'Herbal High' synthetic Cannabinoid composition, released by ESR July 2011. (PDF) . Retrieved on August 7, 2011. [30] Temporary Class Drug Notices. New Zealand Ministry of Health [31] Conviction for sale of herbal smoking material containing a prescription medicine. MedSafe Media release, 28 March 2013 [32] Aung, M. M.; Griffin, G.; Huffman, J. W.; Wu, M. J.; Keel, C.; Yang, B.; Showalter, V. M.; Abood, M. E.; Martin, B. R. (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [33] Devane, W. A., et al. (1992). “A novel probe for the cannabinoid receptor”. Journal of Medical Chemistry 35 (11): 2065–2069. doi:10.1021/jm00089a018. PMID 1317925. [34] Compton, D.; Johnson, M.; Melvin, L.; Martin, B. (1992). “Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents”. The Journal of Pharmacology and Experimental Therapeutics 260 (1): 201–209. PMID 1309872. [35] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted June 7, 2001
18
[36] “Fake pot that acts real stymies law enforcement”. Associated Press. February 17, 2010. Retrieved April 21, 2010. [37] Mir, A; Obafemi, A; Young, A; Kane, C (December 2011). “Myocardial infarction associated with use of the synthetic cannabinoid k2.”. Pediatrics 128 (6): e1622–7. doi:10.1542/peds.2010-3823. PMID 22065271. [38] Schneir, AB; Baumbacher, T (December 13, 2011). “Convulsions Associated with the Use of a Synthetic Cannabinoid Product.”. Journal of Medical Toxicology 8 (1): 62–4. doi:10.1007/s13181-011-0182-2. PMID 22160733. [39] Jeanna Bryner (March 3, 2010). “Fake Weed, Real Drug: K2 Causing hallucinations in Teens”. LiveScience. Retrieved April 21, 2010. [40] Vardakou, I; Pistos, C; Spiliopoulou, Ch (2010). “Spice drugs as a new trend: Mode of action, identification and legislation”. Toxicology Letters 197 (3): 157–62. doi:10.1016/j.toxlet.2010.06.002. PMID 20566335. [41] Auwärter, V., et al. (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. [42] Every-Palmer, S (2010). “Warning: Legal synthetic cannabinoid-receptor agonists such as JWH-018 may precipitate psychosis in vulnerable individuals”. Addiction 105 (10): 1859–60. doi:10.1111/j.13600443.2010.03119.x. PMID 20840203. [43] Müller, H.; Sperling, W.; Köhrmann, M.; Huttner, H.; Kornhuber, J.; Maler, J. (2010). “The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes”. Schizophrenia research 118 (1–3): 309–310. doi:10.1016/j.schres.2009.12.001. PMID 20056392. [44] “Legal highs linked to psychosis”. New Zealand Herald. Apr 5, 2014. [45] Brents, L. K.; Reichard, E. E.; Zimmerman, S. M.; Moran, J. H.; Fantegrossi, W. E.; Prather, P. L. (2011). “Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity”. PLoS ONE 6 (7): e21917. doi:10.1371/journal.pone.0021917. PMC 3130777. PMID 21755008. [46] Coffman, K. (6 September 2013). “Colorado probes three deaths possibly linked to synthetic marijuana”. Reuters (Denver). Retrieved 30 January 2014. [47] Taylor, V. (14 September 2013). “Teen makes miraculous progress nine months after synthetic marijuana nearly kills her”. NY Daily News. Retrieved 30 January 2014. [48] Fantegrossi, W. E.; Moran, J. H.; Radominska-Pandya, A; Prather, P. L. (2014). “Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9 -THC: Mechanism underlying greater toxicity?". Life Sciences 97 (1): 45–54. doi:10.1016/j.lfs.2013.09.017. PMID 24084047.
CHAPTER 3. SYNTHETIC CANNABIS
[49] “Fake Weed, Real Drug: K2 Causing Hallucinations in Teens”. LiveScience. Retrieved November 24, 2010. [50] Zimmermann, U., et al. (2009). “Withdrawal phenomena and dependence syndrome after the consumption of “spice gold"". Deutsches Arzteblatt international 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [51] Müller, H.; Sperling, W.; Köhrmann, M.; Huttner, H.; Kornhuber, J.; Maler, J. (2010). “The synthetic cannabinoid Spice as a trigger for an acute exacerbation of cannabis induced recurrent psychotic episodes”. Schizophrenia research 118 (1–3): 309–310. doi:10.1016/j.schres.2009.12.001. PMID 20056392. [52] Hurst, D; Loeffler, G; McLay, R (October 2011). “Psychosis associated with synthetic cannabinoid agonists: a case series.”. The American Journal of Psychiatry 168 (10): 1119. doi:10.1176/appi.ajp.2011.11010176. PMID 21969050. [53] Every-Palmer, S (September 1, 2011). “Synthetic cannabinoid JWH-018 and psychosis: an explorative study.”. Drug and alcohol dependence 117 (2-3): 152–7. doi:10.1016/j.drugalcdep.2011.01.012. PMID 21316162. [54] Sobolevsky, T.; Prasolov, I.; Rodchenkov, G. (2010). “Detection of JWH-018 metabolites in smoking mixture post-istration urine”. Forensic Science International 200 (1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [55] “Kräutermischung “Spice": Gesundheitsministerium stoppt Handel, December 18, 2008”. Derstandard.at. December 19, 2008. Retrieved June 19, 2010. [56] (AFP) (December 18, 2008). “Austria bans herbal incense 'Spice'". Google. Retrieved June 19, 2010. [57] “Gesundheitsministerium setzt Maßnahme zum Verbot von “Spice"". Bmgfj.gv.at. December 18, 2008. Retrieved June 19, 2010. [58] “Betäubungsmittelrecht: Modedroge Spice wird per Eilverordnung verboten”. Der Spiegel. Retrieved June 19, 2010. [59] “Arrêté du 24 février 2009 modifiant l’arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants”. Journal Officiel De La République Française. February 27, 2009. Retrieved June 19, 2010. [60] “Move on head shops 'not enough' – The Irish Times — Wed, Mar 3, 2010”. The Irish Times. March 3, 2010. Retrieved August 24, 2010. [61] “Noteikumi par Latvijā kontrolējamajām narkotiskajām vielām, psihotropajām vielām un prekursoriem” (in Latvian). likumi.lv. Retrieved June 19, 2010. [62] http://orka.sejm.gov.pl/Druki6ka.nsf/wgdruku/1547 [63] mm, PAP (February 12, 2009). “Sejm za delegalizacją 'dopalaczy'". Wiadomosci.gazeta.pl. Retrieved June 19, 2010.
3.7. REFERENCES
[64] “Senat poparł ustawę zakazującą handlu “dopalaczami” – Wiadomości — WP.PL”. Wiadomosci.wp.pl. Retrieved June 19, 2010. [65] http://www.prezydent.pl/x.node?id=26543130 [66] “OUG 6/2010 pentru modificarea si completarea Legii nr. 143/2000 privind prevenirea si combaterea traficului si consumului ilicit de droguri si pentru completarea Legii nr. 339/2005 privind regimul juridic al plantelor, substantelor si preparatelor stupefiante si psihotrope. Ordonanta de urgenta nr. 6/2010”. Dreptonline.ro. August 3, 2000. Retrieved June 19, 2010. [67] "О запрещении реализации продукции с содержанием шалфея предсказателей, гавайской розы и голубого лотоса". Rospotrebnadzor.ru. Retrieved June 19, 2010. [68] "Постановление от 31 декабря 2009 г. № 1186 О внесении изменений в некоторые постановления Правительства Российской Федерации по вопросам, связанным с оборотом наркотических средств". Government.ru. Retrieved June 19, 2010. [69] “Po ketamíne by sa mala zakázať bylinná zmes Spice”. SME.sk. Retrieved June 19, 2010. [70] [71] “Regeringen förbjuder nätdrogen “Spice” from the website of the Government Offices of Sweden”. Regeringen.se. Retrieved June 19, 2010. [72] Adams, Stephen (February 13, 2009). “Teens in Britain getting legally high on synthetic cannabis banned across Europe”. The Daily Telegraph (UK). Retrieved August 13, 2009. [73] “Sentetik Cannabinoid (Bonzai)". www. uyusturucumaddeler.com. Retrieved 12 August 2014. [74] Portal, Gaetan (December 23, 2009). "'Legal high' drugs banned in UK”. BBC News. Retrieved May 23, 2010. [75] “Chile prohibe uso de spice, La Nacion 24 de Abril 2009”. Lanacion.cl. Retrieved June 19, 2010. [76]
(July 2, 2009). “1 '5- - ’ " (in Korean). . Retrieved February 18, 2010.
[77] Dubai Customs foil 126 attempts to smuggle narcotic [78] Jerga, Josh (June 13, 2011). “Fake cannabis to be outlawed in WA”. The Sydney Morning Herald. Retrieved June 15, 2011. [79] O'Brien, Amanda (April 11, 2011). “Miners working high on synthetic grass”. The Australian. Retrieved April 17, 2011.
19
[82] “NSW law to ban synthetic drugs ed”. September 18, 2013. Retrieved October 28, 2013. [83] Coultan, Mark (September 10, 2013). “NSW law to ban synthetic drugs to stop 'legal highs’". The Australian. Retrieved October 28, 2013. [84] “Cannabis substitute “Spice” now illegal”. TVNZ. April 1, 2009. Retrieved March 2, 2011. [85] Heather, Ben (October 6, 2013). “Kronic king gets the green light”. Retrieved October 28, 2013. [86] “Legal highs banned from midnight”. May 7, 2014. Retrieved May 8, 2014. [87] “Controlled Drugs and Substances Act”. Laws.justice.gc.ca. November 15, 2010. Retrieved November 24, 2010. [88] “Consolidated Index of Drugs and Substances”. Isomerdesign.com. April 24, 2010. Retrieved June 19, 2010. [89] “Ian Bussières : Le spice: la capitale craque pour les “herbes magiques” | Société". Cyberpresse.ca. Retrieved June 19, 2010. [90] “Une pilule une petite granule : Le Spice, un substitut au cannabis ?". Pilule.telequebec.tv. Retrieved June 19, 2010. [91] “K2 Drug Facts”. K2drugfacts.com. Retrieved 2012-0909. [92] “The David Mitchell Rozga Act (S.605 - Dangerous Synthetic Drug Control Act of 2011)". Opencongress.org. Retrieved 2012-09-09. [93] “HU-210”. USDOJ.gov. Retrieved September 16, 2010. [94] Cook, Morgan (February 28, 2011). “Synthetic marijuana illegal as of Tuesday”. North County Times (San Diego). Retrieved February 28, 2011. [95] [96] “Drug Scheduling from the US Drug Enforcement istration website”. Justice.gov. Retrieved June 19, 2010. [97] Donna Leinwand (May 24, 2010). 24, 2010-k2_N.htm “Places race to outlaw K2 'Spice' drug”. USA Today. Retrieved July 26, 2010. [98] Meserve, Jeanne (February 28, 2011). “DEA imposes “emergency” ban to control synthetic marijuana”. CNN. Retrieved March 1, 2011. [99] Ben Paynter: The Big Business of Synthetic Highs, Bloomerg Businessweek June, 2011
[80] Bradbury, David (June 18, 2013). “Competition and Consumer Act 2010 - Consumer Protection Notice No. 3 of [100] The Associated Press. How major issues fared in Kansas Legislature. CNBC. May 23, 2010. Accessed: May 23, 2013 - Imposition of Interim Ban on Certain Consumer 2010 Goods Containing Synthetic Drug Substances”. Retrieved October 28, 2013. [101] Simmons, Andria (May 24, 2010). “Governor signs bill [81] “Synthetic drug substances - national interim ban”. to outlaw synthetic marijuana”. ajc.com. Retrieved June ACCC. Retrieved October 28, 2013. 19, 2010.
20
CHAPTER 3. SYNTHETIC CANNABIS
[102] May 20, 2010 (May 20, 2010). “Alabama Coalition Gets [120] Meserve, Jeanne (February 28, 2011). “DEA imposes Salvia and K2 Banned in Their State”. CADCA. Re“emergency” ban to control synthetic marijuana”. CNN. trieved August 24, 2010. Retrieved March 1, 2011. [103] Haas, Brian. 'K2', 'K3' synthetic drugs are illegal in TN [121] Schlabach, Mark (October 20, 2011). “Sources: LSU starting July 1. The Tennessean. May 30, 2010. Alayers had positive tests”. ESPN.com. Retrieved Novemcessed: June 17, 2010 ber 4, 2011. [104] Gay, Malcolm. (2010-07-10) Synthetic Marijuana Spurs [122] Spice Report Psychonaut Web Mapping Research Project State Bans. New York Times. Retrieved on August 7, [123] “The story of Spice”. Financial Times. February 13, 2011. 2009. Retrieved September 19, 2010. [105] Iowa Code § 124.204(4)(u) (defining a Schedule I controlled substance to include “synthetic equivalents of the [124] Winstock, A.; Mitcheson, L.; Deluca, P.; Davey, Z.; Corazza, O.; Schifano, F. (2010). “Mephedrone, new substances contained in the Cannabis plant, or in the kid for the chop?". Addiction (Abingdon, England) 106 resinous extractives of such plant, and synthetic sub(1): 154–161. doi:10.1111/j.1360-0443.2010.03130.x. stances, derivatives, and their isomers with similar chemPMID 20735367. ical structure and pharmacological activity to those substances contained in the plant....”) [125] K2 – Spice via Partnership at Drugfree.org [106] Gavin Lesnick (July 2, 2010). “Beebe signs emergency ban on K2”. Arkansas Online (Arkansas Democrat Gazette). Retrieved July 26, 2010.
3.8 External links
[107] “Synthetic Cannabis — Controlled Substance Information”. Retrieved October 16, 2010.
• Erowid
[108] Daniel Martynowicz. “Illinois Bans Synthetic Cannabinoids”. Retrieved September 14, 2010.
• Synthetic cannabinoid profile European Monitoring Centre for Drugs and Drug Addiction
[109] http://www.michigan.gov/lara/0,4601,7-154-10573_ 11472-280858--,00.html [110] Argus Leader, "New law bans synthetic drugs,” by John Hult (February 23rd 2012 - retrieved on May 14th, 2012). [111] http://www.in.gov/attorneygeneral/2974.htm [112] “NC Senate OKs synthetic pot ban”. WRAL-TV. 10 February 2011. Retrieved 27 September 2012. [113] “Make Synthetic Cannabinoids Illegal”. General Assembly of North Carolina. 31 January 2011. Retrieved 27 September 2012. [114] Allan, David; Fisher, Cindy. Ruling Clarifies 'Legal' Drug Policy. Stars and Stripes via Military.com. May 23, 2010. Accessed: May 23, 2010 [115] Marines Ban Spice Drug. Military.com. May 23, 2010. Accessed: May 23, 2010 [116] “Air Force officials ban use and possession of spice, mood-altering substances. Air Force News. June 17, 2010. Accessed: June 18, 2010”. Af.mil. Retrieved June 19, 2010. [117] “DEA Moves to Emergency Control Synthetic Marijuana”. DEA Public Affairs. U.S. Drug Enforcement istration. November 24, 2010. Retrieved February 19, 2011. [118] Grim, Ryan (November 24, 2010). “K2 Crackdown: DEA Using Emergency Powers To Ban Fake Pot”. Huffington Post. Retrieved November 24, 2010. [119] By the CNN Wire Staff (November 24, 2010). “Feds move to ban 'fake pot'". CNN. Retrieved November 24, 2010.
Chapter 4
4-HTMPIPO 4-HTMPIPO is a synthetic cannabinoid drug first identified in smoking products purchased from online vendors in 2012.[1] 4-HTMPIPO is the product resulting from the electrophilic addition of water to the cyclopropane moiety of synthetic cannabinoid UR-144.[1] Nothing is known about the in vitro or in vivo pharmacology of 4HTMPIPO.
4.1 See also • AB-001 • JWH-018 • UR-144 • XLR-11
4.2 References [1] Kavanagh, P.; Grigoryev, A.; Savchuk, S.; Mikhura, I.; Formanovsky, A. (2013). “UR-144 in products soldviathe Internet: Identification of related compounds and characterization of pyrolysis products”. Drug Testing and Analysis: n/a. doi:10.1002/dta.1456.
21
Chapter 5
5F-PB-22 5F-PB-22 or Quinolin-8-yl 1-(5-fluoropentyl)−1Hindole-3-8-carboxylate is a designer drug and a possible cannabinoid agonist. The structure of 5F-PB-22 appears to have been designed with an understanding of structure-activity relationships within the indole class of cannabinoids on the Forendex website of potential drugs of abuse.[1] In January 2014, 5F-PB-22 was designated as a Schedule I controlled substance in the United States.[2]
5.1 See also • AM-2201 • JWH-018 • QUCHIC • QUPIC • SDB-001
5.2 References [1] 5F-PB-22 page on Forendex [2] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G; Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C (2014). “Four Postmortem Case Reports with Quantitative Detection of the Synthetic Cannabinoid, 5F-PB-22”. Journal of analytical toxicology. doi:10.1093/jat/bku048. PMID 24876364.
22
Chapter 6
A-40174 A-40174 (SP-1) is an analgesic drug which acts as a potent cannabinoid receptor agonist, and was developed by Abbott Laboratories in the 1970s.[1]
6.1 See also • A-41988 • Menabitan
6.2 References [1] Reggio, Patricia H., ed. (2009). “The Cannabinoid Receptors”. doi:10.1007/978-1-59745-503-9. ISBN 978-158829-712-9.
23
Chapter 7
A-41988 A-41988 (BW29Y) is an analgesic drug which acts as a cannabinoid agonist. It was developed by Abbott Laboratories in the 1970s,[1][2] and researched for potential use in the treatment of glaucoma,[3] but never commercialised.
7.1 See also • A-40174 • Menabitan
7.2 References [1] Winn, M.; Arendsen, D.; Dodge, P.; Dren, A.; Dunnigan, D.; Hallas, R.; Hwang, K.; Kyncl, J.; Lee, Y. H.; Plotnikoff, N.; Young, P.; Zaugg, H. (1976). “Drugs derived from cannabinoids. 5. Delta6a,10aTetrahydrocannabinol and heterocyclic analogs containing aromatic side chains”. Journal of Medicinal Chemistry 19 (4): 461–471. doi:10.1021/jm00226a003. PMID 817021. [2] Guterman A, Somani P, Bachand RT. Clinical Pharmacology and Therapeutics 1979; 25:227. [3] Tiedeman, J. S.; Shields, M. B.; Weber, P. A.; Crow, J. W.; Cocchetto, D. M.; Harris, W. A.; Howes, J. F. (1981). “Effect of synthetic cannabinoids on elevated intraocular pressure”. Ophthalmology 88 (3): 270–277. doi:10.1016/s0161-6420(81)35052-0. PMID 7015221.
24
Chapter 8
A-796,260 A-796,260 is a drug developed by Abbott Laboratories that acts as a potent and selective cannabinoid CB2 receptor agonist. Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids with the 3-tetramethylcyclopropylmethanone group, imparts significant selectivity for CB2 , and A-796,260 was found to be a highly selective CB2 agonist with little affinity for CB1 , having a CB2 Kᵢ of 4.6 nM vs 945 nM at CB1 .[1] It has potent analgesic and anti-inflammatory actions in animal models, being especially effective in models of neuropathic pain, but without producing cannabis-like behavioral effects.[2]
8.1 See also • A-834,735 • A-836,339 • JWH-200 • UR-144 • XLR-11
8.2 References [1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781. [2] Yao BB, et al. (January 2008). “In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models”. British Journal of Pharmacology 153 (2): 390–401. doi:10.1038/sj.bjp.0707568. PMC 2219533. PMID 17994110.
25
Chapter 9
A-834,735 A-834,735 is a drug developed by Abbott Laboratories that acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors, with a Kᵢ of 12nM at CB1 and 0.21nM at CB2 . Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids, with the 3tetramethylcyclopropylmethanone group of A-834,735 and related compounds, imparts significant selectivity for CB2 , with most compounds from this group found to be highly selective CB2 agonists with little affinity for CB1 . However low nanomolar CB1 binding affinity is retained with certain heterocyclic 1-position substituents such as (N-methylpiperidin-2-yl)methyl (cf. AM-1220, AM1248), or the (tetrahydropyran-4-yl)methyl substituent of A-834,735, resulting in compounds that still show significant affinity and efficacy at both receptors despite being CB2 selective overall.[1][2][3][4][5]
9.1 See also • A-796,260 • AB-001 • JTE 7-31 • UR-144 • XLR-11
9.2 References [1] Dart M, et al. (2006). 1-Alkyl-3-keto-indoles: identification and in vitro characterization of a series of potent cannabinoid ligands. In 2006 Symposium on the Cannabinoids. International Cannabinoid Research Society: Burlington, VT. [2] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473.
26
[3] Chin CL, et al. (January 2008). “Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI”. British Journal of Pharmacology 153 (2): 367–79. doi:10.1038/sj.bjp.0707506. PMC 2219521. PMID 17965748. [4] Frost, J. M., et al. (2008). “Indol-3-yltetramethylcyclopropyl Ketones: Effects of Indole Ring Substitution on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 51 (6): 1904. doi:10.1021/jm7011613. PMID 18311894. [5] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781.
Chapter 10
A-836,339 A-836,339 is a drug developed by Abbott Laboratories that acts as a potent cannabinoid receptor full agonist. It is selective for CB2 , with Kᵢ values of 0.64nM at CB2 vs 270nM at the psychoactive CB1 receptor, but while it exhibits selective analgesic, anti-inflammatory and antihyperalgesic effects at low doses,[1] its high efficacy at both targets results in typical cannabis-like effects appearing at higher doses, despite its low binding affinity for CB1 .[2]
10.1 References [1] McGaraughty, S., et al. (2009). “A CB(2) receptor agonist, A-836339, modulates wide dynamic range neuronal activity in neuropathic rats: contributions of spinal and peripheral CB(2) receptors”. Neuroscience 158 (4): 1652– 1661. doi:10.1016/j.neuroscience.2008.11.015. PMID 19063946. [2] Yao, B., et al. (2009). “Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 2,2,3,3tetramethyl-cyclopropanecarboxylic acid 3-(2-methoxyethyl)−4,5-dimethyl-3H-thiazol-(2Z)-ylidene-amide, using in vitro pharmacological assays, in vivo pain models, and pharmacological magnetic resonance imaging”. The Journal of Pharmacology and Experimental Therapeutics 328 (1): 141–151. doi:10.1124/jpet.108.145011. PMID 18931146.
27
Chapter 11
AB-001 AB-001 or 1-pentyl-3-(1-adamantoyl)indole is a designer drug that was found as an ingredient in synthetic cannabis smoking blends in Ireland in 2010 and Hungary and in 2011.[1][2][3] It is unclear who AB-001 was originally developed by, but it is structurally related to compounds such as AM-1248 and its corresponding 1-(tetrahydropyran-4-ylmethyl) analogue, which are known to be potent cannabinoid agonists with moderate to high selectivity for CB2 over CB1 .[4][5] The first published synthesis and pharmacological evaluation of AB-001 revealed that it acts as a full agonist at CB1 (EC50 = 35 nM) and CB2 receptors (EC50 = 48 nM).[6] However, AB-001 was found to possess only weak cannabimimetic effects in rats at doses up to 30 mg/kg, making it less potent than carboxamide analogue SDB001, which possesses potent cannabimimetic activity at doses of 3 mg/kg.[6]
11.1 See also • A-834,735
and identification of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary”. Forensic Science International 214 (1–3): 27–32. doi:10.1016/j.forsciint.2011.07.011. PMID 21813254. [2] Research on Head Shop drugs in Dublin: Part 2 [3] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012). “The detection of the urinary metabolites of 3-\(adamantan1-yl)carbonyl]−1-pentylindole (AB-001), a novel cannabimimetic, by gas chromatography-mass spectrometry”. Drug Testing and Analysis 4 (6): 519–524. doi:10.1002/dta.350. PMID 22102533. [4] US patent 7820144, Makriyannis A, Deng H, “Receptor selective cannabimimetic aminoalkylindoles”, granted 2010-10-26 [5] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781. [6] Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. (2013). “The synthesis and pharmacological evaluation of adamantanederived indoles: Novel cannabimimetic drugs of abuse”. ACS Chemical Neuroscience 4 (7): 130403084729007. doi:10.1021/cn400035r.
• AB-005 • AM-1248 • JWH-018 • JWH-250 • RCS-4 • RCS-8 • SDB-001 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • (1-Pentylindol-3-yl)-(2,2,3,3tetramethylcyclopropyl)methanone
11.2 References [1] Jankovics, P. T.; Váradi, A. S.; Tölgyesi, L. S.; Lohner, S.; Németh-Palotás, J. L.; Balla, J. Z. (2012). “Detection
28
Chapter 12
AB-005 AB-005 or [1-[(1-methyl-2-piperidinyl)methyl]−1Hindol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone is a designer drug offered by online vendors as a cannabimimetic agent. The structure and pharmacological activity of AB-005 was published in 2010, prior to its commercial availability in 2012, where it was reported to have high affinity for both CB1 (Kᵢ = 5.5 nM) and CB2 receptors (Kᵢ = 0.48 nM).[1] AB-005 features groups found in other previously reported synthetic cannabinoids: the tetramethylcyclopropane group of UR-144 and XLR-11 as well as the (1-methyl2-piperidinyl)methyl substituent of AM-1248 and AM-1220. No information regarding the in vivo activity of AB-005 has been published, and only anecdotal reports are known of its psychoactivity in humans.
12.1 Legal status Psychoactive products in New Zealand containing this drug have been given interim approval under recent psychoactive substances legislation.[2]
12.2 See also • AB-001 • AM-1248 • AM-1220 • JWH-018 • UR-144 • XLR-11
12.3 References [1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781.
29
[2] Ministry of Health – Manatū Hauora “Interim Product Approvals”, Ministry of Health NZ, New Zealand, 2 January 2013. Retrieved on 2 January 2013.
Chapter 13
AB-CHMINACA AB-CHMINACA is an indazole-based synthetic cannabinoid. It is a potent agonist of the CB1 receptor.[1]
13.1 References [1] AB-CHMINACA, Cayman Chemicals
30
Chapter 14
AB-FUBINACA AB-FUBINACA is a drug that acts as a potent agonist for the cannabinoid receptors, with Kᵢ values of 0.9nM at CB1 and 23.2nM at CB2 . It was originally developed by Pfizer in 2009 as an analgesic medication,[1] but was never pursued for human use. Subsequently in 2012, this compound was discovered as an ingredient in synthetic cannabis blends in Japan,[2] along with a related compound AB-PINACA which had not previously been reported. In January 2014, AB-FUBINACA was designated as a Schedule I controlled substance in the United States.[3]
14.1 See also • AB-PINACA • ADB-FUBINACA • ADBICA • APICA • APINACA • Benzydamine • NESS-040C5 • PF-03550096
14.2 References [1] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106982 [2] Uchiyama, N.; Matsuda, S.; Wakana, D.; KikuraHanajiri, R.; Goda, Y. (2012). “New cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan2-yl)−1-pentyl-1H-indazole-3-carboxamide (ABPINACA) and N-(1-amino-3-methyl-1-oxobutan-2yl)−1-(4-fluorobenzyl)−1H-indazole-3-carboxamide (AB-FUBINACA) identified as designer drugs in illegal products”. Forensic Toxicology 31: 93. doi:10.1007/s11419-012-0171-4.
31
[3] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G; Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C (2014). “Four Postmortem Case Reports with Quantitative Detection of the Synthetic Cannabinoid, 5F-PB-22”. Journal of analytical toxicology. doi:10.1093/jat/bku048. PMID 24876364.
Chapter 15
AB-PINACA AB-PINACA is a compound that was first identified as a component of synthetic cannabis products in Japan in 2012.[1] The pharmacological properties of this compound have not been formally studied or reported in the scientific literature, but it is presumably a cannabinoid agonist as it was found alongside a structurally related compound AB-FUBINACA which had previously been reported as a cannabinoid agonist in a 2009 Pfizer patent.[2][3]
15.1 See also • AB-FUBINACA • ADB-PINACA • APINACA • PF-03550096
15.2 References [1] Uchiyama, N.; Matsuda, S.; Wakana, D.; KikuraHanajiri, R.; Goda, Y. (2012). “New cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan2-yl)−1-pentyl-1H-indazole-3-carboxamide (ABPINACA) and N-(1-amino-3-methyl-1-oxobutan-2yl)−1-(4-fluorobenzyl)−1H-indazole-3-carboxamide (AB-FUBINACA) identified as designer drugs in illegal products”. Forensic Toxicology 31: 93. doi:10.1007/s11419-012-0171-4. [2] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106980 [3] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106982
32
Chapter 16
Abnormal cannabidiol Abnormal cannabidiol (abn-cbd) is a synthetic regioisomer of cannabidiol, which unlike most other cannabinoids produces vasodilator effects, lowers blood pressure, and induces cell migration, cell proliferation and mitogen-activated protein kinase activation in microglia, but without producing any psychoactive effects.[1][2] It has been shown that the actions of abnormal cannabidiol are mediated through a site separate from the CB1 and CB2 receptors,[2][3] which responds to abnormal cannabidiol, O-1602, and the endogenous ligands: anandamide (AEA), N-arachidonoyl glycine (NAGly) and N-arachidonoyl L-serine.[2][4][5][6] Multiple lines of evidence the proposed identification of this novel target in microglia as the previously “orphan” receptor GPR18.[2] Another possible target of abnormal cannabidiol is GPR55, which has also received much attention as a putative cannabinoid receptor,[7][8] although a growing body of evidence points to lysophosphatidylinositol (LPI) as the endogenous ligand for GPR55.[9][10] Further research suggests there are yet more additional cannabinoid receptors.[11][12][13][14]
the putative abnormal cannabidiol receptor”. BMC Neuroscience 11: 44. doi:10.1186/1471-2202-11-44. PMC 2865488. PMID 20346144. [3] Jarai, Z. (1999). “Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from Proceedings of the NaCB1 or CB2 receptors”. tional Academy of Sciences 96 (24): 14136–14141. doi:10.1073/pnas.96.24.14136. PMC 24203. PMID 10570211. [4] Walter, L; Franklin, A; Witting, A; Wade, C; Xie, Y; Kunos, G; MacKie, K; Stella, N (2003). “Nonpsychotropic cannabinoid receptors regulate microglial cell migration”. Journal of Neuroscience 23 (4): 1398–1405. PMID 12598628. [5] Offertáler, L; Mo, FM; Bátkai, S; Liu, J; Begg, M; Razdan, RK; Martin, BR; Bukoski, RD; Kunos, G (2003). “Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor”. Molecular Pharmacology 63 (3): 699–705. doi:10.1124/mol.63.3.699. PMID 12606780. [6] Milman, G; Maor, Y; Abu-Lafi, S; Horowitz, M; Gallily, R; Batkai, S; Mo, FM; Offertaler, L; Pacher, P; Kunos, G; Mechoulam, R (2006). “N-arachidonoyl l-serine, an endocannabinoid-like brain constituent with vasodilatory properties”. Proceedings of the National Academy of Sciences of the United States of America 103 (7): 2428–2433. doi:10.1073/pnas.0510676103. PMC 1413724. PMID 16467152.
16.1 See also • Cannabinoids • Cannabinoid receptors • Cannabidiol
[7] McCollum, L; Howlett, AC; Mukhopadhyay, S (2007). “Anandamide-mediated CB1/CB2 cannabinoid receptor—independent nitric oxide production in rabbit aortic endothelial cells”. The Journal of Pharmacology and Experimental Therapeutics 321 (3): 930–937. doi:10.1124/jpet.106.117549. PMID 17379772.
• O-1918
16.2 References [1] Adams, MD; Earnhardt, JT; Martin, BR; Harris, LS; Dewey, WL; Razdan, RK (1977). “A cannabinoid with cardiovascular activity but no overt behavioral effects”. Experientia 33 (9): 1204–1205. doi:10.1007/BF01922330. PMID 891878.
[8] Ryberg, E; Larsson, N; Sjögren, S; Hjorth, S; Hermansson, NO; Leonova, J; Elebring, T; Nilsson, K; Drmota, T; Greasley, PJ (2007). “The orphan receptor GPR55 is a novel cannabinoid receptor”. British Journal of Pharmacology 152 (7): 1092–1101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302.
[2] McHugh D, Hu SS, Rimmerman N, Juknat A, Vogil Z, Walker JM, Bradshaw HB (March 2010). “Narachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18,
[9] Kapur, A; Zhao, P; Sharir, H; Bai, Y; Caron, MG; Barak, LS; Abood, ME (2009). “Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands”. The Journal of Biological Chemistry 284 (43): 29817–29827.
33
34
CHAPTER 16. ABNORMAL CANNABIDIOL
doi:10.1074/jbc.M109.050187. PMC 2785612. PMID 19723626. [10] Henstridge, CM; Balenga, NA; Ford, LA; Ross, RA; Waldhoer, M; Irving, AJ (2009). “The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoAdependent Ca2+ signaling and NFAT activation”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 (1): 183– 193. doi:10.1096/fj.08-108670. PMID 18757503. [11] Brown AJ (November 2007). “Novel cannabinoid receptors”. British Journal of Pharmacology 152 (5): 567– 575. doi:10.1038/sj.bjp.0707481. PMC 2190013. PMID 17906678. [12] Johns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.; Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.; Yue, T. -L.; Brown, A. J.; Morrison, A. D.; Douglas, S. A. (2009). “The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects”. British Journal of Pharmacology 152 (5): 825–831. doi:10.1038/sj.bjp.0707419. PMC 2190033. PMID 17704827. [13] McHugh, D; Tanner, C; Mechoulam, R; Pertwee, RG; Ross, RA (2008). “Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2”. Molecular Pharmacology 73 (2): 441–450. doi:10.1124/mol.107.041863. PMID 17965195. [14] Kreutz, S; Koch, M; Böttger, C; Ghadban, C; Korf, HW; Dehghani, F (2009). “2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells”. Glia 57 (3): 286–294. doi:10.1002/glia.20756. PMID 18837048.
Chapter 17
ADB-FUBINACA ADB-FUBINACA is a designer drug identified in synthetic cannabis blends in Japan in 2013.[1] The (S) enantiomer of ADB-FUBINACA is claimed in Pfizer patent WO 2009/106982, with a Kᵢ value of 0.36nM at CB1 .[2] ADB-FUBINACA features a carboxamide group at the 3-indazole position, like SDB-001 and STS-135. ADB-FUBINACA appears to be the product of rational drug design, since it differs from AB-FUBINACA only by the replacement of the isopropyl group with a tertbutyl group. The stereochemistry of the tert-butyl sidechain in the illicitly sold product is unresolved. Nothing is known of the pharmacological activity of ADBFUBINACA in humans or other animals.
17.1 See also • AB-FUBINACA • ADB-PINACA • ADBICA • APINACA • PF-03550096 • SDB-001 • STS-135
17.2 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106982
35
Chapter 18
ADB-PINACA ADB-PINACA is a cannabinoid designer drug that is an ingredient in some synthetic cannabis products.[1][2] It has been linked to multiple hospitalizations due to its use.[3] In the United States, it is a Schedule I controlled substance.[4]
18.1 See also • AB-PINACA • APINACA • ADB-FUBINACA
18.2 References [1] “ADB-PINACA”. Forendex. [2] “ADB-PINACA”. Forensic Drug Review. [3] “CDC: 221 sickened by synthetic pot in Colorado”. USA Today. December 12, 2013. [4] “Schedules of controlled substances: temporary placement of four synthetic cannabinoids into Schedule I. Final order”. Fed Regist. 79 (27): 7577–7582. Feb 10, 2014. PMID 24605391.
36
Chapter 19
ADBICA ADBICA is a designer drug identified in synthetic cannabis blends in Japan in 2013.[1] ADBICA had not previously been reported in the scientific literature prior to its sale as a component of synthetic cannabis blends. ADBICA features a carboxamide group at the 3-indole position, like SDB-001 and STS-135. The stereochemistry of the tert-butyl side-chain in the illicitly sold product is unresolved, though in a large series of indazole derivatives structurally similar to ADBICA that are disclosed in Pfizer patent WO 2009/106980, activity resides exclusively in the (S) enantiomers.[2] Nothing is known of the pharmacological activity of ADBICA in humans or other animals.
19.1 See also • AB-FUBINACA • ADB-FUBINACA • APINACA • PF-03550096 • SDB-001 • STS-135
19.2 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Buchler IP et al, INDAZOLE DERIVATIVES. WO 2009/106980
37
Chapter 20
Ajulemic acid Ajulemic acid (AB-III-56, HU-239, IP-751, L 7075, CT-3, Resunab) is a synthetic cannabinoid derivative of the non-psychoactive THC metabolite 11-nor-9-carboxyTHC that shows useful analgesic and anti-inflammatory effects without causing a subjective “high”.[1] It is being developed for the treatment of neuropathic pain and inflammatory conditions such as arthritis.[2] It does not however share the anti-emetic effects of other cannabinoids but may be useful for treating pain and chronic inflammatory conditions where nausea is not present.[3] Side effects include dry mouth, tiredness and dizziness. The mechanism of action has not yet been fully established, but ajulemic acid may activate the CB2 receptor in the periphery leading to production of resolving eicosanoids. Studies in animals at doses up to 40 mg/kg show minimal psychoactivity of ajulemic acid, comparable to that produced by tetrahydrocannabinol,.[4] Likewise, there was no difference between ajulemic acid and placebo on the “cannabimimetic” assay when used in humans at therapeutic doses.[5][6] A new highly purified composition of ajulemic acid named Resunab is being developed by Corbus Pharmaceuticals (formerly JB Therapeutics)for the treatment of orphan life-threatening inflammatory diseases.
20.1 References [1] Burstein, S.; Karst, M.; Schneider, U.; Zurier, R. (2004). “Ajulemic acid: A novel cannabinoid produces analgesia without a “high"". Life Sciences 75 (12): 1513–1522. doi:10.1016/j.lfs.2004.04.010. PMID 15240185. [2] Mitchell, V.; Aslan, S.; Safaei, R.; Vaughan, C. (2005). “Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain”. Neuroscience letters 382 (3): 231–235. doi:10.1016/j.neulet.2005.03.019. PMID 15925096. [3] Burstein, S. (2005). “Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials”. The AAPS journal 7 (1): E143–E148. doi:10.1208/aapsj070115. PMC 2751505. PMID 16146336. [4] Vann, R.; Cook, C.; Martin, B.; Wiley, J. (2007). “Cannabimimetic properties of ajulemic acid”. The Jour-
38
nal of Pharmacology and Experimental Therapeutics 320 (2): 678–686. doi:10.1124/jpet.106.111625. PMC 2633725. PMID 17105826. [5] Sumariwalla, P.; Gallily, R.; Tchilibon, S.; Fride, E.; Mechoulam, R.; Feldmann, M. (2004). “A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis”. Arthritis and rheumatism 50 (3): 985–998. doi:10.1002/art.20050. PMID 15022343. [6] Sumariwalla, P.F., et al. (2004). “Reply”. Arthritis & Rheumatism 50 (12): 4079. doi:10.1002/art.20806.
Chapter 21
AM-087 AM-087 is an analgesic drug that is a cannabinoid agonist. It is a derivative of Δ8THC substituted on the 3-position side chain. AM-087 is a potent CB1 agonist with a Ki of 0.43nM, making it around 100x more potent than THC itself. This is most likely due to the bulky bromine substituent on the side chain.[1][2][3]
21.1 See also • AM-411
21.2 References [1] Charalambous A, et al. Pharmacological evaluation of halogenated delta 8-THC analogs. Pharmacology, Biochemistry and Behaviour. 1991 Nov;40(3):509-12. PMID 1666915 [2] Nikas SP, et al. The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model. AAPS Journal. 2004 Oct 19;6(4):e30. PMID 15760095 [3] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X
39
Chapter 22
AM-1220 AM-1220 is a drug that acts as a potent and moderately selective agonist for the cannabinoid receptor CB1 , with around 19x selectivity for CB1 over the related CB2 receptor.[1] It was originally invented in the early 1990s by a team led by Thomas D'Ambra at Sterling Winthrop,[2] but has subsequently been researched by many others, most notably the team led by Alexandros Makriyannis at the University of Connecticut. The (piperidin-2-yl)methyl side chain of AM-1220 contains a stereocenter, so there are two enantiomers with quite different potency, the (R) enantiomer having a Kᵢ of 0.27nM at CB1 while the (S) enantiomer has a much weaker Kᵢ of 217nM.[3] A number of related compounds are known with similar potent cannabinoid activity, with modifications such as substitution of the indole ring at the 2- or 6- positions, the naphthoyl ring substituted at the 4- position or replaced by substituted benzoyl rings or other groups, or the 1-(N-methylpiperidin-2-ylmethyl) group replaced by similar heterocyclic groups such as N-methylpyrrolidin-2-ylmethyl or N-methylmorpholin3-ylmethyl.[4][5][6] AM-1220 was first detected as an ingredient of synthetic cannabis smoking blends in 2010.[7]
• AM-2201 • AM-2233 • Cannabipiperidiethanone
22.2 References [1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] US patent 5068234, Thomas E. D'Ambra et al., “3arylcarbonyl-1-(C-attached-N-heteryl)−1H-indoles”, granted 1991-11-26 [3] D'ambra, T. (1996). “C-Attached aminoalkylindoles: potent cannabinoid mimetics”. Bioorganic & Medicinal Chemistry Letters 6: 17–14. doi:10.1016/0960894X(95)00560-G. [4] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut. [5] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D. B.; Mukhin, A. G.; Horti, A. G. (2005). “Synthesis and Structure−Activity Relationship of a Novel Series of Aminoalkylindoles with Potential for Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography”. Journal of Medicinal Chemistry 48 (18): 5813. doi:10.1021/jm0502743. PMID 16134948. [6] US patent 7820144, Alexandros Makriyannis, et al., “Receptor selective cannabimimetic aminoalkylindoles”, granted 2010-10-26
Related 1-(N-methylpyrrolidin-2-ylmethyl) methylmorpholin-3-ylmethyl) derivatives
and
[7] Head Shop ‘Legal Highs’ Active Constituents Identification Chart (July - August 2010)
1-(N-
22.1 See also • A-834,735 • AM-1221 • AM-1248 40
Chapter 23
AM-1221 AM-1221 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2 , with a Kᵢ of 0.28nM at CB2 and 52.3nM at the CB1 receptor, giving it around 180x selectivity for CB2 .[1] The 2-methyl and 6-nitro groups on the indole ring both tend to increase CB2 affinity while generally reducing affinity at CB1 , explaining the high CB2 selectivity of AM-1221. However despite this relatively high selectivity for CB2 , its CB1 affinity is still too strong to make it useful as a truly selective CB2 agonist, so the related compound AM-1241 is generally preferred for research purposes.[2][3]
23.1 See also • AM-630 • AM-1220 • AM-1235 • AM-2233 • UR-144 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
23.2 References [1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut. [3] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
41
Chapter 24
AM-1235 AM-1235 (1-(5-fluoropentyl)−3-(naphthalen-1oyl)−6-nitroindole) is a drug that acts as a potent and reasonably selective agonist for the cannabinoid receptor CB1 .
24.3 References
[2] Deng, Hongfeng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut.
24.1 Pharmacology 24.1.1
Pharmacodynamics
AM-1235 is a cannabinoid receptor agonist with Kᵢ of 1.5nM at CB1 compared to 20.4nM at CB2 .[1] While the 6-nitro substitution on the indole ring reduces affinity for both CB1 and CB2 relative to the unsubstituted parent compound AM-2201, CB2 affinity is reduced much more, resulting in a CB1 selectivity of around 13x.[2] This is in contrast to other related compounds such as AM1221 where a 6-nitro substitution instead confers significant selectivity for CB2 .[3]
24.1.2
[1] US patent 7241799, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200707-10
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 are generally applicable to AM-1235. AM-1235 metabolism differs only slightly from that of JWH-018. AM-1235 N-dealkylation produces fluoropentane instead of pentane (or plain alkanes in general). It has been speculated that the fluoropentane might function as an alkylating agent or is further metabolized into toxic fluoroacetic acid. This is not true since fluoroalkanes do not act as alkylating agents under normal conditions and uneven fluoroalkane chains metabolize into substantially less toxic fluoropropanoic acid.[4][5]
24.2 See also • AM-906 • AM-2389 • O-1812 42
[3] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [4] Millington JE, Pattison FLM. TOXIC FLUORINE COMPOUNDS: XII. ESTERS OF ωFLUOROALCOHOLS. Canadian Journal of Chemistry. 1956 Nov;34(11):1532-1541. [5] Pattison FLM, Howell WC, Woolford RG. TOXIC FLUORINE COMPOUNDS: XIII. ω-FLUOROALKYL ETHERS. Canadian Journal of Chemistry. 1957 Feb;35(2):141-148.
Chapter 25
AM-1241 AM-1241 (1-(methylpiperidin-2-ylmethyl)−3-(2iodo-5-nitrobenzoyl)indole) is a chemical from the aminoalkylindole family that acts as a potent and selective agonist for the cannabinoid receptor CB2 ,[1][2] with a Kᵢ of 3.4nM at CB2 and 80x selectivity over the related CB1 receptor.[3][4] It has analgesic effects in animal studies, particularly against “atypical” pain such as hyperalgesia and allodynia.[5] This is thought to be mediated through CB2 -mediated peripheral release of endogeous opioid peptides,[6] as well as direct activation of the TRPA1 channel.[7] It has also shown efficacy in the treatment of amyotrophic lateral sclerosis in animal models.[8][9]
25.1 Effects in bone cancer model The antihyperalgesic effects of AM-1241 were investigated in a murine bone cancer model. Sarcoma cells were injected into the femur of a mouse, and then mice were injected twice daily with AM-1241. Treatment with AM1241 reduced both spontaneous and evoked pain, as well as reducing the bone loss and subsequent fractures due to the tumor. Pretreatment with the CB2 antagonist SR144,528 reversed the acute effects of AM-1241 on both spontaneous and evoked pain, while having no effect on its own.[10]
25.2 See also
[2] Bingham B, et al. (August 2007). “Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers”. British Journal of Pharmacology 151 (7): 1061– 70. doi:10.1038/sj.bjp.0707303. PMC 2042933. PMID 17549048. [3] Ibrahim MM, et al. (September 2003). “Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS”. Proceedings of the National Academy of Sciences of the United States of America 100 (18): 10529–33. doi:10.1073/pnas.1834309100. PMC 193595. PMID 12917492. [4] Marriott KS, Huffman JW (2008). “Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor”. Current Topics in Medicinal Chemistry 8 (3): 187–204. doi:10.2174/156802608783498014. PMID 18289088. [5] Beltramo M, et al. (March 2006). “CB2 receptormediated antihyperalgesia: possible direct involvement of neural mechanisms”. The European Journal of Neuroscience 23 (6): 1530–8. doi:10.1111/j.14609568.2006.04684.x. PMID 16553616. [6] Ibrahim MM, et al. (February 2005). “CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids”. Proceedings of the National Academy of Sciences of the United States of America 102 (8): 3093– 8. doi:10.1073/pnas.0409888102. PMC 549497. PMID 15705714. [7] Akopian AN, Ruparel NB, Patwardhan A, Hargreaves KM (January 2008). “Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation”. Journal of Neuroscience 28 (5): 1064– 75. doi:10.1523/JNEUROSCI.1565-06.2008. PMID 18234885.
• AM-1220 • AM-1248 • AM-2233
25.3 References [1] Yao BB, et al. (September 2006). “In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor?". British Journal of Pharmacology 149 (2): 145–54. doi:10.1038/sj.bjp.0706838. PMC 2013801. PMID 16894349.
43
[8] Kim K, Moore DH, Makriyannis A, Abood ME (August 2006). “AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis”. European Journal of Pharmacology 542 (1-3): 100–5. doi:10.1016/j.ejphar.2006.05.025. PMID 16781706. [9] Shoemaker JL, et al (April 2007). “The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic
44
CHAPTER 25. AM-1241
mouse model of amyotrophic lateral sclerosis when initiated at symptom onset”. Journal of Neurochemistry 101 (1): 87–98. doi:10.1111/j.1471-4159.2006.04346.x. PMC 2819701. PMID 17241118. [10] Lozano, Alysia (April 2010). “A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss”. Life Sciences 86 (17-18): 646–53. doi:10.1016/j.lfs.2010.02.014. PMC 2871326. PMID 20176037. Retrieved 18 December 2011.
Chapter 26
AM-1248 AM-1248 is a drug that acts as a moderately potent agonist for both the cannabinoid receptors CB1 and CB2 , but with some dispute between sources over its exact potency and selectivity. Replacing the 3-(1-naphthoyl) group found in many indole derived cannabinoid ligands, with an adamantoyl group, generally confers significant CB2 selectivity,[1] but reasonable CB1 affinity and selectivity is retained when an N-methylpiperidin-2-ylmethyl substitution is used at the indole 1-position.[2][3] The related compound 1-pentyl-3-(1-adamantoyl)indole was identified as having been sold as a cannabinoid designer drug in Hungary in 2011, along with another synthetic cannabinoid AM-679.[4]
26.1 See also • A-834,735 • AB-001 • AM-411 • AM-1220 • AM-2233 • Cannabipiperidiethanone
26.2 References [1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q. PMID 19921781. [2] US patent 7820144, Makriyannis A, Deng H, “Receptor selective cannabimimetic aminoalkylindoles”, granted 2010-10-26 [3] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607
45
[4] Jankovics P, et al. (August 2011). “Detection and identification of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary”. Forensic Science International 214 (1-3): 27–32. doi:10.1016/j.forsciint.2011.07.011. PMID 21813254.
Chapter 27
AM-1714 AM-1714 is a drug that acts as a reasonably selective agonist of the peripheral cannabinoid receptor CB2 , with sub-nanomolar affinity and 490x selectivity over the related CB1 receptor. In animal studies it has both analgesic and anti-allodynia effects. The 9-methoxy derivative AM-1710 has similar CB2 affinity but only 54x selectivity over CB1 .[1][2]
27.1 See also • Cannabinol • Canbisol
27.2 References [1] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur GA, Malan TP Jr, Porreca F, Veerappan V, Tian X, George C, Parrish DA, Papahatjis DP, Makriyannis A. Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. Journal of Medicinal Chemistry. 2007 Dec 27;50(26):6493-500. PMID 18038967 [2] Rahn EJ, Zvonok AM, Thakur GA, Khanolkar AD, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats. Journal of Pharmacology and Experimental Therapeutics. 2008 Nov;327(2):584-91. doi: 10.1124/jpet.108.141994. PMID 18664590
46
Chapter 28
AM-2201 AM-2201 (1-(5-fluoropentyl)−3-(1- AM-2201 metabolism differs only slightly from that naphthoyl)indole) is a research chemical that acts as a of JWH-018. AM-2201 N-dealkylation produces fluopotent but nonselective full agonist for the cannabinoid ropentane instead of pentane (or plain alkanes in general). receptor. It is part of the AM series of cannabinoids discovered by Alexandros Makriyannis at Northeastern University. 28.3 Detection A forensic standard of AM-2201 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[5]
28.1 Hazards AM-2201 is widely regarded by recreational s of synthetic cannabinoids as one of the most potent and possibly the most potent substance available in this class of drugs. As the dosage is much smaller than other synthetic cannabinoids, accidental overdose becomes more likely. There have been anecdotal reports of individuals experiencing panic attacks and vomiting at doses as small as 2 mg. Convulsions have been reported[1] including at doses as low as 10 mg.[2] Caution should be taken if using this substance as it is active at doses as small as 500 µg, has a very steep dose-response curve, and tolerance builds up very quickly to the effects. Recreational use of AM-2201 in the United States has led to it being specifically listed in a proposed 2011 amendment to the Controlled Substances Act, aiming to add a number of synthetic drugs into Schedule I.[3] As of November 2011, there have been no reports of death associated with the drug. The acute toxicity and long term side effects associated with the use of AM-2201 are unknown.
28.4 See also • AM-2233 • AM-694 • AM-1235 • AM-2232 • JWH-018
28.5 References [1] David McQuade, Simon Hudson, Paul I. Dargan, David M. Wood (March 2013). “First European case of convulsions related to analytically confirmed use of the synthetic cannabinoid receptor agonist AM-2201”. European Journal of Clinical Pharmacology 69 (3): 373–376. [2] ekaJ (20 February 2011). “The Night I Killed My Friends”. Erowid.org. Retrieved 11 June 2012.
28.2 Pharmacology AM-2201 is a full agonist for cannabinoid receptors. Affinities are: with a Kᵢ of 1.0nM at CB1 and 2.6nM at CB2 .[4] The 4-methyl functional analog MAM-2201 probably has similar affinities.
[3] Synthetic Drug Control Act of 2011. H.R. 1254, 112th Congress, 1st Session (2011). [4] WO patent 0128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200106-07 [5] Southern Association of Forensic Scientists
28.2.1
Pharmacokinetics
See also: JWH-018 § Pharmacokinetics
47
Chapter 29
AM-2232 AM-2232 (1-(4-cyanobutyl)−3-(naphthalen-1oyl)indole) is a drug that acts as a potent but unselective agonist for the cannabinoid receptors, with a Kᵢ of 0.28nM at CB1 and 1.48nM at CB2 .[1]
29.1 See also • AM-2201 • O-1057 • O-1812
29.2 References [1] US patent 7241799, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200707-10
48
Chapter 30
AM-2233 AM-2233 is a drug that acts as a highly potent full agonist for the cannabinoid receptors, with a Kᵢ of 1.8nM at CB1 and 2.2nM at CB2 as the active (R) enantiomer.[1] It was developed as a selective radioligand for the cannabinoid receptors and has been used as its 131 I derivative for mapping the distribution of the CB1 receptor in the brain.[2][3][4][5][6][7] AM-2233 was found to fully substitute for THC in rats, with a potency lower than that of JWH-018 but higher than WIN 55,212-2.[8]
30.1 See also
[5] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.; Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gifford, A. N. (2006). “Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233”. Synapse 60 (2): 93–101. doi:10.1002/syn.20277. PMID 16715483. [6] Leung K (Dec 12, 2006). “R-2-[131I]Iodophenyl(1-(1-methylpiperidin-2-ylmethyl)−1H-indol-3yl)methanone”. Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. PMID 20641836. [7] Pei, Y., et al. (2008). “Ligand-Binding Architecture of Human CB2 Cannabinoid Receptor: Evidence for Receptor Subtype-Specific Binding Motif and Modeling GPCR Activation”. Chemistry & Biology 15: 1207. doi:10.1016/j.chembiol.2008.10.011.
• AM-679 • AM-694 • AM-1220
[8] Järbe TU, Deng H, Vadivel SK, Makriyannis A (September 2011). “Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (Δ9-tetrahydrocannabinol) discrimination for rats”. Behavioural Pharmacology 22 (5-6): 498–507. doi:10.1097/FBP.0b013e328349fbd5. PMC 3212432. PMID 21836461.
• AM-1221 • AM-1241 • Cannabipiperidiethanone
30.2 References [1] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD Dissertation). University of Connecticut. [2] Deng H, et al. (October 2005). “Potent cannabinergic indole analogues as radioiodinatable brain imaging agents for the CB1 cannabinoid receptor”. Journal of Medicinal Chemistry 48 (20): 6386–92. doi:10.1021/jm050135l. PMID 16190764. [3] Hanuš, L. R. O.; Mechoulam, R. (2005). “Cannabinoid chemistry: an overview”. “Cannabinoids as Therapeutics”. Milestones in Drug Therapy MDT. p. 23. doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6. [4] Shen , et al. (February 2006). “F200A substitution in the third transmembrane helix of human cannabinoid CB1 receptor converts AM2233 from receptor agonist to inverse agonist”. European Journal of Pharmacology 531 (1–3): 41–6. doi:10.1016/j.ejphar.2005.12.026. PMID 16438957.
49
Chapter 31
AM-2389 AM-2389 is a classical cannabinoid derivative which acts as a potent and reasonably selective agonist for the CB1 receptor, with a Kᵢ of 0.16 nM, and 26x selectivity over the related CB2 receptor. It has high potency in animal tests of cannabinoid activity, and a medium duration of action.[1][2] Replacing the 1',1'-dimethyl substitution of the dimethylheptyl side chain of classical cannabinoids with cyclopropyl or cyclopentyl results in higher potency than cyclobutyl, but only the cyclobutyl derivatives show selectivity for CB1 over CB2 .[3] High selectivity for CB1 over CB2 is difficult to achieve (cf. AM-906, AM-1235), as almost all commonly used CB1 agonists have similar or greater affinity for CB2 than CB1 , and the only truly highly selective CB1 agonists known as of 2012 are eicosanoid derivatives such as O-1812.
31.1 See also • HHC • AMG-36 • AMG-41
31.2 References [1] Nikas SP, et al. Novel 1',1'-chain substituted hexahydrocannabinols: 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)hexahydrocannabinol (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist. Journal of Medicinal Chemistry. 2010 Oct 14;53(19):6996-7010. PMID 20925434 [2] Järbe TU, et al. AM2389, a high-affinity, in vivo potent CB(1)-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice. Psychopharmacology (Berlin). 2011 Oct 12. PMID 21989802 [3] Papahatjis DP, et al. C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols. Journal of Medicinal Chemistry. 2007 Aug 23;50(17):4048-60. PMID 17672444
50
Chapter 32
AM-4030 AM-4030 is an analgesic drug which is a cannabinoid receptor agonist. It is a derivative of HU-210 which has been substituted with a 6β-((E)−3-hydroxyprop-1-enyl) group. This adds a “southern” aliphatic hydroxyl group to the molecule as seen in the -series of nonclassical cannabinoid drugs, and so AM-4030 represents a hybrid structure between the classical and nonclassical cannabinoid families,[1] with the 6-hydroxyalkyl chain rigidified with a double bond with defined stereochemistry. This gives AM-4030 a greater degree of selectivity, so while it is still a potent agonist at both CB1 and CB2 , it is reasonably selective for CB1 , with a Kᵢ of 0.7nM at CB1 and 8.6nM at CB2 , a selectivity of around 12x.[2][3] Resolution of the enantiomers of AM-4030 yields an even more potent compound, although with less selectivity, with the (-) enantiomer AM-4030a having a Kᵢ of 0.6nM at CB1 and 1.1nM at CB2 .[4]
32.1 See also • AM-919 • AM-938
32.2 References [1] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X [2] Tius MA, Hill WA, Zou XL, Busch-Petersen J, Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji V, Makriyannis A. Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain. Life Sciences. 1995;56(23-24):200712. PMID 7776825 [3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK, Concepcion Fernandez-Garcia M, Fan P, Makriyannis A, Tius MA. Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues. Journal of Medicinal Chemistry. 1998 Sep 10;41(19):3596-608. PMID 9733485 [4] Thakur GA, Palmer SL, Harrington PE, Stergiades IA, Tius MA, Makriyannis A. Enantiomeric resolution of a
51
novel chiral cannabinoid receptor ligand. Journal of Biochemical and Biophysical Methods. 2002 Dec 31;54(13):415-22. PMID 12543516
Chapter 33
AM-411 AM-411 is an analgesic drug that is a cannabinoid agonist. It is a derivative of Δ8THC substituted with an adamantyl group at the 3-position, demonstrating that the binding pocket for the alkyl chain at this position can accommodate significant bulk. AM-411 is a potent and fairly selective CB1 full agonist with a Kᵢ of 6.80nM, but is still also a moderately potent CB2 agonist with a Kᵢ of 52.0nM.[1] It produces similar effects to other cannabinoid agonists such as analgesia, sedation, and anxiolysis.[2][3]
33.1 See also • AM-087 • AM-1248 • KM-233
33.2 References [1] Lu D, et al. Adamantyl cannabinoids: a novel class of cannabinergic ligands. Journal of Medicinal Chemistry. 2005 Jul 14;48(14):4576-85. PMID 15999995 [2] Järbe TU, DiPatrizio NV, Lu D, Makriyannis A. (-)Adamantyl-delta8-tetrahydrocannabinol (AM-411), a selective cannabinoid CB1 receptor agonist: effects on open-field behaviors and antagonism by SR-141716 in rats. Behavioural Pharmacology. 2004 Nov;15(7):51721. PMID 15472574 [3] McLaughlin PJ, et al. Behavioral effects of the novel cannabinoid full agonist AM 411. Pharmacology, Biochemistry and Behaviour. 2005 May;81(1):78-88. PMID 15894067
52
Chapter 34
AM-630 AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2 , with a Kᵢ of 32.1nM at CB2 and 165x selectivity over CB1 , at which it acted as a weak partial agonist.[1][2] It is used in the study of CB2 mediated responses and has been used to investigate the possible role of CB2 receptors in the brain.[3][4] AM-630 is significant as one of the first indole derived cannabinoid ligands substituted on the 6-position of the indole ring, a position that has subsequently been found to be important in determining affinity and efficacy at both the CB1 and CB2 receptors, and has led to the development of a large number of related derivatives.[5][6][7][8][9]
34.1 See also
974–82. doi:10.1016/j.biopsych.2009.09.024. 19931854.
PMID
[5] Eissenstat, M. A.. et al. (1995). “Aminoalkylindoles: Structure-Activity Relationships of Novel Cannabinoid Mimetics”. Journal of Medicinal Chemistry 38 (16): 3094. doi:10.1021/jm00016a013. PMID 7636873. [6] Hongfeng Deng. Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs. PhD Dissertation, University of Connecticut, 2000. [7] Hynes J, et al. (September 2002). “C-3 Amidoindole cannabinoid receptor modulators”. Bioorganic & Medicinal Chemistry Letters 12 (17): 2399– 402. doi:10.1016/S0960-894X(02)00466-3. PMID 12161142. [8] Frost, J. M., et al. (2008). “Indol-3-yltetramethylcyclopropyl Ketones: Effects of Indole Ring Substitution on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 51 (6): 1904. doi:10.1021/jm7011613. PMID 18311894.
• WIN 48,098 (Pravadoline) • WIN 54,461 (6-Bromopravadoline) • AM-1221
[9] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a.
34.2 References [1] Ross RA, et al. (February 1999). “Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630”. British Journal of Pharmacology 126 (3): 665–72. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID 10188977. [2] Murataeva, N.; MacKie, K.; Straiker, A. (2012). “The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons”. Pharmacological Research 66 (5): 437–42. doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID 22921769. [3] Morgan NH, Stanford IM, Woodhall GL (September 2009). “Functional CB2 type cannabinoid receptors at CNS synapses”. Neuropharmacology 57 (4): 356– 68. doi:10.1016/j.neuropharm.2009.07.017. PMID 19616018. [4] Ishiguro H, et al. (May 2010). “Brain cannabinoid CB2 receptor in schizophrenia”. Biological Psychiatry 67 (10):
53
Chapter 35
AM-6545 AM-6545 is a drug which acts as a peripherally selective silent antagonist for the CB1 receptor, and was developed for the treatment of obesity. Other cannabinoid antagonists such as rimonabant have been marketed for this application, but have subsequently been withdrawn from sale because of centrally mediated side effects such as depression and nausea. Because AM-6545 does not cross the blood–brain barrier to any significant extent, it does not produce these kinds of side effects, but has still been shown to effectively reduce appetite and food consumption in animal studies.[1][2][3][4]
35.1 See also • CB-13 – a peripherally selective cannabinoid agonist • O-2050 – a centrally active CB1 silent antagonist • Methylnaltrexone – a peripherally selective mu opioid receptor antagonist • TM-38837 - another peripherally selective cannabinoid antagonist
35.2 References [1] Tam, J.; Vemuri, V. K.; Liu, J.; Bátkai, S. N.; Mukhopadhyay, B.; Godlewski, G.; Osei-Hyiaman, D.; Ohnuma, S.; Ambudkar, S. V.; Pickel, J.; Makriyannis, A.; Kunos, G. (2010). “Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity”. Journal of Clinical Investigation 120 (8): 2953– 2966. doi:10.1172/JCI42551. PMC 2912197. PMID 20664173. PMID 20664173 [2] Randall PA, Vemuri VK, Segovia KN, Torres EF, Hosmer S, Nunes EJ, Santerre JL, Makriyannis A, Salamone JD. The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacology, Biochemistry and Behavior. 2010 Nov;97(1):179-84. PMID 20713079 [3] Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT, Lutz B, Zimmer A, Parker LA,
54
Makriyannis A, Sharkey KA. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. British Journal of Pharmacology. 2010 Oct;161(3):629-42. PMID 20880401 [4] Järbe TU, LeMay BJ, Vemuri VK, Vadivel SK, Zvonok A, Makriyannis A. Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats. Psychopharmacology (Berlin). 2011 Aug;216(3):355-65. PMID 21369753
Chapter 36
AM-679 (cannabinoid) This article is about the cannabinoid agonist. For the FLAP inhibitor, see AM-679 (FLAP inhibitor). AM-679 is a drug that acts as a moderately potent agonist for the cannabinoid receptors, with a Kᵢ of 13.5nM at CB1 and 49.5nM at CB2 .[1] AM-679 was one of the first 3-(2-iodobenzoyl)indole derivatives that was found to have significant cannabinoid receptor affinity, and while AM-679 itself has only modest affinity for these receptors, it was subsequently used as a base to develop several more specialised cannabinoid ligands that are now widely used in research, including the potent CB1 agonists AM-694 and AM-2233, and the selective CB2 agonist AM-1241.[2] AM-679 was first identified as having been sold as a cannabinoid designer drug in Hungary in 2011, along with another novel compound 1-pentyl-3-(1adamantoyl)indole.[3]
36.1 See also • RCS-4 • AM-694 • AM-2233
36.2 References [1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs (PhD. Dissertation). University of Connecticut. [3] Jankovics P, et al. (August 2011). “Detection and identification of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary”. Forensic Science International 214 (1-3): 27–32. doi:10.1016/j.forsciint.2011.07.011. PMID 21813254.
55
Chapter 37
AM-694 AM-694 (1-(5-fluoropentyl)−3-(2-iodobenzoyl)indole) is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB1 . It is used in scientific research for mapping the distribution of CB1 receptors. No public data about AM-694 metabolism is known. AM-694 has already emerged as a designer drug.
37.3 References
37.1 Pharmacology AM-694 is an agonist for cannabinoid receptors. Affinities are: with a Kᵢ of 0.08nM at CB1 and 18x selectivity over CB2 with a Kᵢ 1.44nM.[1] It is unclear what is responsible for this unusually high CB1 binding affinity, but it makes the 18 F radiolabelled derivative of AM-694 useful for mapping the distribution of CB1 receptors in the body.[2]
37.1.1
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 are generally applicable to AM-694. AM-694 metabolism differs only slightly from that of JWH-018. AM-694 N-dealkylation produces fluoropentane instead of pentane (or plain alkanes in general). It has been speculated that the fluoropentane might function as an alkylating agent or is further metabolized into toxic fluoroacetic acid. This is not true since fluoroalkanes do not act as alkylating agents under normal conditions and uneven fluoroalkane chains metabolize into substantially less toxic fluoropropanoic acid.[3][4]
37.2 See also • AM-679 • AM-2201 • AM-2233 56
[1] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607 [2] Willis PG, Katoch-Rouse R, Horti AG. Regioselective F18 radiolabeling of AM694, a CB1 cannabinoid receptor ligand. Journal of Labelled Compounds and Radiopharmaceuticals 2003;46(9):799-804. doi:10.1002/jlcr.720 [3] Millington JE, Pattison FLM. TOXIC FLUORINE COMPOUNDS: XII. ESTERS OF ωFLUOROALCOHOLS. Canadian Journal of Chemistry. 1956 Nov;34(11):1532-1541. [4] Pattison FLM, Howell WC, Woolford RG. TOXIC FLUORINE COMPOUNDS: XIII. ω-FLUOROALKYL ETHERS. Canadian Journal of Chemistry. 1957 Feb;35(2):141-148.
Chapter 38
AM-855 AM-855 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8 Tetrahydrocannabinol with a conformationally restricted side chain which has been bound into a fourth ring fused to the aromatic A-ring of the cannabinoid skeleton. AM-855 is an agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 22.3nM at CB1 and 58.6nM at CB2 .[1]
38.1 References [1] Khanolkara, Atmaram D.; Dai Lua, Pusheng Fana, Xiaoyu Tiana and Alexandros Makriyannis (August 1999). “Novel conformationally restricted tetracyclic analogs of Δ8 -tetrahydrocannabinol”. Bioorganic & Medicinal Chemistry Letters 9 (15): 2119–24. doi:10.1016/S0960894X(99)00355-8. PMID 10465529.
57
Chapter 39
AM-905 AM-905 is an analgesic drug which is a cannabinoid agonist with a conformationally restricted side chain. It is a potent and reasonably selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 1.2nM at CB1 and 5.3nM at CB2 .[1]
39.1 References [1] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos A, Makriyannis A. Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of Medicinal Chemistry. 1998 Mar 26;41(7):1195-200. PMID 9544219
58
Chapter 40
AM-906 AM-906 is an analgesic drug which is a cannabinoid agonist with a conformationally restricted side chain. It is a potent and selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 0.8nM at CB1 and 9.5nM at CB2 , a selectivity of almost 12x.[1]
40.1 See also • AM-1235 • AM-2389
40.2 References [1] Papahatjis DP, et al. Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of Medicinal Chemistry. 1998 Mar 26;41(7):1195-200. PMID 9544219
59
Chapter 41
AM-919 AM-919 is an analgesic drug which is a cannabinoid receptor agonist. It is a derivative of HU-210 which has been substituted with a 6β-(3-hydroxypropyl) group. This adds a “southern” aliphatic hydroxyl group to the molecule as seen in the -series of nonclassical cannabinoid drugs, and so AM-919 represents a hybrid structure between the classical and nonclassical cannabinoid families.[1] AM-919 is somewhat less potent than HU-210 itself, but is still a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 2.2nM at CB1 and 3.4nM at CB2 .[2][3]
41.1 See also • AM-4030
41.2 References [1] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X [2] Tius MA, Hill WA, Zou XL, Busch-Petersen J, Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji V, Makriyannis A. Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain. Life Sciences. 1995;56(23-24):200712. PMID 7776825 [3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK, Concepcion Fernandez-Garcia M, Fan P, Makriyannis A, Tius MA. Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues. Journal of Medicinal Chemistry. 1998 Sep 10;41(19):3596-608. PMID 9733485
60
Chapter 42
AM-938 AM-938 is an analgesic drug which is a cannabinoid receptor agonist. It is a derivative of HU-210 which has been substituted with a 6β-(3-hydroxyprop-1-ynyl) group. This adds a “southern” aliphatic hydroxyl group to the molecule as seen in the -series of nonclassical cannabinoid drugs, and so AM-938 represents a hybrid structure between the classical and nonclassical cannabinoid families,[1] with the 6-hydroxyalkyl chain rigidified with a triple bond. This gives AM-938 a greater degree of selectivity, so while it is still a potent agonist at both CB1 and CB2 , it is reasonably selective for CB2 , with a Kᵢ of 0.3nM at CB2 and 1.2nM at CB1 , a selectivity of around 4x.[2][3]
42.1 See also • AM-4030
42.2 References [1] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X [2] Tius MA, Hill WA, Zou XL, Busch-Petersen J, Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji V, Makriyannis A. Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain. Life Sciences. 1995;56(23-24):200712. PMID 7776825 [3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK, Concepcion Fernandez-Garcia M, Fan P, Makriyannis A, Tius MA. Classical/nonclassical hybrid cannabinoids: southern aliphatic chain-functionalized C-6beta methyl, ethyl, and propyl analogues. Journal of Medicinal Chemistry. 1998 Sep 10;41(19):3596-608. PMID 9733485
61
Chapter 43
AM404 AM404, also known as Narachidonoylaminophenol,[1] is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action.[2] Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.
43.1 Pharmacology AM404 was originally reported to be an endogenous cannabinoid reuptake inhibitor, preventing the transport of anandamide and other related compounds back from the synaptic cleft, much in the same way that common selective serotonin reuptake inhibitor (SSRI) antidepressants prevent the reuptake of serotonin. Earlier work on the mechanism of AM404 suggested that the inhibition of fatty acid amide hydrolase (FAAH) by AM404 was responsible for all of its attributed reuptake properties, since intracellular FAAH hydrolysis of anandamide changes the intra/extracellular anandamide equilibrium.[3] However, this is not the case, as newer research on FAAH knockout mice has found that brain cells internalize anandamide through a selective transport mechanism which is independent of FAAH activity.[4] This mechanism is inhibited by AM404. AM404 is also a TRPV1 agonist and inhibitor of cyclooxygenase COX-1 and COX-2, thus attenuating prostaglandin synthesis. AM404 is thought to induce its analgesic action through its activity on the endocannabinoid, COX, and TRPV systems, all of which are present in pain and thermoregulatory pathways.[5]
43.2 See also • VDM-11
43.3 References [1] Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P (January 2012). “Novel bioactive metabolites of dipyrone (metamizol)". Bioorg. Med.
62
Chem. 20 (1): 101–7. doi:10.1016/j.bmc.2011.11.028. PMC 3248997. PMID 22172309. [2] Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (February 2006). “The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors”. Eur. J. Pharmacol. 531 (1–3): 280–1. doi:10.1016/j.ejphar.2005.12.015. PMID 16438952. [3] Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (April 2003). “Evidence against the presence of an anandamide transporter”. Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4269–74. doi:10.1073/pnas.0730816100. PMC 153082. PMID 12655057. [4] Fegley, D.; Kathuria, S.; Mercier, R.; Li, C.; Goutopoulos, A.; Makriyannis, A.; Piomelli, D. (11 May 2004). “Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysisresistant inhibitor AM1172”. Proceedings of the National Academy of Sciences 101 (23): 8756–8761. doi:10.1073/pnas.0400997101. [5] Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (September 2005). “Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system” (pdf). J. Biol. Chem. 280 (36): 31405–12. doi:10.1074/jbc.M501489200. PMID 15987694.
Chapter 44
AMG-1 AMG-1 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8THC with a rigidified and extended 3-position side chain. AMG-1 is a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 0.6nM at CB1 vs 3.1nM at CB2 .[1]
44.1 References [1] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu W, Pertwee RG, Makriyannis A. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753
63
Chapter 45
AMG-3 AMG-3 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8THC substituted with a dithiolane group on the 3-position side chain.[1] AMG-3 is a potent agonist at both CB1 and CB2 receptors with a Kᵢ of 0.32nM at CB1 and 0.52nM at CB2 ,[2][3] and its particularly high binding affinity has led to it being used as a template for further structural development of novel cannabinoid drugs.[4] It has sedative and analgesic effects, with analgesia lasting for up to 36 hours after istration.[5]
45.1 References [1] Mavromoustakos T, Theodoropoulou E, Zervou M, Kourouli T, Papahatjis D. Structure elucidation and conformational properties of synthetic cannabinoids ()−2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy6H-dibenzo[b,d]pyranyl)−2-hexyl-1,3-dithiolane and its methylated analog. Journal of Pharmaceutical and Biomedical Analysis. 1999 Jan;18(6):947-56. PMID 9925329 [2] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos A, Makriyannis A. Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of Medicinal Chemistry. 1998 Mar 26;41(7):1195-200. PMID 9544219 [3] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu W, Pertwee RG, Makriyannis A. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753 [4] Durdagi S, Papadopoulos MG, Papahatjis DP, Mavromoustakos T. Combined 3D QSAR and molecular docking studies to reveal novel cannabinoid ligands with optimum binding activity. Bioorganic and Medicinal Chemistry Letters. 2007 Dec 15;17(24):6754-63. PMID 17980589 [5] Antoniou K, Galanopoulos A, Vlachou S, Kourouli T, Nahmias V, Thermos K, Panagis G, Daifoti Z, Marselos M, Papahatjis D, Spyraki C. Behavioral pharmacological properties of a novel cannabinoid 1',1'-dithiolane delta8THC analog, AMG-3. Behavioural Pharmacology. 2005 Sep;16(5-6):499-510. PMID 16148456
64
Chapter 46
AMG-36 AMG-36 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8THC substituted with a cyclopentane group on the 3-position side chain. AMG36 is a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 0.4nM at CB1 vs 1.9nM at CB2 .[1][2]
46.1 References [1] Papahatjis DP, et al. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753 [2] Papahatjis DP, et al. C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols. Journal of Medicinal Chemistry. 2007 Aug 23;50(17):4048-60. PMID 17672444
65
Chapter 47
AMG-41 AMG-41 is an analgesic drug which is a cannabinoid agonist. It is a derivative of Δ8-THC substituted with a cyclopropyl group on the C1'-position of the C3-alkyl side chain. AMG-41 is a potent agonist at both CB1 and CB2 , with a Kᵢ of 0.4nM at CB1 vs 0.9nM at CB2 .[1][2][3]
47.1 References [1] Papahatjis DP, Nikas SP, Andreou T, Makriyannis A. Novel 1',1'-chain substituted Delta(8)tetrahydrocannabinols. Bioorganic and Medicinal Chemistry Letters. 2002 Dec 16;12(24):3583-6. PMID 12443781 [2] Papahatjis DP, et al. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753 [3] Papahatjis DP, et al. C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols. Journal of Medicinal Chemistry. 2007 Aug 23;50(17):4048-60. PMID 17672444
66
Chapter 48
APINACA This article is about the synthetic cannabinoid drug. For the Japanese girl group, see AKB48.
48.3 References
AKB48 (APINACA, N-(1-adamantyl)−1-pentyl-1Hindazole-3-carboxamide) is a drug that acts as a reasonably potent agonist for the cannabinoid receptors,[1] with a Kᵢ of 304.5nM and a EC50 of 585nM at CB1 . It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in Japan in March 2012 as an ingredient in synthetic cannabis smoking blends, along with a related compound APICA.[2] Structurally it closely resembles cannabinoid compounds from patent WO 2003/035005 but with a simple pentyl chain on the indazole 1-position, and AKB48 falls within the claims of this patent despite not being disclosed as an example. AKB48 was made illegal in Japan in 2012,[3] and was banned as a temporary class drug in New Zealand from 13 July 2012.[4] It has been banned in Latvia since 14 November 2013. The DEA announced its intent to schedule 16 May 2013. [5]
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [2] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “Identification of two newtype synthetic cannabinoids, N-(1-adamantyl)−1pentyl-1H-indole-3-carboxamide (APICA) and N-(1adamantyl)−1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products”. Forensic Toxicology 30 (2): 114. doi:10.1007/s11419-012-01367. [3] “Designation of “Shitei Yakubutsu” (designated substances) based on the provision of the Pharmaceutical Affairs Law (1960, Law No.145)" (PDF). [4] “Temporary Class Drug Notice”. Department of Internal Affairs. New Zealand. 5 July 2012.
48.1 Detection A forensic standard of AKB48 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[6]
[5] url=http://www.justice.gov/dea/divisions/hq/2013/ hq051613.shtml [6] http://forendex.southernforensic.org/index.php/detail/ index/1221
• http://www.gpo.gov/fdsys/pkg/FR-2013-04-12/ html/2013-08671.htm
48.2 See also • AB-001 • AB-FUBINACA • AB-PINACA • ADB-FUBINACA • ADB-PINACA • RCS-4 • RCS-8 • SDB-001 • STS-135 67
Chapter 49
AR-231,453 AR-231,453 is an agonist for the suggested novel cannabinoid receptor GPR119.[1]
49.1 See also • PSN-375,963 • PSN-632,408
49.2 References [1] Semple G, Fioravanti B, Pereira G, Calderon I, Uy J, Choi K, Xiong Y, Ren A, Morgan M, Dave V, Thomsen W, Unett DJ, Xing C, Bossie S, Carroll C, Chu ZL, Grottick AJ, Ha EK, Leonard J, Jones RM. (2008). “Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119.”. J Med Chem. 51 (17): 5172–5175. doi:10.1021/jm8006867. PMID 18698756.
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Chapter 50
Arachidonyl-2'-chloroethylamide Arachidonyl-2'-chloroethylamide (ACEA) is a synthetic agonist of the cannabinoid receptor 1 (CB1R). ACEA is considered to be a selective cannabinoid agonist as it binds primarily to the CB1R and has low affinity to the cannabinoid receptor 2 (CB2R) (Kᵢ = 1.4 nM for CB1R; Kᵢ = 3100 nM for CB2R). [1]
50.1 References [1] Hillard, CJ; Manna, S; Greenberg, MJ; Dicamelli, R; Ross, RA; Stevenson, LA; Murphy, V; Pertwee, RG; Campbell, WB (1999). “Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1)". The Journal of Pharmacology and Experimental Therapeutics 289 (3): 1427–33. PMID 10336536.
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Chapter 51
Arachidonylcyclopropylamide Arachidonylcyclopropylamide (AA) is a synthetic agonist of the cannabinoid receptor 1 (CB1R). AA is considered to be a selective cannabinoid agonist as it binds primarily to the CB1R and has low affinity to the cannabinoid receptor 2 (CB2R) (Kᵢ = 2.2 nM for CB1R; Kᵢ = 700 nM for CB2R).[1]
51.1 References [1] Hillard, CJ, et al. (1999). “Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1)". The Journal of Pharmacology and Experimental Therapeutics 289 (3): 1427–33. PMID 10336536.
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Chapter 52
N-Arachidonylglycine N-Arachidonylglycine (NAGly) is a carboxylic analog of the endocannabinoid anandamide.[1] Since it was first synthesized in 1996,[2] NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids.[3] Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor.[4][5] NaGly is found throughout the body and research on its explicit functions is on going.
52.1 Synthesis The exact biosynthesis of NaGly is not completely understood, but there are two proposed pathways found in vitro for its biosynthesis: 1) enzymatically regulated conjugation of arachidonic acid and glycine and 2) the oxidative metabolism of the endogenous cannabinoid anandamide.[6][7] In the first pathway, Cytochrome c catalyzes the in vitro synthesis of NaGly from arachidonoyl coenzyme A and glycine in the presence of hydrogen peroxide.[8] In the second pathway, alcohol dehydrogenase catalyzes the oxidation of anandamide into Narachidonoyl glycine.[9]
52.2 Research 52.2.1
Effects on the nervous system
NAGly has been hypothesized to have a neurophysiological function of pain suppression, ed by evidence that it suppresses formalin-induced pain behavior in rats.[10] In particular, peripherally istered NAGly inhibited phase 2 pain behavior, suggesting either a direct suppresion of nociceptive afferents on the nerve or an indirect modulation of the afferents’ interstitial environment.[10] In either case, these findings hold promise for NAGly as a means of mitigating postoperative or chronic pain. NAGly is also effective in acute pain
models, reducing mechanical allodynia and thermal hyperalgesia induced by intraplantar injection of Fruend’s complete adjuvant.[11] Similar mechanical allydonia induced by partial ligation of the sciatic nerve was also reduced by NaGly.[12] Other arachidonic acid-amino acid conjugates did not have the same effects and the actions of NaGly were not affected by cannabinoid receptor agonists in either study, suggesting a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain.[11][12] NaGly was shown to be endogenous ligand for the Gprotein couple receptor GPR92 along with farnesyl pyrophosphate.[13] In the dorsal root ganglia (DRG), where GPR92 was found to be localized NaGly increased intracellular calcium levels in DRG neurons, indicating a role of NaGly in the sensory nervous system through the activation of GPR92.[13]
52.2.2 Effects on the immune system NAGly has been the focus of research on the immune system because of its antinociceptive effects and inhibitory action on components of the immune system. Specifically, it significantly inhibited TNFα and IFNγ production, and it shows potential as a therapeutic treatment for chronic inflammation.[14] Moreover, NAGly has been shown to act as a substrate for cyclooxygenase-2 (COX-2), the enzyme primarily known for producing prostaglandins associated with increases in inflammation and hyperalgesia. In many mammalian tissues that express COX-2, significant levels of NAGly are naturally present, and in these tissues COX-2 selectively metabolizes NAGly prostaglandin (PG) H2 glycine and HETEGly.[15]
52.2.3 Cell migration NAGly has been hypothesized to induce cell migration in BV-2 microglia cells.[4] The same research suggests that this migration occurs through GPR18. This was verified using GPR18 transfected HEK-293 cells. The same migration wasn't witnessed using nontransfected and GPR55 transfected HEK-293.[4] Addi-
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CHAPTER 52. N-ARACHIDONYLGLYCINE
tionally, tetrahydrocannabinol and NaGly are full agonists at the GPR18 receptors and induce migration in human endometrial HEC-1B cells.[16] Understanding functions of NaGly in such structures provides a promising future in helping treat diseases such as endometriosis.
52.2.4
Other targets
Insulin secretion
ligand for orphan G-protein-coupled receptor GPR18.”. Biochemical and biophysical research communications 347 (3): 827–32. PMID 16844083. [6] Bradshaw, Heather B; Rimmerman, Neta; Hu, Sherry; Benton, Valery M; Stuart, Jordyn M; Masuda, Kim; Cravatt, Benjamin F; O'Dell, David K; Walker, J Michael (1 January 2009). “The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways”. BMC Biochemistry 10 (1): 14. doi:10.1186/1471-2091-10-14.
NaGly was identified as a novel insulin secretagogue and was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium channels.[17] Additionally, this action was dependent on extracellular glucose level.[17]
[7] Aneetha, Halikhedkar; O’Dell, David K.; Tan, Bo; Walker, J. Michael; Hurley, Thomas D. (1 January 2009). “Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: Synthesis of N-acyl glycinals”. Bioorganic & Medicinal Chemistry Letters 19 (1): 237–241. doi:10.1016/j.bmcl.2008.10.087.
Additional biochemical interactions
[8] McCue, JM; Driscoll, WJ; Mueller, GP (Jan 11, 2008). “Cytochrome c catalyzes the in vitro synthesis of arachidonoyl glycine.”. Biochemical and biophysical research communications 365 (2): 322–7. PMID 17986381.
NaGly has been shown to inhibit the glycine transporter GLYT2a in a non-competitive fashion with arachidonic acids and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachodnoyl amino acids, especially because other conjugated amino acids had similar effects.[18]
52.3 References [1] Burstein, Sumner; Huang, S.M.; Petros, T.J.; Rossetti, R.G.; Walker, J.M.; Zurier, R.B. (30 April 2002). “Regulation of anandamide tissue levels by N-arachidonylglycine”. Biochemical Pharmacology 64 (7): 1147–1150. doi:10.1016/S0006-2952(02)01301-1. PMID 12234618. [2] Sheskin, Tzviel; Hanus, L.; Slager, J.; Vogel, Z.; Mechoulam, R. (1997). “Structural Requirements for Binding of Anandamide-Type Compounds to the Brain Cannabinoid Receptor”. Journal of Medicinal Chemistry 40 (5): 659–667. doi:10.1021/jm960752x. PMID 9057852. [3] Bradshaw, Heather; Rimmerman, N.; Hu, S.J.; Burstein, S.; Walker, J.M. (2009). “Novel Endogenous N-Acyl Glycines: Identification and Characterization”. Vitamins and Hormones. Vitamins & Hormones 81: 191–205. doi:10.1016/S0083-6729(09)81008-X. ISBN 9780123747822. PMID 19647113. [4] McHugh, Douglas; Hu, Sherry SJ; Rimmerman, Neta; Juknat, Ana; Vogel, Zvi; Walker, J Michael; Bradshaw, Heather B (1 January 2010). “N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor”. BMC Neuroscience 11 (1): 44. doi:10.1186/1471-2202-11-44. [5] Kohno, M; Hasegawa, H; Inoue, A; Muraoka, M; Miyazaki, T; Oka, K; Yasukawa, M (Sep 1, 2006). “Identification of N-arachidonylglycine as the endogenous
[9] Aneetha, H; O'Dell, DK; Tan, B; Walker, JM; Hurley, TD (Jan 1, 2009). “Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: synthesis of N-acyl glycinals.”. Bioorganic & medicinal chemistry letters 19 (1): 237–41. PMID 19013794. [10] Huang, Susan M.; Bisogno, T., Petros, T.J., Chang, S.Y., Zavitsanos, P.A., Zipkin, R.E., Sivakumar, R., Coop, A., Maeda, D.Y., De Petrocellis, L., Burstein, S., Di Marzo, V., Walker, J.M. (November 16, 2001). “Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain”. The Journal of Biological Chemistry 276 (46): 42639–42644. doi:10.1074/jbc.M107351200. PMID 11518719. [11] Succar, Rebecca; Mitchell, Vanessa A; Vaughan, Christopher W (August 2007). “Actions of N-arachidonylglycine in a rat inflammatory pain model”. Molecular Pain 3 (1): 24. doi:10.1186/1744-8069-3-24. [12] Vuong, Leeza A.Q.; Mitchell, Vanessa A.; Vaughan, Christopher W. (1 January 2008). “Actions of N-arachidonyl-glycine in a rat neuropathic pain model”. Neuropharmacology 54 (1): 189–193. doi:10.1016/j.neuropharm.2007.05.004. [13] Oh, D. Y.; Yoon, J. M.; Moon, M. J.; Hwang, J.I.; Choe, H.; Lee, J. Y.; Kim, J. I.; Kim, S.; Rhim, H.; O'Dell, D. K.; Walker, J. M.; Na, H. S.; Lee, M. G.; Kwon, H. B.; Kim, K.; Seong, J. Y. (22 May 2008). “Identification of Farnesyl Pyrophosphate and NArachidonylglycine as Endogenous Ligands for GPR92”. Journal of Biological Chemistry 283 (30): 21054–21064. doi:10.1074/jbc.M708908200. [14] Ferrante, A; Poulos A; Pitt M; Easton C; Sleigh M; Rathjen D; Widmer F. “Methods of Treating Immunopathologies Using Polyunsaturated Fatty Acids”. United States patent publication WO 97/38688.
52.3. REFERENCES
[15] Prusakiewicz, J; Kingsley P; Kozak K; Marnett L (2002). “Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2”. Biochemical and Biophysical Research Communications (296): 612–617. [16] McHugh, Douglas; Page, Jeremy; Dunn, Emily; Bradshaw, Heather B (1 April 2012). "Δ9Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells”. British Journal of Pharmacology 165 (8): 2414–2424. doi:10.1111/j.1476-5381.2011.01497.x. [17] Ikeda, Yukio; Iguchi, Haruhisa; Nakata, Masanori; Ioka, Ryoichi X.; Tanaka, Toshiya; Iwasaki, Satoshi; Magoori, Kenta; Takayasu, Shinobu; Yamamoto, Tokuo T.; Kodama, Tatsuhiko; Yada, Toshihiko; Sakurai, Takeshi; Yanagisawa, Masashi; Sakai, Juro (1 August 2005). “Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin Secretagogues”. Biochemical and Biophysical Research Communications 333 (3): 778–786. doi:10.1016/j.bbrc.2005.06.005. [18] Wiles, Amy L.; Pearlman, Rhonda-Jo; Rosvall, Mari; Aubrey, Karin R.; Vandenberg, Robert J. (1 November 2006). “N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a”. Journal of Neurochemistry 99 (3): 781–786. doi:10.1111/j.1471-4159.2006.04107.x.
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Chapter 53
AZ-11713908 AZ-11713908 is a drug developed by AstraZeneca which is a peripherally selective cannabinoid agonist, acting as a potent agonist at the CB1 receptor and a partial agonist at CB2 . It has poor blood–brain barrier penetration, and so while it is an effective analgesic in animal tests, it produces only peripheral effects at low doses, with much weaker symptoms of central effects compared to other cannabinoid drugs such as WIN 55,212-2.[1] A large number of related benzimidazole derived cannabinoid ligands are known.[2][3][4][5]
53.1 See also • AM-6545 • CB-13
53.2 References [1] Yu XH, Cao CQ, Martino G, Puma C, Morinville A, StOnge S, Lessard E, Perkins MN, Laird JM (November 2010). “A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain”. Pain 151 (2): 337–44. doi:10.1016/j.pain.2010.07.019. PMID 20696525. [2] Verbist BM, De Cleyn MA, Surkyn M, Fraiponts E, Aerssens J, Nijsen MJ, Gijsen HJ (April 2008). “5-Sulfonyl-benzimidazoles as selective CB2 agonists”. Bioorganic & Medicinal Chemistry Letters 18 (8): 2574–9. doi:10.1016/j.bmcl.2008.03.048. PMID 18394887. [3] Pagé D, Balaux E, Boisvert L, Liu Z, Milburn C, Tremblay M, Wei Z, Woo S, Luo X, Cheng YX, Yang H, Srivastava S, Zhou F, Brown W, Tomaszewski M, Walpole C, Hodzic L, St-Onge S, Godbout C, Salois D, Payza K, Payza K (July 2008). “Novel benzimidazole derivatives as selective CB2 agonists”. Bioorganic & Medicinal Chemistry Letters 18 (13): 3695–700. doi:10.1016/j.bmcl.2008.05.073. PMID 18522867. [4] WO patent 2004/108688, LIU Z, PAGÈ D, WALPOLE C, YANG H, “BENZIMIDAZOLE DERIVATIVES, COMPOSITIONS CONTAINING THEM, PREPARATION THEREOF AND USES THEREOF”, granted 16.12.2004
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[5] WO patent 2004/108712, LIU Z, PAGÈ D, WALPOLE C, YANG H, “BENZIMIDAZOLE DERIVATIVES, COMPOSITIONS CONTAINING THEM, PREPARATION THEREOF AND USES THEREOF”, granted 16.12.2004
Chapter 54
BAY 38-7271 Originally synthesized by chemist Wayne E. Kenney, BAY 38-7271 (KN 38-7271) is a drug which is a cannabinoid receptor agonist developed by Bayer AG. It has analgesic and neuroprotective effects and is used in scientific research, with proposed uses in the treatment of traumatic brain injury.[1][2] It is a full agonist with around the same potency as 55,940 in animal studies, and has fairly high affinity for both CB1 and CB2 receptors, with Kᵢ values of 2.91nM at CB1 and 4.24nM at CB2 .[3][4] It has now been licensed to KeyNeurotek Pharmaceuticals for clinical development,[5] and is currently in Phase II trials.[6] But its development appears stopped.
54.1 References [1] Mauler F, Horváth E, De Vry J, Jäger R, Schwarz T, Sandmann S, Weinz C, Heinig R, Böttcher M. BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury. CNS Drug Reviews. 2003 Winter;9(4):343-58. PMID 14647528 [2] Mauler F, Hinz V, Augstein KH, Fassbender M, Horváth E. Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271. Brain Research. 2003 Oct 31;989(1):99-111. PMID 14519516 [3] Mauler F, Mittendorf J, Horváth E, De Vry J. Characterization of the diarylether sulfonylester (-)-(R)−3(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties. Journal of Pharmacology and Experimental Therapeutics. 2002 Jul;302(1):359-68. PMID 12065738 [4] De Vry J, Rüdiger Jentzsch K. Discriminative stimulus effects of BAY 38-7271, a novel cannabinoid receptor agonist. European Journal of Pharmacology. 2002 Dec 20;457(2-3):147-52. PMID 12464360 [5] Pipeline [6] KeyNeurotek Pharmaceuticals AG Reports Positive Phase I Data of Its Cannabinoid Receptor-Agonist
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Chapter 55
BAY 59-3074 BAY 59-3074 is a drug which is a cannabinoid receptor partial agonist developed by Bayer AG. It has analgesic effects and is used in scientific research. It is orally active in animals, and has modest affinity for both CB1 and CB2 receptors, with Kᵢ values of 48.3nM at CB1 and 45.5nM at CB2 .[1][2]
55.1 References [1] De Vry J, Denzer D, Reissmueller E, Eijckenboom M, Heil M, Meier H, Mauler F. 3-[2-cyano-3(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1butanesulfonate (BAY 59-3074): a novel cannabinoid Cb1/Cb2 receptor partial agonist with antihyperalgesic and antiallodynic effects. Journal of Pharmacology and Experimental Therapeutics. 2004 Aug;310(2):620-32. PMID 15140913 [2] De Vry J, Jentzsch KR. Discriminative stimulus effects of the structurally novel cannabinoid CB1/CB2 receptor partial agonist BAY 59-3074 in the rat. European Journal of Pharmacology. 2004 Nov 28;505(1-3):127-33. PMID 15556145
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Chapter 56
BML-190 BML-190 (Indomethacin morpholinylamide) is a drug used in scientific research that acts as a selective CB2 inverse agonist.[1] BML-190 is structurally derived from the NSAID indomethacin but has a quite different biological activity.[2] The activity produced by this compound is disputed, with some sources referring to it as a CB2 agonist rather than an inverse agonist;[3][4] this may reflect an error in classification, or alternatively it may produce different effects in different tissues, more research is required to resolve this dispute.
56.1 References [1] New, DC; Wong, YH (2003). “BML-190 and AM251 act as inverse agonists at the human cannabinoid CB2 receptor: signalling via cAMP and inositol phosphates”. FEBS Letters 536 (1–3): 157–60. doi:10.1016/S00145793(03)00048-6. PMID 12586356. [2] Klegeris, A; Bissonnette, CJ; McGeer, PL (2003). “Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor”. British Journal of Pharmacology 139 (4): 775– 86. doi:10.1038/sj.bjp.0705304. PMC 1573900. PMID 12813001. [3] Melck, D; De Petrocellis, L; Orlando, P; Bisogno, T; Laezza, C; Bifulco, M; Di Marzo, V (2000). “Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation”. Endocrinology 141 (1): 118–26. doi:10.1210/en.141.1.118. PMID 10614630. [4] Scutt, A; Williamson, EM (2007). “Cannabinoids stimulate fibroblastic colony formation by bone marrow cells indirectly via CB2 receptors”. Calcified tissue international 80 (1): 50–9. doi:10.1007/s00223-006-0171-7. PMID 17205329.
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Chapter 57
(C6)- 47,497 (C6)- 47,497 ( 47,497 dimethylhexyl homologue) is a synthetic cannabinoid, a 47,497 homologue. Its systematic name is 2-[(1R,3S)−3hydroxycyclohexyl]−5-(1,1-dimethylhexyl)phenol.
57.1 See also • Synthetic cannabis • (C7)- 47,497 ( 47,497 itself) • (C8)- 47,497 • (C9)- 47,497
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Chapter 58
(C9)- 47,497 (C9)- 47,497 ( 47,497 dimethylnonyl homologue) is a synthetic cannabinoid, a 47,497 homologue. Its systematic name is 2-[(1R,3S)−3hydroxycyclohexyl]−5-(1,1-dimethylnonyl)phenol.
58.1 See also • Synthetic cannabis • (C6)- 47,497 • (C7)- 47,497 ( 47,497 itself) • (C8)- 47,497
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Chapter 59
Canbisol Canbisol (Nabidrox), is a synthetic cannabinoid derivative that is the dimethylheptyl homologue of 9-nor−9βhydroxyhexahydrocannabinol (HHC). It is a potent agonist at both the CB1 and CB2 receptors, with a binding affinity of 0.1nM at CB1 and 0.2nM at CB2 .[1] It is mainly used in scientific research, in receptor binding studies to determine the structure and function of the cannabinoid receptors,[2][3][4] but has been made illegal in some countries due to its possible abuse potential as a cannabinomimetic drug.[5]
59.1 See also • HU-210 • HU-243 • Nabilone
59.2 References [1] Rhee MH, et al. (September 1997). “Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase”. Journal of Medicinal Chemistry 40 (20): 3228–33. doi:10.1021/jm970126f. PMID 9379442. [2] Rhee MH, et al. (December 2000). “Functional role of tryptophan residues in the fourth transmembrane domain of the CB(2) cannabinoid receptor”. Journal of Neurochemistry 75 (6): 2485–91. PMID 11080201. [3] Rhee MH (September 2002). “Functional role of serine residues of transmembrane dopamin VII in signal transduction of CB2 cannabinoid receptor”. Journal of Veterinary Science 3 (3): 185–91. PMID 12514330. [4] Zhang R, et al. (July 2005). “Cysteine 2.59(89) in the second transmembrane domain of human CB2 receptor is accessible within the ligand binding crevice: evidence for possible CB2 deviation from a rhodopsin template”. Molecular Pharmacology 68 (1): 69–83. doi:10.1124/mol.104.007823. PMID 15840841. [5] The Misuse of Drugs Act 1971 (Amendment) Order 2009
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Chapter 60
Cannabichromene Cannabichromene (abbreviated as CBC) is a cannabinoid found in the cannabis plant. It bears structural similarity to the other natural cannabinoids, including tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol, and cannabinol, among others. Evidence has suggested that it may play a role in the anti-inflammatory and anti-viral effects of cannabis, and may contribute to the overall analgesic effects of medical cannabis. However, more research into the compound may be needed before any definite medical effects can be verified.[1] CBC has two stereoisomers. It is not scheduled by the Convention on Psychotropic Substances. CBC is nonpsychotropic.[2]
60.1 Medical uses A 2011 study in the British Journal of Pharmacology found that CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control.[2] A study in Neurochemistry International suggested that cannabichromene might stimulate the growth of brain cells by stimulating adult neural stem progenitor cells (NSPCs). The study said “our results suggest that CBC raises the viability of NSPCs while inhibiting their differentiation into astroglia, possibly through upregulation of ATP and adenosine signalling.[3]
60.2 References [1] Gaoni, Y.; Mechoulam, R. (1966). “Cannabichromene, a new active principle in hashish”. Chemical Communications 1: 20–1. doi:10.1039/C19660000020. [2] Maione, Sabatino; Piscitelli, Fabiana; Gatta, Luisa; Vita, Daniela; De Petrocellis, Luciano; Palazzo, Enza; De Novellis, Vito; Di Marzo, Vincenzo (2011). “Nonpsychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action”. British Journal of Pharmacology 162 (3): 584–96. doi:10.1111/j.14765381.2010.01063.x. PMID 20942863.
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[3] Shinjyo, Noriko; Di Marzo, Vincenzo (2013). “The effect of cannabichromene on adult neural stem/progenitor cells”. Neurochemistry International 63 (5): 432–7. doi:10.1016/j.neuint.2013.08.002. PMID 23941747.
Chapter 61
Cannabicyclohexanol Cannabicyclohexanol (CCH, 47,497 dimethyloctyl homologue, (C8)- 47,497) is a cannabinoid receptor agonist drug, developed by Pfizer in 1979. On 19 January 2009, the University of Freiburg in announced that an analog of 47,497 was the main active ingredient in the herbal incense product Spice, specifically the 1,1-dimethyloctyl homologue of 47,497, which is now known as cannabicyclohexanol.[2][3][4][5] The 1,1-dimethyloctyl homologue of 47,497 is in fact several times more potent than the parent compound,[6] which is somewhat unexpected as the 1,1-dimethylheptyl is the most potent substituent in classical cannabinoid compounds such as HU-210.[7]
61.1 See also • Synthetic cannabis • (C6)- 47,497 • (C7)- 47,497 ( 47,497 itself) • (C9)- 47,497 • O-1871
61.2 References [1] Cook, Morgan (2011-02-28). “Synthetic marijuana illegal as of Tuesday”. North County Times (San Diego). Retrieved 2011-02-28. [2] Hauptwirkstoff von „Spice“ identifiziert, University of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm. 2009-01-19.19/ [3] Spice - weitere Analyseresultate http://www. basg.at/servlet/sls/Tornado/web/ages/content/ 4E5A4B86295BF5C0C125753E006A5E3C [4] Auwärter V, et al. 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? Journal of Mass Spectrometry. 2 February 2009. PMID 19189348
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[5] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda Y (May 2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1-3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892. [6] Compton DR, Johnson MR, Melvin LS, Martin BR. Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents. Journal of Pharmacology and Experimental Therapeutics. 1992 Jan;260(1):201-9. PMID 1309872 [7] Martin BR, et al. Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacology, Biochemistry and Behavior. 1991 Nov;40(3):471-8. PMID 1666911
Chapter 62
Cannabicyclol Cannabicyclol (CBL) is a non-psychotomimetic cannabinoid found in the Cannabis species. CBL is a degradative product like cannabinol. Light converts cannabichromene to CBL. It has 16 stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
62.1 See also • Cannabinoids • Cannabis • Medical marijuana
62.2 External links • CTD’s Cannabicyclol page from the Comparative Toxicogenomics Database • Erowid Compounds found in Cannabis sativa • http://www.wiley-vch.de/stmdata/pdf/ CompoundList.pdf • http://www.a1b2c3.com/drugs/mj028.htm
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Chapter 63
Cannabidiol Not to be confused with Cannabinol.
63.1.2 Neurological effects
Cannabidiol (CBD) is one of at least 85 active cannabinoids identified in cannabis.[4] It is a major phytocannabinoid, ing for up to 40% of the plant’s extract.[5] CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol (THC).[5] An orally-istered liquid containing CBD has received orphan drug status in the US, for use as a treatment for dravet syndrome, under the brand name Epidiolex.[6]
A 2010 study found that strains of cannabis containing higher concentrations of cannabidiol did not produce short-term memory impairment vs. strains with similar concentrations of THC, but lower concentrations of CBD. The researchers attributed this attenuation of memory effects to CBD’s role as a CB1 antagonist. Transdermal CBD is neuroprotective in animals.[8]
63.1 Clinical applications
63.1.3 Psychotropic effect
The bud of a Cannabis sativa flower coated with trichomes
63.1.1
Antimicrobial actions
Cannabidiol’s strong antioxidant properties have been shown to play a role in the compound’s neuroprotective and anti-ischemic effects.[9]
CBD has anti-psychotic effects and may counteract the potential psychotomimetic effects of THC on individuals with latent schizophrenia;[5] some reports show it to be an alternative treatment for schizophrenia that is safe and well-tolerated.[10] Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA.[10][11] Leweke et al. performed a double blind, 4 week, explorative controlled clinical trial to compare the effects of purified cannabidiol and the atypical antipsychotic amisulpride on improving the symptoms of schizophrenia in 42 patients with acute paranoid schizophrenia. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale. While there was no statistical difference between the two treatment groups, cannabidiol induced significantly fewer side effects (extrapyramidal symptoms, increase in prolactin, weight gain) when compared to amisulpride.[12] Studies have shown cannabidiol decreases activity of the limbic system[13] and decreases social isolation induced by THC.[14] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.[15][16]
CBD absorbed transcutaneously may attenuate the in- Chronic cannabidiol istration in rats was found creased sebum production at the root of acne, according to produce anxiogenic-like effects, indicating that to an untested hypothesis.[7] prolonged treatment with cannabidiol might incite 84
63.4. PHARMACOLOGY
85
anxiogenic effects.[17] Those results have been contested cannabionoid profile consistently around 1% cannabidiol by,[18] and contradict [19] whose experimentation cover (CBD) with THC less than 0.1%.[32] the same duration. Extraction can be done with olive oil, ethanol, or CO2, Cannabidiol has demonstrated antidepressant-like effects and other nonpolar to semipolar solvents. in animal models of depression.[20][21][22] Hemp world production is around 30000 tonnes per year.
63.1.4
Dravet syndrome
See also: Charlotte’s Web (cannabis) Dravet syndrome is a rare form of epilepsy that is difficult to treat. Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and catastrophic form of intractable epilepsy that begins in infancy. Initial seizures are most often prolonged events and in the second year of life other seizure types begin to emerge.[23] While high profile and anecdotal reports of results from high-CBD/low-THC preparations have sparked interest in treatment with cannabinoids,[24] there is insufficient medical evidence to draw conclusions about their safety or efficacy.[24][25]
63.4 Pharmacology 63.4.1 Pharmacodynamics
Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.[9] While one would assume that this would cause cannabidiol to reduce the effects of THC, it may potentiate THC’s effects by increasing CB1 receptor density or through another CB1 -related mechanism.[33] It is also an inverse agonist of CB2 receptors.[9][34] Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[35] Cannabidiol has also been shown to act as a 5-HT₁A receptor agonist,[36] an action which is involved in its antidepressant,[20][37] anxiolytic,[37][38] and neuroprotective[39][40] effects. Cannabidiol is an 63.2 CBD-enhanced cannabis allosteric modulator of μ and δ-opioid receptors.[41] Decades ago, selective breeding by growers in US dra- Cannabidiol’s pharmacological effects have also been atreceptor agonism and intracellular matically lowered the CBD content of cannabis; their cus- tributed to PPAR-γ [5] calcium release. tomers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[26] To meet the demands of medical cannabis patients, growers are cur63.4.2 Pharmacokinetic interactions rently developing more CBD-rich strains.[27] In November 2012, Tikun Olam, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.[28][29] The researchers said the cannabis plant, enriched with CBD, “can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes”. Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, a cannabinoid researcher, said "...Avidekel is thought to be the first CBD-enriched cannabis plant with no THC to have been developed in Israel”.[30] In February 2014, a patent application was filed for a cannabis plant named 'avidekel'.[31]
63.3 Industrial hemp
There is some preclinical evidence to suggest that cannabidiol may reduce THC clearance, modestly increasing THC’s plasma concentrations resulting in a greater amount of THC available to receptors, increasing the effect of THC in a dose-dependent manner.[42][43] Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[44]
63.4.3 Pharmaceutical preparations Nabiximols (USAN, trade name Sativex) is an aerosolized mist for oral istration containing a near 1:1 ratio of CBD and THC. The drug was approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis.[45][46][47]
63.5 Isomerism
Several industrial hemp varieties can be legally cultivated in western Europe. They might seem to contain Based on: Nagaraja, Kodihalli Nanjappa, Synthesis of very small portion of cannabinoid, which is true in one delta-3-cannabidiol and the derived rigid analogs, Arisense. Nevertheless a variety such as “Fedora 17” has a zona University 1987.
86
CHAPTER 63. CANNABIDIOL hemp oil high in cannabidiol, are legal in the United States for this reason. Some cannabidiol oil is derived from marijuana and is therefore high in THC.[61] This type of cannabidiol oil would be considered a Schedule I as a result. However, cannabidiol derived from industrial hemp is legal and unscheduled itself.[61] In other words, cannabidiol’s legal status depends on where it is derived from, as cannabidiol itself is not scheduled.[57]
Cannabidiol numbering
63.8 US patent See also: Tetrahydrocannabinol#Isomerism, Abnormal In October 2003, U.S. patent #6630507 entitled cannabidiol. “Cannabinoids as antioxidants and neuroprotectants” was assigned to “The United States Of America As Represented By The Department Of Health And Human Ser63.6 Chemistry vices.” The patent was filed in April 1999 and listed as the inventors: Aidan J. Hampson, Julius Axelrod, and MaurCannabidiol is insoluble in water but soluble in organic izio Grimaldi, who all held positions at the National Instisolvents, such as pentane. At room temperature it is a tute of Mental Health (NIMH) in Bethesda, MD, which is colorless crystalline solid.[48] In strongly basic medium part of the National Institutes of Health (NIH), an agency and the presence of air it is oxidized to a quinone.[49] Un- of the United States Department of Health and Human der acidic conditions it cyclizes to THC.[50] The synthesis Services (HHS). The patent mentions cannabidiol’s abilof cannabidiol has been accomplished by several research ity as an antiepileptic, to lower intraocular pressure in the groups.[51][52][53] treatment of glaucoma, lack of toxicity or serious side effects in large acute doses, its neuroprotectant properties, its ability to prevent neurotoxicity mediated by NMDA, AMPA, or kainate receptors; its ability to attenuate glu63.6.1 Biosynthesis tamate toxicity, its ability to protect against cellular damCannabis produces CBD-carboxylic acid through the age, its ability to protect brains from ischemic damage, same metabolic pathway as THC, until the last step, its anxiolytic effect, and its superior antioxidant activity where CBDA synthase performs catalysis instead of which can be used in the prophylaxis and treatment of oxidation associated diseases.[62] THCA synthase.[54] On November 17, 2011, the Federal published that the National Institutes of Health of the United States Department of Health and Human Services was “contem63.7 Legal status plating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507” to the Cannabidiol is not scheduled by the Convention on Psy- company KannaLife based in New York, for the develchotropic Substances. opment and sale of cannabinoid and cannabidiol based Cannabidiol is a Schedule II drug in Canada.[55] therapeutics for the treatment of hepatic encephalopathy in humans.[63][64][65] Cannabidiol’s legal status in the United States:
On July 9, 2012 — KannaLife Sciences, Inc. (“KannaLife”) Signed an Exclusive License Agreement With National Institutes of Health – Office of Technology Transfer (“NIH-OTT”) aka the United States Federal Government for the Commercialization of U.S. Patent 6,630,507, “Cannabinoids as Antioxidants and NeuroMarijuana is defined by 21 U.S.C. §802(16), which is part protectants” (the “’507 Patent”). of the Controlled Substances Act. The mature stalks and seeds of the Cannabis sativa L. plant, as well as prod- http://www.kannalife.com/ ucts derived from the mature stalks and seeds are ex- kannalife-sciences-inc-signs-exclusive-license-agreement-with-national-in plicitly exempt from classification as marijuana.[57][58][59] On March 31, 2014 KannaLife Sciences, Inc. Under this exception, what are known as industrial hemp- (“KannaLife”) and Kannaway LLC (“Kannaway”, a finished products are legally imported into the United multi-level marketing program similar to Amway), States each year.[60] Hemp finished products, including have entered into a five year sales, marketing While the DEA Drug Schedule classifies THC (Tetrahydrocannabinols) and marijuana as Schedule I, cannabidiol is not found on the list.[56] Other synthetic cannabinoids such as JWH-019,073,081,122,200,203,250,398 are also listed in Schedule I, but cannabidiol is absent.[56]
63.9. REFERENCES
87
and product development agreement (the “Agree- [10] Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS (April 2006). “Cannabidiol, a Cannabis ment”). - See more at: http://globenewswire.com/ sativa constituent, as an antipsychotic drug”. Braz. J. Med. news-release/2014/03/31/622898/10074649/en/ Biol. Res. (Review) 39 (4): 421–9. doi:10.1590/S0100KannaLife-Sciences-Inc-and-Kannaway-LLC-Sign-Long-Term-Sales-Marketing-and-Product-Development-Agreement. 879X2006000400001. PMID 16612464. html#sthash.pnvD6OXs.dpuf KannaLife-Sciences-Inc-and-Kannaway-LLCSign-Long-Term-Sales-Marketing-and-ProductDevelopment-Agreement
[11] Long, L. E.; Malone, D. T.; Taylor, D. A. (2005). “Cannabidiol Reverses MK-801-Induced Disruption of Prepulse Inhibition in Mice”. Neuropsychopharmacology 31 (4): 795–803. doi:10.1038/sj.npp.1300838. PMID 16052245.
63.9 References
[12] Leweke, FM; Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M and Koethe D. (2012). “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia”. Translational Psychiatry 2 (3): e94–. doi:10.1038/tp.2012.15. PMC 3316151. PMID 22832859.
[1] Mechoulam R, Parker LA, Gallily R (November 2002). “Cannabidiol: an overview of some pharmacological aspects”. J Clin Pharmacol (Review) 42 (11 Suppl): 11S–19S. doi:10.1177/0091270002238789. PMID 12412831. [2] Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G (May 2009). “Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders”. Phytother Res (Review) 23 (5): 597–602. doi:10.1002/ptr.2625. PMID 18844286. [3] Martland JM, Russo EB (2001). “Cannabis and cannabis extracts: greater than the sum of their parts?". Journal of Cannabis Therapeutics 1 (3/4): 103–132. doi:10.1300/J175v01n03_08. [4] Borgelt LM, Franson KL, Nussbaum AM, Wang GS (February 2013). “The pharmacologic and clinical effects of medical cannabis”. Pharmacotherapy (Review) 33 (2): 195–209. doi:10.1002/phar.1187. PMID 23386598. [5] Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (December 2012). “Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders”. Philos. Trans. R. Soc. Lond., B, Biol. Sci. (Review) 367 (1607): 3364– 78. doi:10.1098/rstb.2011.0389. PMC 3481531. PMID 23108553. [6] Wilner, AN (25 March 2014). “Marijuana for Epilepsy: Weighing the Evidence”. Medscape Neurology. WebMD. Retrieved 2 April 2014. [7] Russo EB (August 2011). “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”. Br. J. Pharmacol. (Review) 163 (7): 1344–64. doi:10.1111/j.1476-5381.2011.01238.x. PMC 3165946. PMID 21749363. [8] Liput, D. J.; Hammell, D. C.; Stinchcomb, A. L.; Nixon, K (2013). “Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder”. Pharmacology Biochemistry and Behavior 111: 120–7. doi:10.1016/j.pbb.2013.08.013. PMID 24012796. [9] Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (August 2007). “Cannabidiol--recent advances”. Chem. Biodivers. (Review) 4 (8): 1678–92. doi:10.1002/cbdv.200790147. PMID 17712814.
[13] José Alexandre de Souza Crippa, Antonio Waldo Zuardi, Griselda E J Garrido, Lauro Wichert-Ana, Ricardo Guarnieri, Lucas Ferrari, Paulo M Azevedo-Marques, Jaime Eduardo Cecílio Hallak, Philip K McGuire and Geraldo Filho Busatto (October 2003). “Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow”. Neuropsychopharmacology 29 (2): 417–426. doi:10.1038/sj.npp.1300340. PMID 14583744. [14] Daniel Thomas Malone, Dennis Jongejana and David Alan Taylora (August 2009). “Cannabidiol reverses the reduction in social interaction produced by low dose Δ9-tetrahydrocannabinol in rats”. Pharmacology Biochemistry and Behavior 93 (2): 91–96. doi:10.1016/j.pbb.2009.04.010. PMID 19393686. [15] Mateus M Bergamaschi, Regina Helena Costa Queiroz, Marcos Hortes Nisihara Chagas, Danielle Chaves Gomes de Oliveira, Bruno Spinosa De Martinis, Flávio Kapczinski, João Quevedo, Rafael Roesler, Nadja Schröder, Antonio E Nardi, Rocio Martín-Santos, Jaime Eduardo Cecílio (May 2011). “Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients”. Neuropsychopharmacology 36 (6): 1219–1226. doi:10.1038/npp.2011.6. PMC 3079847. PMID 21307846. [16] Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simões MV, Bhattacharyya S, Fusar-Poli P, Atakan Z, Santos Filho A, Freitas-Ferrari MC, McGuire PK, Zuardi AW, Busatto GF, Hallak JE. (January 2011). “Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report”. J Psychopharmacol. 25 (1): 121–130. doi:10.1177/0269881110379283. PMID 20829306. [17] ElBatsh, MM; Assareh, N; Marsden, CA; Kendall, DA (May 2012). “Anxiogenic-like effects of chronic cannabidiol istration in rats”. Psychopharmacology 221 (2): 239–247. doi:10.1007/s00213-011-2566-z. PMID 22083592. [18] Gururajan, A (2012). “Comment on: “Anxiogenic-like effects of chronic cannabidiol istration in rats” (Elbatsh MM, Assareh N, Marsden CA, Kendall DA, Psychopharmacology 2012)". Psychopharmacology 222 (4):
88
CHAPTER 63. CANNABIDIOL
725–6; author reply 727. doi:10.1007/s00213-012-27803. PMID 22760485. [19] Réus, Gislaine Z. (2011). “istration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala”. Acta Neuropsychiatrica 23 (5): 241–248. doi:10.1111/j.16015215.2011.00579.x. [20] Zanelati, T; Biojone, C; Moreira, F; Guimarães, F; Joca, S (January 2010). “Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors”. British Journal of Pharmacology 159 (1): 122–8. doi:10.1111/j.1476-5381.2009.00521.x. PMC 2823358. PMID 20002102. [21] Réus, GZ; Stringari, RB; Ribeiro, KF; Luft, T; Abelaira, HM; Fries, GR; Aguiar, BW; Kapczinski, F; Hallak, JE; Zuardi, AW; Crippa JA; Quevedo, J (October 2011). “istration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala”. Acta Neuropsychiatrica 23 (5): 241– 248. doi:10.1111/j.1601-5215.2011.00579.x. [22] El-Alfy, AT; Ivey, K; Robinson, K; Ahmed, S; Radwan, M; Slade, D; Khan, I; ElSohly, M; Ross, S (June 2010). “Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”. Pharmacology Biochemistry and Behavior 95 (4): 434– 442. doi:10.1016/j.pbb.2010.03.004. PMC 2866040. PMID 20332000. [23] http://www.dravetfoundation.org/dravet-syndrome/ what-is-dravet-syndrome#sthash.jAC0bZ89.dpuf What is Dravet Syndrome? [24] Melville, Nancy A. (14 Aug 2013), Seizure Disorders Enter Medical Marijuana Debate, Medscape Medical News., retrieved 2014-01-14 [25] Gloss D, Vickrey B (13 June 2012). “Cannabinoids for epilepsy”. Cochrane Database Syst Rev (Review) 6: CD009270. doi:10.1002/14651858.CD009270.pub2. PMID 22696383. [26] Romney, Lee (13 September 2012). “On the frontier of medical pot to treat boy’s epilepsy”. Los Angeles Times. [27] Good, Alastair (26 October 2010). “Growing marijuana that won't get you high”. The Daily Telegraph (London). [28] Sidner, Sara (8 November 2012). “Medical marijuana without the high” (video). CNN. “An Israeli company has cultivated a new type of medical marijuana.” [29] Solon, Olivia (5 July 2012). “Medical Marijuana Without the High”. Wired.com [30] Lubell, Maayan (3 July 2012). “What a drag, Israeli firm grows 'highless’ marijuana”. Reuters. Retrieved 31 Jan 2014. [31] Cohen, Ytzchak (11 September 2014). “Cannabis plant named 'avidekel'". USPTO. Retrieved 7 October 2014.
[32] Fournier, G.; Beherec, O.; Bertucelli, S. (2003). “Intérêt du rapport Δ−9-THC / CBD dans le contrôle des cultures de chanvre industriel”. Annales de Toxicologie Analytique 15 (4): 250. doi:10.1051/ata/2003003. [33] Hayakawa, K.; Mishima, K.; Hazekawa, M.; Sano, K.; Irie, K.; Orito, K.; Egawa, T.; Kitamura, Y.; Uchida, N.; Nishimura, R.; Egashira, N.; Iwasaki, K.; Fujiwara, M. (2008). “Cannabidiol potentiates pharmacological effects of Δ9-tetrahydrocannabinol via CB1 receptordependent mechanism”. Brain Research 1188: 157–164. doi:10.1016/j.brainres.2007.09.090. PMID 18021759. [34] Pertwee, R. G. (2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9tetrahydrocannabivarin”. British Journal of Pharmacology 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291. [35] Ryberg E, Larsson N, Sjögren S, et al. (2007). “The orphan receptor GPR55 is a novel cannabinoid receptor”. British Journal of Pharmacology 152 (7): 1092– 101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302. [36] Russo EB, Burnett A, Hall B, Parker KK (August 2005). “Agonistic properties of cannabidiol at 5-HT1a receptors”. Neurochemical Research 30 (8): 1037–43. doi:10.1007/s11064-005-6978-1. PMID 16258853. [37] Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS (January 2009). “5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats”. British Journal of Pharmacology 156 (1): 181–8. doi:10.1111/j.1476-5381.2008.00046.x. PMC 2697769. PMID 19133999. [38] Campos AC, Guimarães FS (August 2008). “Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats”. Psychopharmacology 199 (2): 223–30. doi:10.1007/s00213-008-1168-x. PMID 18446323. [39] Mishima K, Hayakawa K, Abe K, et al. (May 2005). “Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism”. Stroke; a Journal of Cerebral Circulation 36 (5): 1077–82. doi:10.1161/01.STR.0000163083.59201.34. PMID 15845890. [40] Hayakawa K, Mishima K, Nozako M, et al. (March 2007). “Repeated treatment with cannabidiol but not Delta9tetrahydrocannabinol has a neuroprotective effect without the development of tolerance”. Neuropharmacology 52 (4): 1079–87. doi:10.1016/j.neuropharm.2006.11.005. PMID 17320118. [41] Kathmann, Markus; Flau, Karsten; Redmer, Agnes; Tränkle, Christian; Schlicker, Eberhard (2006). “Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors”. Naunyn-Schmiedeberg’s Archives of Pharmacology 372 (5): 354–361. doi:10.1007/s00210-006-0033-x. PMID 16489449.
63.10. EXTERNAL LINKS
89
[42] Bornheim, LM; Kim, KY; Li, J; Perotti, BY; Benet, LZ (August 1995). “Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain”. Drug Metabolism and Disposition 23 (8): 825– 831. PMID 7493549.
[55] Controlled Drugs and Substances Act - Schedule II
[43] Klein, C; Karanges, E; Spiro, A; Wong, A; Spencer, J; Huynh, T; Gunasekaran, N; Karl, T; Long, LE; Huang, XF; Liu, K; Arnold, JC; McGregor, IS (November 2011). “Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats”. Psychopharmacology 218 (2): 443–457. doi:10.1007/s00213-011-2342-0. PMID 21667074.
[58] Title 21 US Code Controlled Substances Act, text of the CSA.
[44] Hunt, CA; Jones, RT; Herning, RI; Bachman, J (June 1981). “Evidence that Cannabidiol Does Not Significantly Alter the Pharmacokinetics of Tetrahydrocannabinol in Man”. Journal of Pharmacokinetics and Biopharmaceutics 9 (3): 245–260. doi:10.1007/BF01059266. PMID 6270295.
[61] Cannabidiol: The side of marijuana you don't know
[45] United States Adopted Names Council: Statement on a nonproprietary name [46] “Fact Sheet — Sativex”. Health Canada. Retrieved 16 May 2013. [47] GWPharma- Welcome [48] Jones PG, Falvello L, Kennard O, Sheldrick GM Mechoulam R (1977). “Cannabidiol”. Acta Cryst. B33 (10): 3211–3214. doi:10.1107/S0567740877010577. [49] Mechoulam R, Ben-Zvi Z (1968). “Hashish—XIII On the nature of the beam test”. Tetrahedron 24 (16): 5615– 5624. doi:10.1016/0040-4020(68)88159-1. PMID 5732891. [50] Gaoni Y, Mechoulam R (1966). “Hashish—VII The isomerization of cannabidiol to tetrahydrocannabinols”. Tetrahedron 22 (4): 1481–1488. doi:10.1016/S00404020(01)99446-3. [51] Petrzilka T, Haefliger W, Sikemeier C, Ohloff G, Eschenmoser A (1967). “Synthese und Chiralität des ()-Cannabidiols”. Helv. Chim. Acta 50 (2): 719–723. doi:10.1002/hlca.19670500235. PMID 5587099. [52] Gaoni Y, Mechoulam R (1985). “Boron trifluoride etherate on alumuna — a modified Lewis acid reagent. An improved synthesis of cannabidiol”. Tetrahedron Letters 26 (8): 1083–1086. doi:10.1016/S0040-4039(00)98518-6. [53] Kobayashi Y, Takeuchi A, Wang YG (2006). “Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate”. Org. Lett. 8 (13): 2699–2702. doi:10.1021/ol060692h. PMID 16774235. [54] Marks, M.; Tian, L.; Wenger, J.; Omburo, S.; SotoFuentes, W.; He, J.; Gang, D.; Weiblen, G.; Dixon, R. (2009). “Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa”. Journal of Experimental Botany 60 (13): 3715– 3726. doi:10.1093/jxb/erp210. PMC 2736886. PMID 19581347.
[56] CSA Schedule, List of drugs by schedule. [57] Definition of marijuana under the Controlled Substances Act.
[59] Hemp Industries Assn., v. Drug Enforcement ., 9th Circuit Court of Appeals case involving industrial hemp. [60] Hemp, Many definitions of common associated with hemp, including the history of hemp use.
[62] US patent 6630507, Hampson, Aidan J.; Axelrod, Julius; Grimaldi, Maurizio, “Cannabinoids as antioxidants and neuroprotectants”, issued 2003-10-07 [63] “Federal | Prospective Grant of Exclusive License: Development of Cannabinoid(s) and Cannabidiol(s) Based Therapeutics To Treat Hepatic Encephalopathy in Humans”. Federal.gov. November 17, 2011. Retrieved August 13, 2013. [64] “KannaLife Sciences, Inc. Signs Exclusive License Agreement With National Institutes Of Health Office Of Technology Transfer (NIH-OTT)". thestreet.com. Retrieved 2012-07-09. [65] “KannaLife in R&D Collaboration for CannabinoidBased Drugs”. Genengnews.com. Retrieved 2013-04-04.
63.10 External links • Project CBD Non-profit educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol.
Chapter 64
Cannabidivarin Cannabidivarin (CBDV) is a non-psychoactive cannabinoid found in Cannabis. It is a homolog of cannabidiol (CBD), with the side-chain shortened by two methylene bridges (CH2 units). Plants with relatively high levels of CBDV have been reported in feral populations of C. indica ( = C. sativa ssp. indica var. kafiristanica) from northwest India, and in hashish from Nepal.[1][2] Similarly to CBD, it has 7 double bond isomers and 30 stereoisomers (see: Cannabidiol#Double bond isomers and their stereoisomers). It is not scheduled by Convention on Psychotropic Substances.
64.1 See also • Cannabinoids • Cannabis • Medical marijuana
64.2 References [1] Turner, C.E., P. C. Cheng, G.S. Lewis, M.H.Russell and G.K. Sharma. 1979. Constituents of Cannabis sativa XV: Botanical and chemical profile of Indian variants. Planta medica 37(3): 217-225. [2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). American Journal of Botany 91(6): 966975.
64.3 External links • Erowid Compounds found in Cannabis sativa
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Chapter 65
Cannabigerol Cannabigerol (CBG) is a non-psychoactive cannabinoid found in the Cannabis genus of plants. Cannabigerol is found in higher concentrations in hemp rather than in varieties of Cannabis cultivated for high THC content and their corresponding psychoactive properties. Cannabigerol has been found to act as a high affinity α2 -adrenergic receptor agonist, moderate affinity 5HT₁A receptor antagonist, and low affinity CB1 receptor antagonist.[1] It also binds to the CB2 receptor, but whether it acts as an agonist or antagonist at this site is unknown.[1] Cannabigerol has been shown to relieve interocular pressure, which may be of benefit in the treatment of glaucoma.[2][3] It can also be used to treat inflammatory bowel disease. [4] It has two E/Z isomers. It is not scheduled by Convention on Psychotropic Substances.
65.1 See also • Cannabinoid • Medical cannabis
65.2 References [1] Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee R (December 2009). “Evidence that the plant cannabinoid cannabigerol is a highly potent alpha(2)adrenoceptor agonist and moderately potent 5HT receptor antagonist”. British Journal of Pharmacology 159 (1): 129–141. doi:10.1111/j.1476-5381.2009.00515.x. PMC 2823359. PMID 20002104. [2] Colasanti, B. (1990). “A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol”. Journal of ocular pharmacology 6 (4): 259–269. doi:10.1089/jop.1990.6.259. PMID 1965836. [3] Colasanti, B.; Craig, C.; Allara, R. (1984). “Intraocular pressure, ocular toxicity and neurotoxicity after istration of cannabinol or cannabigerol”. Experimental eye research 39 (3): 251–259. doi:10.1016/00144835(84)90013-7. PMID 6499952.
91
[4] http://www.ncbi.nlm.nih.gov/pubmed/23415610
Chapter 66
Cannabinoidergic Cannabinoidergic, or cannabinergic, means related to the endocannabinoid neurotransmitters. As with such as dopaminergic and serotonergic, related proteins and cellular components involved endocannabinoid signaling, such as the cannabinoid (CB1 ) receptor, as well as exogenous compounds, such as phytocannabinoids or other cannabinoids which modulate the activity of endocannabinoid system, can be described as cannabinoidergic.[1]
66.1 See also • Adenosinergic • Cholinergic • GABAergic • Glutamatergic • Glycinergic • Histaminergic • Monoaminergic • Opioidergic
66.2 References [1] Palmer, SL; Thakur GA; Makriyannis A (December 31, 2002). “Cannabinergic ligands”. Chemistry and physics of lipids 121 (1-2): 3–19. doi:10.1016/s00093084(02)00143-3. PMID 12505686.
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Chapter 67
Cannabinol Not to be confused with Cannabidiol. Cannabinol (CBN) is a weak psychoactive cannabinoid found only in trace amounts in Cannabis sativa and Cannabis indica.[5] It is mostly a metabolite of tetrahydrocannabinol (THC).[6] CBN acts as a weak agonist of CB1 receptors but has a higher affinity to CB2 receptors, with lower affinities in comparison to THC.[7][8] Because of its somewhat selective CB2 agonism, it is used experimentally as an immunosuppressant.
[8] Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998). “Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors”. Life Sciences 63 (1): PL1–6. doi:10.1016/S0024-3205(98)00238-0. PMID 9667767.
67.3 External links
In contrast to tetrahydrocannabinol, it has no double bond isomers nor stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
67.1 See also • Cannabinoids
67.2 References [1] Cannabinol in the ChemIDplus database. [2] David R. Lide (2012). CRC Handbook of Chemistry and Physics. CRC Press. pp. 3–90. ISBN 1-43988049-2. [3] Sigma-Aldrich Co., Cannabinol solution, 1.0 mg/mL in methanol, analytical standard, for drug analysis. [4] Biotrend: Cannabinol (PDF: 21 kB) [5] Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE (1975). “Effects of delta9-tetrahydrocannabinol and cannabinol in man”. Pharmacology 13 (6): 502–12. doi:10.1159/000136944. PMID 1221432. [6] McCallum ND, Yagen B, Levy S, Mechoulam R (May 1975). “Cannabinol: a rapidly formed metabolite of delta1- and delta-6-tetrahydrocannabinol”. Experientia 31 (5): 520–1. doi:10.1007/bf01932433. PMID 1140243. [7] Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK (October 2000). “Novel cannabinol probes for CB1 and CB2 cannabinoid receptors”. Journal of Medicinal Chemistry 43 (20): 3778–85. doi:10.1021/jm0001572. PMID 11020293.
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• Erowid Compounds found in Cannabis sativa
Chapter 68
Cannabivarin Cannabivarin, also known as cannabivarol or CBV, is a non-psychoactive cannabinoid found in minor amounts in the hemp plant Cannabis sativa. It is an analog of cannabinol (CBN) with the side chain shortened by two methylene bridges (-CH2 -). CBV is an oxidation product of tetrahydrocannabivarin (THCV, THV).[1] It has no double bond isomers nor stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
68.1 References [1] Keith Bailey, Denise Gagné (October 1975). “Distinction of synthetic cannabidiol, cannabichromene, and cannabivarin by GLC using on-column methylation”. Journal of Pharmaceutical Sciences 64 (10): 1719–1720. doi:10.1002/jps.2600641033.
68.2 See also • Cannabinoids • Cannabis • Medical marijuana
68.3 External links • Erowid Compounds found in Cannabis sativa
94
Chapter 69
Caryophyllene • Black Caraway (Carum nigrum) [7.8%][13]
Caryophyllene /ˌkæri.ɵfɪˈliːn/, or (−)-β-caryophyllene, is a natural bicyclic sesquiterpene that is a constituent of many essential oils, especially clove oil, the oil from the stems and flowers of Syzygium aromaticum (cloves),[1] the essential oil of hemp Cannabis sativa,[2] rosemary Rosmarinus oficinalis,[3] and hops.[4] It is usually found as a mixture with isocaryophyllene (the cis double bond isomer) and α-humulene (obsolete name: α-caryophyllene), a ring-opened isomer. Caryophyllene is notable for having a cyclobutane ring, a rarity in nature.
• Cloves (Syzygium aromaticum)[1] [1.7%−19,5% of clove bud essential oil][14][15] • Hops (Humulus lupulus)[16] [5.1–14.5%][17] • Basil (Ocimum spp.)[18] [5.3–10.5% O. gratissimum; 4.0–19.8% O. micranthum][19] • Oregano (Origanum [4.9%−15.7][21][22]
Caryophyllene is one of the chemical compounds that contributes to the spiciness of black pepper. In a study conducted by Jürg Gertsch et al. from the Swiss Federal Institute of Technology (ETH Zurich), betacaryophyllene was shown to be selective agonist of cannabinoid receptor type-2 (CB2 ) and to exert significant cannabimimetic antiinflammatory effects in mice.[2] Antinociceptive,[5] neuroprotective,[6] anxiolytic and antidepressant [7] and anti-alcoholism [8] activity have been uncovered. Because the widespread plant natural product beta-caryophyllene is an FDA approved food additive and ingested daily with food it is the first dietary cannabinoid. Whether this compound is able to modulate inflammatory processes in humans via the endocannabinoid system is yet unknown. Beta-caryophyllene does not bind to the centrally expressed cannabinoid receptor type-1 (CB1 ) and therefore does not exert psychomimetic effects.
• Black pepper (Piper nigrum) [7.29%][23] • West African Pepper (Piper guineense) [57.59% (black); 51.75% (white)][23] • Lavender (Lavandula angustifolia) [4.62% of lavender oil][24] • Rosemary (Rosmarinus officinalis)[3] [0.1–8.3%][25] • True cinnamon (Cinnamomum zeylanicum) [6.9– 11.1%][26] • Malabathrum (Cinnamomum tamala) [25.3%][27]
The first total synthesis of caryophyllene in 1964 by E.J. Corey was considered one of the classic demonstrations of the possibilities of synthetic organic chemistry at the time.[9] Caryophyllene oxide is the component responsible for cannabis identification by drug-sniffing dogs[10][11]
vulgare)[20]
• Cananga odorata [3.1%−10.7%][28] • Copaiba oil (Copaifera spp.)
[29][30][31][32]
69.2 Compendial status • Food Chemical Codex [33], [34]
69.1 Natural sources The approximate quantity of caryophyllene in the essential oil of each source is given in square brackets ([ ]):
69.3 Notes and references
• Cannabis, hemp, marijuana (Cannabis sativa)[2] [3.8–37.5% of cannabis flower essential oil][12] 95
[1] Ghelardini C, Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A (2001). “Local anaesthetic activity of beta-caryophyllene”. Farmaco 56 (5–7): 387–9. doi:10.1016/S0014-827X(01)01092-8. PMID 11482764.
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[2] Gertsch J, Leonti M, Raduner S, et al. (July 2008). “Beta-caryophyllene is a dietary cannabinoid”. Proceedings of the National Academy of Sciences of the United States of America 105 (26): 9099–104. doi:10.1073/pnas.0803601105. PMC 2449371. PMID 18574142. [3] Ormeño E, Baldy V, Ballini C, Fernandez C (September 2008). “Production and diversity of volatile terpenes from plants on calcareous and siliceous soils: effect of soil nutrients”. J. Chem. Ecol. 34 (9): 1219–29. doi:10.1007/s10886-008-9515-2. PMID 18670820. [4] Glenn Tinseth, “Hop Aroma and Flavor”, January/February 1993, Brewing Techniques.
CHAPTER 69. CARYOPHYLLENE
[13] Singh G, Marimuthu P, de Heluani CS, Catalan CA (January 2006). “Antioxidant and biocidal activities of Carum nigrum (seed) essential oil, oleoresin, and their selected components”. J. Agric. Food Chem. 54 (1): 174–81. doi:10.1021/jf0518610. PMID 16390196. [14] Alma, M. Hakkı; Ertaş, Murat; Nitz, Siegfrie; Kollmannsberger, Hubert (May 2007). Lucia, Lucian A.; Hubbe, Martin A., eds. “Chemical composition and content of essential oil from the bud of cultivated Turkish clove” (PDF). BioResources (Raleigh, North Carolina, USA: North Carolina State University) 2 (2): 265–269. ISSN 1930-2126. Retrieved September 6, 2010. “The results showed that the essential oils mainly contained about [...] 3.56% β-Caryophyllene” [15] Clove Essential Oil
[5] Katsuyama S., Mizoguchi H., Kuwahata H., et al. (2013). “Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception”. European journal of pain 17 (5): 664–675. doi:10.1002/j.1532-2149.2012.00242.x.
[16] Wang G, Tian L, Aziz N, et al. (November 2008). “Terpene Biosynthesis in Glandular Trichomes of Hop”. Plant Physiol. 148 (3): 1254–66. doi:10.1104/pp.108.125187. PMC 2577278. PMID 18775972.
[6] Guimarães-Santos, Adriano (2012). “Copaiba OilResin Treatment Is Neuroprotective and Reduces Neutrophil Recruitment and Microglia Activation after Motor Cortex Excitotoxic Injury”. Evidence-Based Complementary and Alternative Medicine 2012: 1–9. doi:10.1155/2012/918174. PMC 3291111.
[17] Bernotienë, Genovaitë; Nivinskienë, Ona; Butkienë, Rita; Mockutë, Danutë (2004). “Chemical composition of essential oils of hops (Humulus lupulus L.) growing wild in Auk taitija”. Chemija. 2 (Vilnius, Lithuania: Lithuanian Academy of Sciences) 4: 31–36. ISSN 0235-7216. Retrieved September 6, 2010.
[7] Bahi Amine, Al Mansouri Shamma, Al Memari Elyazia, Al Ameri Mouza, Nurulain Syed M., Ojha Shreesh. (2014). "β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice.”. Physiology & behavior 135: 119– 124. doi:10.1016/j.physbeh.2014.06.003.
[18] Zheljazkov VD, Cantrell CL, Tekwani B, Khan SI (January 2008). “Content, composition, and bioactivity of the essential oils of three basil genotypes as a function of harvesting”. J. Agric. Food Chem. 56 (2): 380–5. doi:10.1021/jf0725629. PMID 18095647.
[8] Al Mansouri Shamma, Ojha Shreesh, Al Maamari Elyazia, Al Ameri Mouza, Nurulain Syed M., Bahi Amine. (2014). “The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice.”. Pharmacology, biochemistry, and behavior. 2014;124C:260-268 124: 260–268. doi:10.1016/j.pbb.2014.06.025. [9] Corey EJ, Mitra RB, Uda H (1964). “Total Synthesis of d,l-Caryophyllene and d,l-Isocaryophyllene”. Journal of the American Chemical Society 86 (3): 485–492. doi:10.1021/ja01057a040. [10] Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects Ethan B Russo. Br J Pharmacol. 2011 August; 163(7): 1344–1364.
[19] Silva, Maria Goretti de Vasconcelos; Matos, Francisco José de Abreu; Lopes, Paulo Roberto Oliveira; Silva, Fábio Oliveira; Holanda, Márcio Tavares (August 2, 2004). Cragg, Gordon M.; Bolzani, Vanderlan S.; Rao, G. S. R. Subba, eds. “Composition of essential oils from three Ocimum species obtained by steam and microwave distillation and supercritical CO2 extraction” (PDF). Arkivoc (ARKAT USA, Inc.) 2004 (vi): 66–71. doi:10.3998/ark.5550190.0005.609. ISSN 1424-6376. Retrieved September 6, 2010. [20] Harvala C, Menounos P, Argyriadou N (February 1987). “Essential Oil from Origanum dictamnus”. Planta Med. 53 (1): 107–9. doi:10.1055/s-2006-962640. PMID 17268981.
[11] Stahl E, Kunde R. Die Leitsubstanzen der HaschischSuchhunde. Kriminalistik: Z Gesamte Kriminal Wiss Prax. 1973;27:385–389.
[21] Calvo-Irabien, L. M.; Yam-Puc, J. A.; Dzib, G.; Escalante-Erosa, F.; Peña-Rodriguez, L. M. (July 2009). “Effect of Postharvest Drying on the Composition of Mexican Oregano (Lippia graveolens) Essential Oil”. Journal of Herbs, Spices & Medicinal Plants (London, UK: Taylor & Francis) 15 (3): 281–287. doi:10.1080/10496470903379001. ISSN 1540-3580.
[12] Mediavilla, Vito; Simon Steinemann. “Essential oil of Cannabis sativa L. strains”. International Hemp Association. Retrieved 11 July 2008.
[22] The essential oil of Origanum vulgare L. ssp. vulgare growing wild in vilnius district (Lithuania) Phytochemistry. 2001 May;57(1):65-9.
69.3. NOTES AND REFERENCES
97
[23] Jirovetz L, Buchbauer G, Ngassoum MB, Geissler M (November 2002). “Aroma compound analysis of Piper nigrum and Piper guineense essential oils from Cameroon using solid-phase microextraction-gas chromatography, solid-phase microextraction-gas chromatography-mass spectrometry and olfactometry”. J Chromatogr A 976 (1–2): 265–75. doi:10.1016/S0021-9673(02)00376-X. PMID 12462618. [24] A. Prashar, I. C. Locke, C. S. Evans (2004). Cytotoxicity of lavender oil and its major components to human skin cells. Cell Proliferation 37 (3), 221–229. [25] Jamshidi, R.; Afzali, Z.; Afzali, D. (February 2009). “Chemical Composition of Hydrodistillation Essential Oil of Rosemary in Different Origins in Iran and Comparison with Other Countries” (PDF). American-Eurasian Journal of Agricultural & Environmental Sciences (Pakistan: IDOSI Publications) 5 (1): 78–81. ISSN 1990-4053. Retrieved September 6, 2010. [26] Kaul PN, Bhattacharya AK, Rao BRR, et al. (2003). “Volatile constituents of essential oils isolated from different parts of cinnamon (Cinnamomum zeylanicum Blume)". Journal of the Science of Food and Agriculture 83 (1): 53–55. doi:10.1002/jsfa.1277. [27] Ahmed A, Choudhary MI, Farooq A, et al. (2000). “Essential oil constituents of the spice Cinnamomum tamala (Ham.) Nees & Eberm.”. Flavour and Fragrance Journal 15 (6): 388–390. doi:10.1002/10991026(200011/12)15:6<388::AID-FFJ928>3.0.CO;2-F. [28] Ylang Ylang Essential Oil [29] . PMID 22466849. Missing or empty |title= (help) [30] . PMID 21095089. Missing or empty |title= (help) [31] http://staff.najah.edu/sites/default/files/Within_plant_ distribution_and_emission_of_sesquiterpenes_from_ Copaifera_officinalis.pdf [32] http://www.rain-tree.com/copaiba.htm [33] The United States Pharmacopeial Convention. “Revisions to FCC, First Supplement”. Retrieved 29 June 2009. [34] Therapeutic Goods istration. stances”. Retrieved 29 June 2009.
“Chemical sub-
Chapter 70
CB-13 CB-13 (SAB-378)[1] is a cannabinoid drug, which acts as a potent agonist at both the CB1 and CB2 receptors, but has poor blood–brain barrier penetration, and so produces only peripheral effects at low doses, with symptoms of central effects such as catalepsy only appearing at much higher dose ranges. It has antihyperalgesic properties in animal studies,[2] and has progressed to preliminary human trials.[3]
70.1 See also • AM-6545 • AZ-11713908
70.2 References [1] Cluny, N. L.; Keenan, C. M.; Duncan, M.; Fox, A.; Lutz, B.; Sharkey, K. A. (2010). “Naphthalen-1-yl(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a Peripherally Restricted Cannabinoid CB1/CB2 Receptor Agonist, Inhibits Gastrointestinal Motility but Has No Effect on Experimental Colitis in Mice”. Journal of Pharmacology and Experimental Therapeutics 334 (3): 973. doi:10.1124/jpet.110.169946. PMID 20571060. [2] Dziadulewicz, E. K.; Bevan, S. J.; Brain, C. T.; Coote, P. R.; Culshaw, A. J.; Davis, A. J.; Edwards, L. J.; Fisher, A. J.; Fox, A. J.; Gentry, C.; Groarke, A.; Hart, T. W.; Huber, W.; James, I. F.; Kesingland, A.; La Vecchia, L.; Loong, Y.; Lyothier, I.; McNair, K.; O'Farrell, C.; Peacock, M.; Portmann, R.; Schopfer, U.; Yaqoob, M.; Zadrobilek, J. (2007). “Naphthalen-1-yl-(4pentyloxynaphthalen-1-yl)methanone: A Potent, Orally Bioavailable Human CB1/CB2Dual Agonist with Antihyperalgesic Properties and Restricted Central Nervous System Penetration”. Journal of Medicinal Chemistry 50 (16): 3851–3856. doi:10.1021/jm070317a. PMID 17630726. [3] Gardin A, Kucher K, Kiese B, Appel-Dingemanse S (April 2009). “Cannabinoid receptor agonist 13, a novel cannabinoid agonist: first in human pharmacokinetics and safety”. Drug Metabolism and Disposition: the Biological Fate of Chemicals 37 (4): 827–33. doi:10.1124/dmd.108.024000. PMID 19144772.
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Chapter 71
CBS-0550 CBS-0550 is a drug developed by Taisho Pharmaceutical, which acts as a potent and selective cannabinoid CB2 receptor agonist, with 1400x selectivity for CB2 over the related CB1 receptor. Unlike most cannabinoid agonists, CBS-0550 has good solubility in water, and in animal studies it was found to produce analgesic and antihyperalgesic effects.[1]
71.1 See also • A-836,339 • SER-601
71.2 References [1] Ohta H, et al. Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic action. Bioorganic and Medicinal Chemistry. 2008 Feb 1;16(3):1111-24. PMID 18006322
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Chapter 72
47,497 47,497 or (C7)- 47,497 is a cannabinoid receptor 72.2 agonist drug, developed by Pfizer in the 1980s.[1] It has analgesic effects and is used in scientific research. It is a 72.2.1 potent CB1 agonist with a K of 2.1nM.[2][3][4]
Legal status
On 22 January 2009, 47,497 was added to the German controlled drug schedules (“Betäubungsmittelgesetz”),[12] along with its dimethylhexyl, dimethyloctyl and dimethylnonyl homologues.[13]
72.1 Homologue On the 19th of January 2009, the University of Freiburg in announced that an analog of 47,497 is the main active ingredient in the herbal “incense” product Spice, specifically the 1,1-dimethyloctyl homologue of 47,497. Both the dimethylheptyl and dimethyloctyl homologues were detected in different batches, with considerable variation in the concentration present in different samples that were analysed. The weaker dimethylhexyl and dimethylnonyl homologues were not found in any batches of smoking blends tested, but have been legally scheduled alongside the others in some jurisdictions, to forestall any potential use for this purpose.[5][6][7] The 1,1-dimethyloctyl homologue of 47,497 is in fact several times more potent than the parent compound,[8] which is somewhat unexpected as the 1,1-dimethylheptyl is the most potent substituent in classical cannabinoid compounds such as HU-210.[9] The unapproved use of these compounds in herbal smoking blends has led to a resurgence in legitimate scientific research into their use,[10] and consequently the C8 homologue of 47,497 has been assigned a proper name, cannabicyclohexanol.[11]
72.2.2 47,497 and its C6, C8, and C9 homologues were made illegal in on 24 February 2009.[14]
72.2.3 Latvia 47,497 and its C6, C8, and C9 homologues were made illegal in Latvia on 28 November 2009.[15]
72.2.4 Lithuania 47,497 and its C6, C8, and C9 homologues were made illegal in Lithuania on 5 June 2009.[16]
72.2.5 Sweden 47,497 and its C6, C7, C8, and C9 homologues were made illegal in Sweden on 15 September 2009.
72.2.6 Romania 47,497 and its C6, C7, C8, and C9 homologues were made illegal in Romania on 15 February 2010.(Illegal Substances in Romania after 15.02.2010
72.2.7 United States Cannabicyclohexanol
As of March 1, 2011, it is a schedule 1 drug.[17][18] 100
72.4. REFERENCES
72.3 See also • (C6)- 47,497 • (C8)- 47,497 • (C9)- 47,497 • 50,556-1 • 55,244 • 55,940 • -945,598 • HHC • O-1871
72.4 References [1] Weissman A, Milne GM, Melvin LS Jr. Cannabimimetic activity from -47,497, a derivative of 3phenylcyclohexanol. Journal of Pharmacology and Experimental Therapeutics. 1982 Nov;223(2):516-23. PMID 6290642 [2] Shim JY, Welsh WJ, Howlett AC. Homology model of the CB1 cannabinoid receptor: sites critical for nonclassical cannabinoid agonist interaction. Biopolymers. 2003;71(2):169-89. PMID 12767117 [3] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168. Springer. ISBN 3-54022565-X [4] Little PJ, et al. Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. Journal of Pharmacology and Experimental Therapeutics 1988; 247:1046–1051. [5] Hauptwirkstoff von „Spice“ identifiziert, University of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm. 2009-01-19.19/ [6] Spice - weitere Analyseresultate http://www. basg.at/servlet/sls/Tornado/web/ages/content/ 4E5A4B86295BF5C0C125753E006A5E3C [7] Auwärter V, et al. 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? Journal of Mass Spectrometry. 2009 Feb 2. PMID 19189348 [8] Compton DR, Johnson MR, Melvin LS, Martin BR. Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents. Journal of Pharmacology and Experimental Therapeutics. 1992 Jan;260(1):201-9. PMID 1309872 [9] Martin BR, et al. Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacology, Biochemistry and Behavior. 1991 Nov;40(3):471-8. PMID 1666911
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[10] Uchiyama N, et al. Effects of synthetic cannabinoids on electroencephalogram power spectra in rats. Forensic Science International. 2011 Jun 1. PMID 21640532 [11] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda Y (May 2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1-3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892. [12] Modedroge “Spice” ist verboten! [13] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19. Januar 2009, S. 49–50. [14] Décrets, arrêtés, circulaires: Arrêté du 24 février 2009 modifiant l’arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants [15] Grozījumi Ministru kabineta 2005.gada 8.novembra noteikumos Nr.847 “Noteikumi par Latvijā kontrolējamajām narkotiskajām vielām, psihotropajām vielām un prekursoriem” [16] http://www3.lrs.lt/pls/inter3/dokpaieska.showdoc_l?p_ id=345197 [17] Cook, Morgan (2011-02-28). “Synthetic marijuana illegal as of Tuesday”. North County Times (San Diego). Retrieved 2011-02-28. [18] https://federal.gov/a/2011-4428
Chapter 73
55,244 55,244 is a compound which is a cannabinoid receptor agonist. It has analgesic effects and is used in scientific research. It is an extremely potent CB1 full agonist with a Kᵢ of 0.21nM, making it more potent than the commonly used full agonist HU-210.[1]
73.1 See also • 47,497
73.2 References [1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649
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Chapter 74
55,940 55,940 is a cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis). 55,940 was created by Pfizer in 1974 but was never marketed. It is currently used to study the endocannabinoid system. Some effects that have been noted are a greatly decreased rates of lever pressing in exposed mice, and a greater reaction to opiates in exposed mice. A study found that 55,940 can upregulate 5-HT2A receptors in mice.[1] 55,940 is 45 times more potent than Δ9 -THC, and fully antagonized by rimonabant (SR141716A).[2] 55,940 is considered a full agonist at both CB1 and CB2 receptors and has Kᵢ values of 0.58nM and 0.68nM respectively, but is an antagonist at GPR55, the putative “CB3 " receptor.[3] 55,940 showed protective effects on rat brain mitochondria upon paraquat exposure.[4] It also showed neuroprotective effects by reducing intracellular calcium release and reducing hippocampal cell death in cultured neurons subjected to high levels of NMDA.[5]
of binding sites for [3 H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain”. Life Sciences 58 (15): 1239–1247. doi:10.1016/00243205(96)00085-9. PMID 8614277. [3] Kapur, A.; Zhao, P.; Sharir, H.; Bai, Y.; Caron, M. G.; Barak, L. S.; Abood, M. E. (2009). “Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands”. The Journal of Biological Chemistry 284 (43): 29817–29827. doi:10.1074/jbc.M109.050187. PMC 2785612. PMID 19723626. [4] Velez-Pardo, C.; Jimenez-Del-Rio, M.; Lores-Arnaiz, S.; Bustamante, J. (2010). “Protective effects of the synthetic cannabinoids 55,940 and JWH-015 on rat brain mitochondria upon paraquat exposure”. Neurochemical Research 35 (9): 1323–1332. doi:10.1007/s11064-0100188-1. PMID 20514518. [5] Zhuang, S. Y.; Bridges, D.; Grigorenko, E.; McCloud, S.; Boon, A.; Hampson, R. E.; Deadwyler, S. A. (2005). “Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodinesensitive stores”. Neuropharmacology 48 (8): 1086– 1096. doi:10.1016/j.neuropharm.2005.01.005. PMID 15910885.
55,940 induced cell death in NG 108-15 Mouse neuroblastoma x Rat glioma hybrid brain cancer (genetically engineered mouse x rat brain cancer) cells.[6][7]
[6] Tomiyama, K.; Funada, M. (2011). “Cytotoxicity of synthetic cannabinoids found in 'Spice' products: The role of cannabinoid receptors and the caspase cascade in the NG 108-15 cell line”. Toxicology Letters 207 (1): 12–17. doi:10.1016/j.toxlet.2011.08.021. PMID 21907772.
74.1 See also
[7] “General Cell Collection: NG108-15”. Public Health England Culture Collections.
• 47,497
74.2 References [1] Franklin, J. M.; Carrasco, G. A. (2013). “Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT₂A) receptor activity via ERK1/2 signaling”. Synapse 67 (3): 145–159. doi:10.1002/syn.21626. PMID 23151877. [2] Rinaldi-Carmona, M.; Pialot, F.; Congy, C.; Redon, E.; Barth, F.; Bachy, A.; Brelière, J. C.; Soubrié, P.; le Fur, G. (1996). “Characterization and distribution
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Chapter 75
Dexanabinol Dexanabinol (HU-211 or ETS2101[1] ) is a synthetic cannabinoid derivative that is the “unnatural” enantiomer of the potent cannabinoid agonist HU-210.[2] Unlike other cannabinoid derivatives, HU-211 does not act as a cannabinoid receptor agonist, but instead has NMDA antagonist effects.[3] It therefore does not produce cannabislike effects, but is anticonvulsant and neuroprotective, and is widely used in scientific research as well as currently being studied for practical applications such as treatment of head injury or stroke or cancer.[4][5][6] It was shown to be safe in clinical trials[7] and is currently undergoing Phase I trials for the treatment of brain cancer.[8]
75.1 References [1] e-therapeutics Clinical Development Pipeline [2] Pop E (September 2000). “Nonpsychotropic synthetic cannabinoids”. Current Pharmaceutical Design 6 (13): 1347–60. doi:10.2174/1381612003399446. PMID 10903397. [3] Feigenbaum JJ, et al. (December 1989). “Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker”. Proceedings of the National Academy of Sciences of the United States of America 86 (23): 9584–7. doi:10.1073/pnas.86.23.9584. PMC 298542. PMID 2556719. [4] Biegon A; Joseph AB (August 1995). “Development of HU-211 as a neuroprotectant for ischemic brain damage”. Neurological Research 17 (4): 275–80. PMID 7477742. [5] Darlington CL (October 2003). “Dexanabinol: a novel cannabinoid with neuroprotective properties”. IDrugs : the Investigational Drugs Journal 6 (10): 976–9. PMID 14534855. [6] Vink R; Nimmo AJ (January 2009). “Multifunctional drugs for head injury”. Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 6 (1): 28–42. doi:10.1016/j.nurt.2008.10.036. PMID 19110197. [7] Maas AI, et al. (January 2006). “Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial”. Lancet Neurol 5 (1): 38–45. doi:10.1016/S14744422(05)70253-2. PMID 16361021.
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[8] University of California, San Diego "Synthetic Cannabinoid May Be Used as Brain Cancer Treatment". (28 September 2012) Laboratory Equipment. Retrieved 28 September 2012.
Chapter 76
Dimethylheptylpyran Dimethylheptylpyran (DMHP, 3-(1,2dimethylheptyl)-Δ6a,10a -THC, 1,2-dimethylheptylΔ3 THC, A-40824, EA-1476) is a synthetic analogue of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9 -THC, the active component of cannabis.[1] DMHP is a pale yellow, viscous oil which is insoluble in water, but dissolves in alcohol or non-polar solvents.
76.1 Effects DMHP is similar in structure to THC, differing only in the position of one double bond, and the replacement of the 3-pentyl chain with a 3-(1,2-dimethylheptyl) chain.[2] It produces similar activity to THC, such as sedative effects, but is considerably more potent,[3] especially having much stronger analgesic and anticonvulsant effects than THC, although comparatively weaker psychological effects. It is thought to act as a CB1 agonist, in a similar manner to other cannabinoid derivatives.[4]
76.2 Investigation as non-lethal incapacitating agent DMHP and its O-acetate ester were extensively investigated by the US military chemical weapons program in the Edgewood Arsenal experiments, as possible nonlethal incapacitating agents.[5] DMHP has three stereocenters and consequently has eight possible stereoisomers, which differ considerably in potency. The racemic mix of all eight isomers of the O-acetyl ester was given the code number EA-2233, with the eight individual isomers numbered EA-2233-1 through EA-2233-8. The most potent isomer was EA2233-2, with an active dose range in humans of 0.5–2.8 μg/kg (i.e. ~35–200 μg for a 70 kg adult). Active doses varied markedly between individuals, but when the dose of EA-2233 was taken up to 1–2 mg, all volunteers were considered to be incapable of performing military duties, with the effects lasting as long as 2–3 days.
ducing the active metabolite 11-hydroxy-DMHP, but the lipophilicity of DMHP is even higher than that of THC itself, giving it a long duration of action and an extended half-life in the body of between 20–39 hours, with the half-life of the 11-hydroxy-DMHP metabolite being longer than 48 hours. Cannabinoids as a class are generally safe compounds with a large safety margin, making potent cannabinoid drugs ideal as potential non-lethal incapacitating agents. DMHP and its esters produce sedation and mild hallucinogenic effects similar to large doses of THC, but in addition to this they also cause pronounced hypotension (low blood pressure) which occurs at doses well below the hallucinogenic dose, and can lead to severe dizziness, fainting, ataxia and muscle weakness, sufficient to make it difficult to stand upright or carry out any kind of vigorous physical activity (an effect known colloquially as “couch lock”). The acute toxicity of DMHP was found to be low in both human and animal studies, with the ratio of ED50 to LD50 (Therapeutic Index) in animals being around 2000x, with death ultimately resulting from a combination of hypotension and hypothermia and preventable with ive treatment. The combination of strong incapacitating effects and a favourable safety margin led the Edgewood Arsenal team to conclude that DMHP and its derivatives, especially the O-acetyl ester of the most active isomer, EA-2233-2, were among the more promising non-lethal incapacitating agents to come out of their research program. However they were disadvantaged by producing severe hypotension at incapacitating doses, and were not as effective as the more widely publicised anticholinergic agents such as 3-Quinuclidinyl benzilate which had also already been weaponised.[6] Funding for continued development was ultimately not approved, and the cannabinoid research program was indefinitely suspended along with the rest of the Edgewood Arsenal experiments in the late 1970s, in accordance with the US commitment to cease research into chemical weapons under disarmament treaties.
DMHP is metabolised in a similar manner to THC, pro105
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Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
76.3 Isomerism Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6Hbenzo[c]chromen-1-ol. See also: Tetrahydrocannabinol § Isomerism
76.4 References [1] Adams R, Harfenist M, Loewe S (1949). Journal of the American Chemical Society 71 (5): 1624. doi:10.1021/ja01173a023. [2] Razdan RK (1980). “The Total Synthesis of Cannabinoids”. Total Synthesis of Natural Products, Volume 4. Wiley-Interscience. doi:10.1002/9780470129678.ch2. ISBN 9780471054603. [3] Wilkison, DM; Pontzer, N; Hosko, MJ (1982). “Slowing of cortical somatosensory evoked activity by delta 9tetrahydrocannabinol and dimethylheptylpyran in alphachloralose-anesthetized cats”. Neuropharmacology 21 (7): 705–9. doi:10.1016/0028-3908(82)90014-4. PMID 6289158. [4] Parker, LA; Mechoulam, R (2003). “Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats”. Integrative physiological and behavioral science : the official journal of the Pavlovian Society 38 (2): 133–45. doi:10.1007/BF02688831. PMID 14527182. [5] Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents. Vol. 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Commission on Life Sciences. The National Academies Press. 1984. pp. 79–99. [6] Ketchum, James S. (2006) Chemical Warfare Secrets Almost Forgotten. ChemBooks Inc. ISBN 978-1-42430080-8
CHAPTER 76. DIMETHYLHEPTYLPYRAN
Chapter 77
Docosatetraenoylethanolamide Docosatetraenoylethanolamide (DEA) is an endogenous ethanolamide that has been shown to act on the cannabinoid (CB1 ) receptor.[1] DEA is similar in structure to anandamide (AEA, a recognized endogenous ligand for the CB1 receptor), containing docosatetraenoic acid in place of arachidonic acid. While DEA has been shown to bind to the CB1 receptor with similar potency and efficacy as AEA, its role as a cannabinergic neurotransmitter is not well understood.
77.1 References [1] Hanus, L., Gopher, A., Almog, S., et al. (1993). “Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor”. J Med Chem 36 (20): 3032–3034. doi:10.1021/jm00072a026. PMID 8411021.
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Chapter 78
Drinabant Drinabant (INN; AVE-1625) is a drug that acts as a selective CB1 receptor antagonist, which was under investigation varyingly by Sanofi-Aventis as a treatment for obesity, schizophrenia, Alzheimer’s disease, Parkinson’s disease, and nicotine dependence.[1][2][3] Though initially studied as a potential treatment for a variety of different medical conditions, Sanofi-Aventis eventually narrowed down the therapeutic indications of the compound to just appetite suppression. Drinabant reached phase IIb clinical trials for this purpose in the treatment of obesity but was shortly thereafter discontinued,[4] likely due to the observation of severe psychiatric side effects including anxiety, depression, and thoughts of suicide in patients treated with the now-withdrawn rimonabant, another CB1 antagonist that was also under development by Sanofi-Aventis.[5]
78.1 See also • Cannabinoid receptor antagonist
78.2 References [1] Lange JH, Kruse CG (2008). “Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives”. Chemical Record (New York, N.Y.) 8 (3): 156–68. doi:10.1002/tcr.20147. PMID 18563799. [2] Kwon MO, Herrling P (2005). “List of drugs in development for neurodegenerative diseases. Update September 2005”. Neuro-degenerative Diseases 2 (2): 61–108. doi:10.1159/000089285. PMID 16909049. [3] Gerald Litwack (14 August 2009). Anandamide. Academic Press. p. 172. ISBN 978-0-12-374782-2. Retrieved 13 May 2012. [4] Reggio, Patricia H. (2009). “Toward the design of cannabinoid CB1 receptor inverse agonists and neutral antagonists”. Drug Development Research 70 (8). doi:10.1002/ddr.20337. ISSN 0272-4391. [5] Lee HK, Choi EB, Pak CS (2009). “The current status and future perspectives of studies of cannabinoid
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receptor 1 antagonists as anti-obesity agents”. Current Topics in Medicinal Chemistry 9 (6): 482–503. doi:10.2174/156802609788897844. PMID 19689362.
Chapter 79
EAM-2201 EAM-2201 (4'-ethyl-AM-2201, 5"-fluoro-JWH-210) is a drug that presumably acts as a potent agonist for the cannabinoid receptors. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in Japan in July 2012 as an ingredient in synthetic cannabis smoking blends.[1] Like the closely related MAM-2201 which had been first reported around a year earlier, EAM-2201 thus appears to be another novel compound invented by designer drug suppliers specifically for recreational use. Structurally, EAM2201 is a hybrid of two known cannabinoid compounds JWH-210 and AM-2201, both of which had previously been used as active ingredients in synthetic cannabis blends before being banned in many countries.
79.4 References
79.1 Pharmacology Nothing has been published on the pharmacology of EAM-2201, though it presumably has similar properties to the closely related AM-2201 and JWH-210, which are both full agonists and unselectively bind to CB1 and CB2 cannabinoid receptors with low nanomolar affinity.
79.2 Legal status EAM-2201 was banned in New Zealand as a temporary class drug from 6 December 2012, after reports of addiction and psychosis associated with use of products containing EAM-2201 as an active ingredient, however this has been protested by some s who claim to have found medical benefits in the treatment of conditions such as phantom limb pain, since medicinal marijuana is not available in New Zealand and synthetic cannabis products are used as a legal alternative.[2][3]
79.3 Detection A forensic standard of EAM-2201 is available and commonly used in mass spectrometry, and the compound has been cited on the Forendex website of potential drugs of abuse.[4][5] 109
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [2] I was possessed by a demon, says ex-legal high . New Zealand Herald, Monday 1 Oct 2012 [3] Amputee: K2 'takes away my pain'. New Zealand Herald, Wednesday 28 Nov 2012 [4] https://www.caymanchem.com/app/template/Product. vm/catalog/ISO00127 [5] Peter Rösner, G. Fritschi, Southern Association of Forensic Scientists, http://forendex.southernforensic. org/s/references/Molecular_Index_Of_ _Cannabimimetics_(2).pdf
Chapter 80
Endocannabinoid reuptake inhibitor Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit or completely stop the reabsorption of endocannabinoid neurotransmitters into their corresponding pre-synaptic neurons.
80.1 Etymology There are several parts to the phrase endocannabinoid reuptake inhibitor. First, a reuptake inhibitor is a substance that prevents its respective neurotransmitters from being reabsorbed into the pre-sypnatic neurones, which makes them continually recycle themselves, thus creating a large increase in neurotransmission. Next, a cannabinoid is simply a class of closely related substances such as Tetrahydrocannabinol and Cannabidiol. 'Endo' is a prefix used to describe a cannabinoid that is naturally found within an animal. In retrospect, an endocannabinoid reuptake inhibitor is a substance that when ingested by an animal prevents reuptake of its endogenous cannabinoids. Endocannabinoid uptake inhibitors that bind to fatty acid binding protons (FABPs) have been described.
docannabinoid system using VDM-11 and AA-5-HT reduced the ultimate size of the tumors in the treated rats. These findings suggest that the use of cannabinoids and/or eCBR inhibitors could be used to effectively treat tumors and/or cancer, which only adds to the controversy around cannabinoids and the cannabis plant as medicine. As one might expect, combining a cannabinoid receptor antagonist with an eCBRI reverses the effects of the reuptake inhibitor, and therefore could hinder treatment. Cannabinoid receptor antagonists aren't something common, so normally this isn't something to worry about. But if smoked cannabis or cannabis extract is to be used as a treatment, it would be necessary to cultivate varieties with little to no amounts of these compounds, as they are found in low concentrations in most varieties. One example of these antagonist compounds which is found in the cannabis plant is THCV (tetrahydrocannabivarin).
80.4 Examples of eCBRIs • AM404 • O-2093
80.2 Pharmacology
• OMDM-2
The inhibition of endocannabinoid reuptake raises the amount of those neurotransmitters available in the synaptic cleft and therefore increases neurotransmission. Following the increase of neurotransmission in the endocannabinoid system is the stimulation of its functions which, in humans, include: suppression of pain perception (analgesia), increased appetite, mood elevation and inhibition of short-term memory.
• UCM-707 • VDM-11 • URB597
80.5 See also • Endocannabinoid system
80.3 Use in medicine Other than toxicity research and recreational use, eCBRIs could have some potential in fighting tumors and possibly cancer. A study done in 2004 on rats with thyroid tumors showed that reuptake inhibition of the en110
• Reuptake inhibitor • Cannabinoid receptor antagonist • Endocannabinoid transporters
80.6. REFERENCES
80.6 References 1. http://www.fasebj.org/cgi/content/full/18/13/1606 2. http://www.ncbi.nlm.nih.gov/pubmed/16770320 3. PLOS ONE
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Chapter 81
Endocannabinoid system The endocannabinoid system is a group of neuromodulatory lipids and their receptors in the brain that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory; it mediates the psychoactive effects of cannabis and, broadly speaking, includes:
that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement.[10] In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps • The endogenous arachidonate-based lipids, explain why cannabinoids possess a greater efficacy in alanandamide (N-arachidonoylethanolamide, AEA) tering rodent motor movements than they do in humans. and 2-arachidonoylglycerol (2-AG); these are A recent analysis of cannabinoid binding in CB1 and known as "endocannabinoids" and are physio- CB2 receptor knockout-mice found cannabinoid responlogical ligands for the cannabinoid receptors. siveness even when these receptors were not being exEndocannabinoids are all eicosanoids.[1] pressed, indicating that an additional binding receptor may be present in the brain.[10] Binding has been demon• The enzymes that synthesize and degrade the endo- strated by 2-arachidonoylglycerol (2-AG) on the TRPV1 cannabinoids, such as fatty acid amide hydrolase or receptor suggesting that this receptor may be a candidate monoacylglycerol lipase. for the established response.[11] • The cannabinoid receptors CB1 and CB2 , two G protein-coupled receptors that are located in the 81.1.2 central and peripheral nervous systems.
The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators[2][3][4] for a variety of physiological processes, including motor learning,[5] synaptic plasticity,[6] appetite,[7] and pain sensation.[8]
81.1 Basic overview 81.1.1
Expression of receptors
For a more thorough description on receptor localization, see Cannabinoid receptor type 1 (CB1 ) and Cannabinoid receptor type 2 (CB2 ).
Endocannabinoid synthesis, lease, and degradation
re-
During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades. Based on the cell, these effects may result in the onsite synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.[9] Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized. This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the stria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered the synthesis of anandamide.[11]
Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain Evidence suggests that the depolarization-induced influx and immune system respectively.[9] Density of expression of calcium into the post-synaptic neuron causes the acvaries based on species and correlates with the efficacy tivation of an enzyme called transacylase. This enzyme 112
81.1. BASIC OVERVIEW is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acylphosphatidylethanolamine (NAPE). Experiments have shown that phospholipase D cleaves NAPE to yield anandamide.[12][13] In NAPE-phospholipase D (NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis.[14] The synthesis of 2-AG is less established and warrants further research.
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but also the PI3/PKB and MEK/ERK pathway (GalveRoperh et al., 2002; Davis et al., 2005; Jones et al., 2005; Graham et al., 2006). Results from rat hippocampal gene chip data after acute istration of tetrahydrocannabinol (THC) showed an increase in the expression of transcripts encoding myelin basic protein, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin and ribosomal RNAs (Kittler et al., 2000). In addition, CB1 activation has been demonstrated to increase the activity of tranOnce released into the extracellular space by a puta- scription factors like c-Fos and Krox-24 (Graham et al., 2006). tive endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves 81.1.4 Binding and neuronal excitability anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL), and 2-AG into arachi- The molecular mechanisms of CB1 -mediated changes donic acid and glycerol.[15] While arachidonic acid is a to the membrane voltage have also been studied in desubstrate for leukotriene and prostaglandin synthesis, it tail. CB1 agonists reduce calcium influx by blocking N-, P/Q- and L-type is unclear whether this degradative byproduct has novel the activity of voltage-dependent [19][20] [16][17] calcium channels. In addition to acting on calfunctions in the central nervous system. Emerging cium channels, activation of Gi/o and Gs, the two most data in the field also points to FAAH being expressed commonly coupled G-proteins to cannabinoid receptors, in postsynaptic neurons complementary to presynaptic has been shown to modulate potassium channel activity. neurons expressing cannabinoid receptors, ing the Recent studies have found that CB activation specif1 conclusion that it is major contributor to the clearance ically facilitates GIRK, a potassium channel belonging and inactivation of anandamide and 2-AG after endo[20] Both Guo & Ikeda and Binzen et cannabinoid reuptake.[10] A neuropharmacological study to the Kir3 family. al. performed a series of immunohistochemistry experdemonstrated that an inhibitor of FAAH (URB597) seiments that demonstrated CB1 co-localized with GIRK lectively increases anandamide levels in the brain of roand Kv1.4 potassium channels, suggesting that these two dents and primates. Such approaches could lead to the [21] may interact in physiological contexts. development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompa- In the central nervous system, CB1 receptors influence nied by overt signs of abuse liability.[18] neuronal excitability, reducing the incoming synaptic [22] This mechanism, known as presynaptic inhiNotably, a series of recent studies have found that the input. bition, occurs when a postsynaptic neuron releases enexpression of endocannabinoids does not correlate with docannabinoids in retrograde transmission, which then the distribution of cannabinoid receptors in the brain, bind to cannabinoid receptors on the presynaptic termisuggesting that these molecules may also be interactnal. CB receptors then reduce the amount of neurotrans1 ing with other receptors or be involved with other cell [10] mitter released, so that subsequent excitation in the presyprocesses. naptic neuron results in diminished effects on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, 81.1.3 Binding and intracellular effects although recent evidence has shown that CB1 receptors Cannabinoid receptors are G-protein coupled receptors can also regulate neurotransmitter release by a non-ion located on the pre-synaptic membrane. While there have channel mechanism, i.e. through Gi/o-mediated inhibibeen some papers that have linked concurrent stimula- tion of adenylyl cyclase and Protein Kinase A.[23] Still, tion of dopamine and CB1 receptors to an acute rise in direct effects of CB1 receptors on membrane excitabilcyclic adenosine monophosphate (cAMP) production, it ity have been reported, and strongly impact the firing of is generally accepted that CB1 activation via cannabi- cortical neurons[24] In a series of behavioral experiments, noids causes a decrease in cAMP concentration by inhi- Palazzo et al. demonstrated that NMDA, an ionotropic bition of adenylyl cyclase and a rise in the concentration glutamate receptor, and the metabotropic glutamate reof mitogen-activated protein kinase (MAP kinase).[1][10] ceptors (mGluRs) work in concert with CB1 to induce The relative potency of different cannabinoids in inhi- analgesia in mice, although the mechanism underlying bition of adenylyl cyclase correlates with their varying this effect is unclear. Together, these findings suggest that efficacy in behavioral assays. This inhibition of cAMP CB1 influences neuronal excitability by a variety of mechis followed by phosphorylation and subsequent activa- anisms, and these effects are relevant to perception and tion of not only a suite of MAP kinases (p38/p42/p44), behavior.
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CHAPTER 81. ENDOCANNABINOID SYSTEM
81.2 Functions of the endocannabinoid system
ilar post-synaptic receptor dependencies were found in the striatum, but here both effects relied on presynaptic CB1 receptors.[11] These findings provide the brain a direct mechanism to selectively inhibit neuronal excitabil81.2.1 Memory ity over variable time scales. By selectively internalizing different receptors, the brain may limit the production of Mice treated with tetrahydrocannabinol (THC) show sup- specific endocannabinoids to favor a time scale in accorpression of long-term potentiation in the hippocampus, a dance with its needs. process that is essential for the formation and storage of long-term memory.[25] These results concur with anecdotal evidence suggesting that smoking Cannabis impairs short-term memory.[26] Consistent with this finding, mice without the CB1 receptor show enhanced memory and 81.2.2 Appetite long-term potentiation indicating that the endocannabinoid system may play a pivotal role in the extinction of old Evidence for the role of the endocannabinoid system in memories. In contrast, a recent study found that the high- food-seeking behavior comes from a variety of cannabidose treatment of rats with the synthetic cannabinoid HU- noid studies. Emerging data suggests that THC acts via 210 over several weeks resulted in stimulation of neural CB1 receptors in the hypothalamic nuclei to directly ingrowth in the rats’ hippocampus region, a part of the lim- crease appetite.[30] It is thought that hypothalamic neubic system playing a part in the formation of declarative rons tonically produce endocannabinoids that work to and spatial memories.[27] Taken together, these findings tightly regulate hunger. The amount of endocannabisuggest that the effects of endocannabinoids on memory noids produced is inversely correlated with the amount of are dependent on what type of neurons are being targeted leptin in the blood.[31] For example, mice without leptin (excitatory vs. inhibitory) and the location of these net- not only become massively obese but express abnormally works in the brain. high levels of hypothalamic endocannabinoids as a comRole in hippocampal neurogenesis In the adult brain, the endocannabinoid system facilitates the neurogenesis of hippocampal granule cells.[27][28] In the subgranular zone of the dentate gyrus, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region.[29] NPs in the hippocampus have been shown to possess fatty acid amide hydrolase (FAAH) and express CB1 and utilize 2-AG.[28] Intriguingly, CB1 activation by endogenous or exogenous cannabinoids promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.[27][28]
pensatory mechanism.[7] Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as rimonabant, food intake was reduced.[7] When the CB1 receptor is knocked-out in mice, these animals tend to be leaner and less hungry than wild-type mice. A related study examined the effect of THC on the hedonic (pleasure) value of food and found enhanced dopamine release in the nucleus accumbens and increased pleasure-related behavior after istration of a sucrose solution.[32] A related study found that endocannabinoids affect taste perception in taste cells[33] In taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet tastes, whereas leptin decreased the strength of this same response. While there is need for more research, these results suggest that cannabinoid activity in the hypothalamus and nucleus accumbens is related to appetitive, food-seeking behavior.[30]
Induction of synaptic depression The inhibitory effects of cannabinoid receptor stimulation on neurotransmitter release have caused this system to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of the stria terminalis found that the endurance of the depressant effects was mediated by two different signaling pathways based on the type of receptor activated. 2AG was found to act on presynaptic CB1 receptors to mediate retrograde short-term depression (STD) following activation of L-type calcium currents, while anandamide was synthesized after mGluR5 activation and triggered autocrine signalling onto postsynapic TRPV1 receptors that induced long-term depression (LTD). Sim-
81.2.3 Energy balance & metabolism The endocannabinoid system has been shown to have a homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It acts on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. It has also been implied in modulating insulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such as obesity, diabetes, and atherosclerosis, which may also give it a cardiovascular role.[34]
81.2. FUNCTIONS OF THE ENDOCANNABINOID SYSTEM
81.2.4
Stress response
While the secretion of glucocorticoids in response to stressful stimuli is an adaptive response necessary for an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of the hypothalamic-pituitary-adrenal axis (HPA axis) to repeated exposure to restraint stress. Studies have demonstrated differential synthesis of anandamide and 2-AG during tonic stress. A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB1 antagonist AM251, ing the conclusion that these effects were cannabinoid-receptor dependent.[35] These findings show that anandamide and 2-AG divergently regulate the HPA axis response to stress: while habituation of the stress-induced HPA axis via 2-AG prevents excessive secretion of glucocorticoids to non-threatening stimuli, the increase of basal corticosterone secretion resulting from decreased anandamide allows for a facilitated response of the HPA axis to novel stimuli.
Exploration, social behavior, and anxiety Prolonged, systemic exposure to cannabinoids has often been associated with anti-social effects. To investigate this theory, a cannabinoid receptor-knockout mouse study examined the effect that these receptors play on exploratory behavior. Researchers selectively targeted glutamatergic and GABAergic cortical interneurons and studied results in open field, novel object, and sociability tests. Eliminating glutamaterigic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement.[36] These contrasting effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: excessive excitation produces anxiety that limited the mice from exploring both animate and inanimate objects. In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism’s overall sense of arousal during novel situations.
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81.2.5 Immune function Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.[1] Functionally, the activation of cannabinoid receptors has been demonstrated to play a role in the activation of GTPases in macrophages, neutrophils, and BM cells. These receptors have also been implicated in the proper migration of B cells into the marginal zone (MZ) and the regulation of healthy IgM levels.[37] Interestingly, some disorders seem to trigger an upregulation of cannabinoid receptors selectively in cells or tissues related to symptom relief and inhibition of disease progression, such as in that rodent neuropathic pain model, where receptors are increased in the spinal cord microglia, dorsal root ganglion, and thalmic neurons.[9]
Multiple sclerosis Historical records from ancient China and Greece suggest that preparations of Cannabis Indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity. It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans.[38][39] Due to increasing use of medical Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief.[26] In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum.[40] Serial sections of cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease.[40] Other studies suggest that CB1 agonists promote the survival of oligodendrocytes in vitro in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; MollnaHolgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002). 2-AG stimulates proliferation of a microglial cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.[41]
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81.2.6
CHAPTER 81. ENDOCANNABINOID SYSTEM
Female reproduction
See also: Cannabis in pregnancy The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low.[42] These results suggest that intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.[43][44]
81.2.7
Autonomic nervous system
Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.[10]
names Normast and PeaPure as nutraceuticals. Endocannabinoids are involved in placebo induced analgesia responses.[46]
81.2.9 Thermoregulation Anandamide and N-arachidonoyl dopamine (NADA) have been shown to act on temperature-sensing TRPV1 channels, which are involved in thermoregulation.[47] TRPV1 is activated by the exogenous ligand capsaicin, the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates the TRPV1 channel with an EC50 of approximately of 50 nM. The high potency makes it the putative endogenous TRPV1 agonist.[48] Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation.[10] TRPV1 may also be activated by methanandamide and arachidonyl-2'chloroethylamide (ACEA).[1]
81.2.10 Sleep
Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects. Intercerebroventricular istration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep.[49] istration of anandamide into the basal forebrain of rats has also been shown to increase levels of adenosine, which plays a role in promoting sleep and suppressing arousal.[50] REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system.[51] Furthermore, anandamide levels possess a 81.2.8 Analgesia circadian rhythm in the rat, with levels being higher in At the spinal cord, cannabinoids suppress noxious- the light phase of the day, which is when rats are usually stimulus-evoked responses of neurons in the dorsal horn, asleep or less active, since they are nocturnal.[52] possibly by modulating descending noradrenaline input from the brainstem.[10] As many of these fibers are primarily GABAergic, cannabinoid stimulation in the spinal 81.3 Experimental use of CB1 -/column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuliphenotype processing in the periphery and dorsal root ganglion. The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor, the TRPV receptor and the GRP55 receptor. Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications[45] and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethanolamide is available under the brand
Neuroscientists often utilize transgenic CB1 knock-out mice to discern novel roles for the endocannabinoid system. While CB1 knock-out mice are healthy and live into adulthood, there are significant differences between CB1 knock-out and wild-type mice. When subjected to a high-fat diet, CB1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype.[53] Compared to wildtype, CB1 knockout mice exhibit severe deficits in motor learning, memory retrieval, and increased difficulty in completing the Morris water maze.[5][54][55] There is also evidence indicating that these knockout animals have an increased incidence and severity of stroke and seizure.[56][57]
81.4. REFERENCES
81.4 References [1] Pertwee RG (April 2006). “The pharmacology of cannabinoid receptors and their ligands: an overview”. Int J Obes (Lond) 30 (Suppl 1): S13–8. doi:10.1038/sj.ijo.0803272. PMID 16570099. [2] Fortin DA, Levine ES (2007). “Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons”. Cereb. Cortex 17 (1): 163– 74. doi:10.1093/cercor/bhj133. PMID 16467564. [3] Good CH (2007). “Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells”. J. Neurosci. 27 (1): 1–3. doi:10.1523/JNEUROSCI.4842-06.2007. PMID 17205618. [4] Hashimotodani Y, Ohno-Shosaku T, Kano M (2007). “Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus”. J. Neurosci. 27 (5): 1211–9. doi:10.1523/JNEUROSCI.415906.2007. PMID 17267577. [5] Kishimoto Y, Kano M (2006). “Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning”. J. Neurosci. 26 (34): 8829–37. doi:10.1523/JNEUROSCI.1236-06.2006. PMID 16928872. [6] Brenowitz SD, Regehr WG (2005). “Associative short-term synaptic plasticity mediated by endocannabinoids”. Neuron 45 (3): 419–31. doi:10.1016/j.neuron.2004.12.045. PMID 15694328. [7] Di Marzo V, Goparaju SK, Wang L, et al. (April 2001). “Leptin-regulated endocannabinoids are involved in maintaining food intake”. Nature 410 (6830): 822–5. doi:10.1038/35071088. PMID 11298451. [8] Cravatt BF, Demarest K, Patricelli MP, et al. (July 2001). “Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase”. Proc. Natl. Acad. Sci. U.S.A. 98 (16): 9371–6. Bibcode:2001PNAS...98.9371C. doi:10.1073/pnas.161191698. JSTOR 3056353. PMC 55427. PMID 11470906. [9] Pertwee RG (January 2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin”. Br. J. Pharmacol. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291. [10] Elphick MR, Egertová M (March 2001). “The neurobiology and evolution of cannabinoid signalling”. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486. [11] Puente N, Cui Y, Lassalle O, et al. (December 2011). “Polymodal activation of the endocannabinoid system in the extended amygdala”. Nat. Neurosci. 14 (12): 1542– 7. doi:10.1038/nn.2974. PMID 22057189.
117
[12] Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (February 2004). “Molecular characterization of a phospholipase D generating anandamide and its congeners”. J. Biol. Chem. 279 (7): 5298–305. doi:10.1074/jbc.M306642200. PMID 14634025. [13] Liu J, Wang L, Harvey-White J, et al. (September 2006). “A biosynthetic pathway for anandamide”. Proc. Natl. Acad. Sci. U.S.A. 103 Bibcode:2006PNAS..10313345L. (36): 13345–50. doi:10.1073/pnas.0601832103. PMC 1557387. PMID 16938887. [14] Leung D, Saghatelian A, Simon GM, Cravatt BF (April 2006). “Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids”. Biochemistry 45 (15): 4720–6. doi:10.1021/bi060163l. PMC 1538545. PMID 16605240. [15] Pazos MR, Núñez E, Benito C, Tolón RM, Romero J (June 2005). “Functional neuroanatomy of the endocannabinoid system”. Pharmacol. Biochem. Behav. 81 (2): 239–47. doi:10.1016/j.pbb.2005.01.030. PMID 15936805. [16] Yamaguchi T, Shoyama Y, Watanabe S, Yamamoto T (January 2001). “Behavioral suppression induced by cannabinoids is due to activation of the arachidonic acid cascade in rats”. Brain Res. 889 (1–2): 149–54. doi:10.1016/S0006-8993(00)03127-9. PMID 11166698. [17] Brock TG (December 2005). “Regulating leukotriene synthesis: the role of nuclear 5-lipoxygenase”. J. Cell. Biochem. 96 (6): 1203–11. doi:10.1002/jcb.20662. PMID 16215982. [18] Clapper JR, Mangieri RA, Piomelli D (2009). “The endocannabinoid system as a target for the treatment of cannabis dependence”. Neuropharmacology 56 (Suppl 1): 235–43. doi:10.1016/j.neuropharm.2008.07.018. PMC 2647947. PMID 18691603. [19] Twitchell W, Brown S, Mackie K (1997). “Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons”. J. Neurophysiol. 78 (1): 43–50. PMID 9242259. [20] Guo J, Ikeda SR (2004). “Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons”. Mol. Pharmacol. 65 (3): 665–74. doi:10.1124/mol.65.3.665. PMID 14978245. [21] Binzen U, Greffrath W, Hennessy S, Bausen M, SaalerReinhardt S, Treede RD (2006). “Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons”. Neuroscience 142 (2): 527– 39. doi:10.1016/j.neuroscience.2006.06.020. PMID 16889902. [22] Freund TF, Katona I, Piomelli D (2003). “Role of endogenous cannabinoids in synaptic signaling”. Physiol.
118
CHAPTER 81. ENDOCANNABINOID SYSTEM
Rev. 83 (3): 1017–66. doi:10.1152/physrev.00004.2003 (inactive 2010-07-25). PMID 12843414. [23] Chevaleyre V, Heifets BD, Kaeser PS, Südhof TC, Purpura DP, Castillo PE (2007). “ENDOCANNABINOIDMEDIATED LONG-TERM PLASTICITY REQUIRES cAMP/PKA SIGNALING AND RIM1α". Neuron 54 (5): 801–12. doi:10.1016/j.neuron.2007.05.020. PMC 2001295. PMID 17553427. [24] Bacci A, Huguenard JR, Prince DA (2004). “Longlasting self-inhibition of neocortical interneurons mediated by endocannabinoids”. Nature 431 (7006): 312–6. Bibcode:2004Natur.431..312B. doi:10.1038/nature02913. PMID 15372034. [25] Hampson RE, Deadwyler SA (1999). “Cannabinoids, hippocampal function and memory”. Life Sci. 65 (6–7): 715–23. doi:10.1016/S0024-3205(99)00294-5. PMID 10462072. [26] Pertwee RG (2001). “Cannabinoid receptors and pain”. Prog. Neurobiol. 63 (5): 569–611. doi:10.1016/S03010082(00)00031-9. PMID 11164622. [27] Jiang W, Zhang Y, Xiao L et al. (2005). “Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects”. J. Clin. Invest. 115 (11): 3104– 16. doi:10.1172/JCI25509. PMC 1253627. PMID 16224541. [28] Aguado T, Monory K, Palazuelos J et al. (2005). “The endocannabinoid system drives neural progenitor proliferation”. FASEB J. 19 (12): 1704–6. doi:10.1096/fj.053995fje. PMID 16037095. [29] Christie BR, Cameron HA (2006). “Neurogenesis in the adult hippocampus”. Hippocampus 16 (3): 199–207. doi:10.1002/hipo.20151. PMID 16411231. [30] Kirkham TC, Tucci SA (2006). “Endocannabinoids in appetite control and the treatment of obesity”. CNS Neurol Disord Drug Targets 5 (3): 272–92. doi:10.2174/187152706777452272. PMID 16787229.
[34] Bellocchio L, Cervino C, Pasquali R, Pagotto U (June 2008). “The endocannabinoid system and energy metabolism”. J. Neuroendocrinol. 20 (6): 850– 7. doi:10.1111/j.1365-2826.2008.01728.x. PMID 18601709. [35] Hill MN, McLaughlin RJ, Bingham B, et al. (May 2010). “Endogenous cannabinoid signaling is essential for stress adaptation”. Proc. Natl. Acad. Sci. U.S.A. 107 (20): 9406–11. Bibcode:2010PNAS..107.9406H. doi:10.1073/pnas.0914661107. PMC 2889099. PMID 20439721. [36] Häring M, Kaiser N, Monory K, Lutz B (2011). “Circuit specific funcBurgess, Harold A, ed. tions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration”. PLoS ONE Bibcode:2011PLoSO...626617H. 6 (11): e26617. doi:10.1371/journal.pone.0026617. PMC 3206034. PMID 22069458. [37] Basu S, Ray A, Dittel BN (December 2011). “Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses”. J. Immunol. 187 (11): 5720–32. doi:10.4049/jimmunol.1102195. PMC 3226756. PMID 22048769. [38] Baker D, Pryce G, Croxford JL et al. (2000). “Cannabinoids control spasticity and tremor in a multiple sclerosis model”. Nature 404 (6773): 84–7. doi:10.1038/35003583. PMID 10716447. [39] Baker D, Pryce G, Croxford JL et al. (2001). “Endocannabinoids control spasticity in a multiple sclerosis model”. FASEB J. 15 (2): 300–2. doi:10.1096/fj.000399fje. PMID 11156943. [40] Cabranes A, Pryce G, Baker D, Fernández-Ruiz J (August 2006). “Changes in CB1 receptors in motor-related brain structures of chronic relapsing experimental allergic encephalomyelitis mice”. Brain Res. 1107 (1): 199–205. doi:10.1016/j.brainres.2006.06.001. PMID 16822488.
[31] Di Marzo V, Sepe N, De Petrocellis L, et al. (December 1998). “Trick or treat from food endocannabinoids?". Nature 396 (6712): 636–7. Bibcode:1998Natur.396..636D. doi:10.1038/25267. PMID 9872309.
[41] Carrier EJ, Kearn CS, Barkmeier AJ, et al. (April 2004). “Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism”. Mol. Pharmacol. 65 (4): 999–1007. doi:10.1124/mol.65.4.999. PMID 15044630.
[32] De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G (July 2012). “Cannabinoid facilitation of behavioral and biochemical hedonic taste responses”. Neuropharmacology 63 (1): 161–8. doi:10.1016/j.neuropharm.2011.10.018. PMC 3705914. PMID 22063718.
[42] Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A (2000). “Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage”. Lancet 355 (9212): 1326–9. doi:10.1016/S0140-6736(00)02115-2. PMID 10776746.
[33] Yoshida R, Ohkuri T, Jyotaki M, et al. (January 2010). “Endocannabinoids selectively enhance sweet taste”. Proc. Natl. Acad. Sci. U.S.A. 107 (2): 935–9. Bibcode:2010PNAS..107..935Y. doi:10.1073/pnas.0912048107. JSTOR 40535875. PMC 2818929. PMID 20080779.
[43] Das SK, Paria BC, Chakraborty I, Dey SK (1995). “Cannabinoid ligand-receptor signaling in the mouse uterus”. Proc. Natl. Acad. Sci. U.S.A. 92 (10): 4332–6. Bibcode:1995PNAS...92.4332D. doi:10.1073/pnas.92.10.4332. PMC 41938. PMID 7753807.
81.5. FURTHER READING
[44] Paria BC, Das SK, Dey SK (1995). “The preimplantation mouse embryo is a target for cannabinoid ligandreceptor signaling”. Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9460–4. Bibcode:1995PNAS...92.9460P. doi:10.1073/pnas.92.21.9460. PMC 40821. PMID 7568154. [45] Keppel Hesselink, J.M. (2002). “New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide”. The Open Pain Journal () 5: 12–23. doi:10.2174/1876386301205010012. Retrieved 2014-01-15. [46] Colloca, Luana (2013-08-28). Placebo and Pain: From Bench to Bedside (1st ed.). Elsevier Science. pp. 11–12. ISBN 9780123979315. [47] Ross RA (November 2003). “Anandamide and vanilloid TRPV1 receptors”. Br. J. Pharmacol. 140 (5): 790– 801. doi:10.1038/sj.bjp.0705467. PMC 1574087. PMID 14517174.
119
[55] Niyuhire F, Varvel SA, Martin BR, Lichtman AH (2007). “Exposure to marijuana smoke impairs memory retrieval in mice”. J. Pharmacol. Exp. Ther. 322 (3): 1067–75. doi:10.1124/jpet.107.119594. PMID 17586723. [56] Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS (September 2002). “Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control”. J. Neurosci. 22 (17): 7695–711. PMID 12196593. [57] Marsicano G, Goodenough S, Monory K, et al. (October 2003). “CB1 cannabinoid receptors and on-demand defense against excitotoxicity”. Science Bibcode:2003Sci...302...84M. 302 (5642): 84–8. doi:10.1126/science.1088208. PMID 14526074.
81.5 Further reading
[48] Huang SM, Bisogno T, Trevisani M, et al. (June 2002). “An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors”. Proc. Natl. Acad. Sci. U.S.A. 99 (12): 8400–5. Bibcode:2002PNAS...99.8400H. doi:10.1073/pnas.122196999. PMC 123079. PMID 12060783.
• Neumeister A, Normandin MD, Pietrzak RH, et al. (2013). “Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study”. Molecular Psychiatry. doi:10.1038/mp.2013.61. Lay summary – ScienceDaily (May 14, 2013).
[49] Murillo-Rodríguez E, Sánchez-Alavez M, Navarro L, Martínez-González D, Drucker-Colín R, Prospéro-García O (November 1998). “Anandamide modulates sleep and memory in rats”. Brain Res. 812 (1–2): 270–4. doi:10.1016/S0006-8993(98)00969-X. PMID 9813364.
• Földy C, Malenka RC, Südhof TC (May 2013). “Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling”. Neuron 78 (3): 498–509. doi:10.1016/j.neuron.2013.02.036. PMC 3663050. PMID 23583622. Lay summary – ScienceDaily (April 11, 2013).
[50] Santucci V, Storme JJ, Soubrié P, Le Fur G (1996). “Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis”. Life Sci. 58 (6): PL103–10. doi:10.1016/00243205(95)02319-4. PMID 8569415. [51] Wang L, Yang T, Qian W, Hou X (January 2011). “The role of endocannabinoids in visceral hyposensitivity induced by rapid eye movement sleep deprivation in rats: regional differences”. Int. J. Mol. Med. 27 (1): 119–26. doi:10.3892/ijmm.2010.547. PMID 21057766. [52] Murillo-Rodriguez E, Désarnaud F, Prospéro-García O (May 2006). “Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat”. Life Sci. 79 (1): 30–7. doi:10.1016/j.lfs.2005.12.028. PMID 16434061. [53] Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrié P (2004). “CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity”. Int. J. Obes. Relat. Metab. Disord. 28 (4): 640–8. doi:10.1038/sj.ijo.0802583. PMID 14770190. [54] Varvel SA, Lichtman AH (2002). “Evaluation of CB1 receptor knockout mice in the Morris water maze”. J. Pharmacol. Exp. Ther. 301 (3): 915–24. doi:10.1124/jpet.301.3.915. PMID 12023519.
• Puighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A (September 2009). “Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling”. Nat. Neurosci. 12 (9): 1152–8. doi:10.1038/nn.2369. PMID 19648913. Lay summary – ScienceDaily (August 4, 2009). • Niehaus JL, Liu Y, Wallis KT, et al. (December 2007). “CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a”. Mol. Pharmacol. 72 (6): 1557– 66. doi:10.1124/mol.107.039263. PMC 2644445. PMID 17895407. Lay summary – ScienceDaily (November 30, 2007).
81.6 External links • Homepage of the ICRS - The International Cannabinoid Research Society • Homepage of the ECSN - The Endocannabinoid System Network
Chapter 82
Endocannabinoid transporters Most neurotransmitters are water-soluble and require transmembrane proteins to transport them across the cell membrane. The endocannabinoids (anandamide, AEA, and 2-arachidonoylglycerol, 2-AG) on the other hand, are non-charged lipids that readily cross lipid membranes.[1][2][3][4][5] However, since the endocannabinoids are water immiscible, protein transporters have been described that act as carriers to solubilize and transport the endocannabinoids through the aqueous cytoplasm. These include the heat shock proteins (Hsp70s) and fatty acid binding proteins for anandamide (FABPs).[6][7] FABP inhibitors attenuate the breakdown of anandamide by the enzyme fatty acid amide hydrolase (FAAH) in cell culture.[6] One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds (named the “truxilloids’) that act as a anti-nociceptive agent with mild anti-inflammatory activity in mice.[8] These truxillic acids and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice[9] and are active components of a Chinese herbal medicine ((-)-Incarvillateine Incarvillea sinensis) used to treat rheumatism and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their antinociceptive effects.
82.1 References [1] Kaczocha, Martin; Lin, Qingqing; Nelson, Lindsay D.; McKinney, Michelle K.; Cravatt, Benjamin F.; London, Erwin; Deutsch, Deutsch (2012). “Anandamide Externally Added to Lipid Vesicles Containing-Trapped Fatty Acid Amide Hydrolase (FAAH) Is Readily Hydrolyzed in a Sterol-Modulated Fashion”. ACS Chemical Neuroscience 3 (5): 364–368. doi:10.1021/cn300001w. PMID 22860204. [2] Bojesen, Inge N.; Hansen, Harald S. (2005). “Membrane transport of anandamide through resealed human red blood cell membranes”. The Journal of Lipid Research. 46 no. (8): 1652–1659. doi:10.1194/jlr.M400498JLR200. [3] Kaczocha, Martin; Hermann, Anita; Glaser, Sherrye T.; Bojesen, Inge N.; Deutsch, Dale G. (2006). “Anandamide
120
Uptake Is Consistent with Rate-limited Diffusion and Is Regulated by the Degree of Its Hydrolysis by Fatty Acid Amide Hydrolase”. The Journal of Biological Chemistry 281 (14): 9066–9075. doi:10.1074/jbc.M509721200. PMID 16461355. [4] Sandberg, A.; Fowler, C.J. (2005). “Measurement of saturable and non-saturable components of anandamide uptake into P19 embryonic carcinoma cells in the presence of fatty acid-free bovine serum albumin.”. Chemistry and Physics of Lipids 134 (2): 131– 139. doi:10.1016/j.chemphyslip.2004.12.010. PMID 15784231. [5] Di Pasquale, E.; Chahinian, H.; Sanchez, P.; Fantini, J. (2009). “The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both CholesterolDependent” [Translated title]. PLoS ONE 4 (3): e4989. doi:10.1371/journal.pone.0004989. PMID 19330032. [6] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). “Identification of intracellular carriers for the endocannabinoid anandamide”. Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565. [7] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgro, A.; Maccarrone, M. (2009). “Molecular identification of albumin and Hsp70 as cytosolic anandamidebinding proteins”. Chemistry & Biology 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. [8] Berger, W.T.; Ralph, B.P.; Kaczocha, M.; Sun, J.; Balius, T.E.; Rizzo, R.C.; Haj-Dahmane, S.; Ojima, I.; Deutsch, D.G. (2012). “Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs”. PLoS ONE 12 (7): e50968. doi:10.1371/journal.pone.0050968. [9] Nakamura, M.; Chi, Y.M.; Yan, W.M.; Nakasugi, Y.; Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nahara, T.; Sakurada, S. (1999). “Strong antinociceptive effect of incarvillateine, a novel monoterpene alkaloid from Incarvillea sinensis”. Journal of Natural Products 62 (9): 1293–1294. doi:10.1021/np990041c. PMID 10514316.
Chapter 83
GW-405,833 GW-405,833 (L-768,242) is a drug that acts as a potent and selective partial agonist for the cannabinoid receptor subtype CB2 , with an EC50 of 0.65nM and selectivity of around 1200x for CB2 over CB1 receptors.[1][2] Animal studies have shown it to possess antiinflammatory and anti-hyperalgesic effects at low doses, followed by ataxia and analgesic effects when the dose is increased.[3][4] Selective CB2 agonist drugs such as GW-405,833 are hoped to be particularly useful in the treatment of allodynia and neuropathic pain for which current treatment options are often inadequate.[5][6]
83.1 References [1] Huffman JW. The search for selective ligands for the CB2 receptor. Current Pharmaceutical Design. 2000 Sep;6(13):1323-37. doi:10.2174/1381612003399347 PMID 10903395 [2] Marriott KS, Huffman JW. Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. Current Topics in Medicinal Chemistry. 2008;8(3):187-204. doi:10.2174/156802608783498014 PMID 18289088 [3] Clayton N, Marshall FH, Bountra C, O'Shaughnessy CT. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain. 2002 Apr;96(3):253-60. PMID 11972997 [4] Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL, Mark L, Pearson MS, Miller W, Shan S, Rabadi L, Rotshteyn Y, Chaffer SM, Turchin PI, Elsemore DA, Toth M, Koetzner L, Whiteside GT. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology. 2005 Apr;48(5):658-72. PMID 15814101 [5] Beltramo M, Bernardini N, Bertorelli R, Camla M, Nicolussi E, Fredduzzi S, Reggiani A. CB2 receptormediated antihyperalgesia: possible direct involvement of neural mechanisms. European Journal of Neuroscience. 2006 Mar;23(6):1530-8. doi:10.1111/j.14609568.2006.04684.x PMID 16553616
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[6] Leichsenring A, Andriske M, Bäcker I, Stichel CC, Lübbert H. Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain. Naunyn Schmiedebergs Archives of Pharmacology. 2009 Jan 18. PMID 19152053
Chapter 84
GW-842,166X GW-842,166X is a drug which acts as a potent and selective cannabinoid CB2 receptor agonist, with a novel chemical structure based on a pyrimidine core. It has potent analgesic, anti-inflammatory and anti-hyperalgesic actions in animal models, but without cannabis-like behavioural effects due to its extremely low affinity for the CB1 receptor.[1][2][3]
84.1 References [1] Giblin GM, O'Shaughnessy CT, Naylor A, Mitchell WL, Eatherton AJ, Slingsby BP, Rawlings DA, Goldsmith P, Brown AJ, Haslam , Clayton NM, Wilson AW, Chessell IP, Wittington AR, Green R (May 2007). “Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro2H-pyran-4-yl)methyl]−4-(trifluoromethyl)5pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain”. Journal of Medicinal Chemistry 50 (11): 2597–600. doi:10.1021/jm061195+. PMID 17477516. [2] Giblin GM, Billinton A, Briggs M, Brown AJ, Chessell IP, Clayton NM, Eatherton AJ, Goldsmith P, Haslam C, Johnson MR, Mitchell WL, Naylor A, Perboni A, Slingsby BP, Wilson AW (October 2009). “Discovery of 1-[4-(3-chlorophenylamino)−1methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]−1-morpholin4-ylmethanone (GSK554418A), a brain penetrant 5-azaindole CB2 agonist for the treatment of chronic pain”. Journal of Medicinal Chemistry 52 (19): 5785–8. doi:10.1021/jm9009857. PMID 19743867. [3] Han, S.; Thatte, J.; Jones, R. M. (2009). “Chapter 11: Recent Advances in the Discovery of CB2 Selective Agonists”. Annual Reports in Medicinal Chemistry 44: 227. doi:10.1016/S0065-7743(09)04411-X.
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Chapter 85
Hemopressin Hemopressin (Hp) is an alpha hemoglobin fragment with the sequence PVNFKFLSH, originally identified in extracts of rat brain using an enzyme capture technique.[1] It binds cannabinoid receptors, acting as an inverse agonist at CB1 receptors.[2] Longer forms of hemopressin containing 2-3 additional amino acids on the N-terminus have been identified in extracts of mouse brain. These longer hemopressin peptides, named RVD-Hpα and VDHpα, bind to CB1 receptors and are agonists.[3] In addition to the Hp peptides from alpha hemoglobin, a related peptide from beta hemoglobin has been found in mouse brain extracts; this peptide, named VD-Hpβ, is also an agonist at CB1 cannabinoid receptors.[3]
85.3 References
The original Hp peptide reduces sensitivity to painful stimuli in an experimental model of hyperalgesia.[4] Hp also reduces food intake in mice.[5] However, it remains to be shown if Hp is an endogenous brain peptide. The original purification used boiling acid to extract the peptide from rat brain, and hot acid can specifically cleave D-P bonds. The N-terminally-extended forms RVDHpα and VD-Hpα may represent the true endogenous forms.[6]
[1] Rioli V, Gozzo FC, Heimann AS, et al. (March 2003). “Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme”. J. Biol. Chem. 278 (10): 8547–55. doi:10.1074/jbc.M212030200. PMID 12500972. [2] Heimann AS, Gomes I, Dale CS, et al. (December 2007). “Hemopressin is an inverse agonist of CB1 cannabinoid receptors”. Proc. Natl. Acad. Sci. U.S.A. 104 (51): 20588–93. Bibcode:2007PNAS..10420588H. doi:10.1073/pnas.0706980105. PMC 2154475. PMID 18077343. [3] Gomes I, Grushko JS, Golebiewska U, et al. (September 2009). “Novel endogenous peptide agonists of cannabinoid receptors”. FASEB J. 23 (9): 3020– 9. doi:10.1096/fj.09-132142. PMC 2735371. PMID 19380512. [4] Dale CS, Pagano Rde L, Rioli V, et al. (March 2005). “Antinociceptive action of hemopressin in experimental hyperalgesia”. Peptides 26 (3): 431–6. doi:10.1016/j.peptides.2004.10.026. PMID 15652650. [5] Dodd GT, Mancini G, Lutz B, et al. (May 2010). “The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice”. J Neurosci. 30 (21): 7369–76. doi:10.1523/JNEUROSCI.545509.2010. PMID 20505104.
85.1 Role in diet Scientists at the University of Manchester have discovered that hemopressin could be used as an appetite suppressant without having the side effects of many other drugs that are used for this purpose. In laboratory tests hemopressin was istrated to mice and rats, which significantly reduced food intake. Hemopressin works by affecting the reward centres of the brain which make us feel happy when we eat too much. A further research should be carried out in order to confirm these effects and the safety on people.[7]
85.2 See also • RVD-Hpα 123
[6] Gelman JS, Sironi J, Castro LM, et al. (May 2010). “Hemopressins and other hemoglobin-derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in efat/fat mice”. J Neurochem. 113 (4): 871–80. doi:10.1111/j.14714159.2010.06653.x. PMC 2867603. PMID 20202081. [7] http://uk.health.lifestyle.yahoo.net/ hemopressin-naturally-supresses-appetite.htm
Chapter 86
HU-210 HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from (1R,5S)-myrtenol[3] by a group led by Professor Raphael Mechoulam at the Hebrew University.[4][5][6] HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action.[7] HU-210 is the (–)−1,1-dimethylheptyl analog of 11-hydroxy- Δ8 - tetrahydrocannabinol; in some references it is called 1,1-dimethylheptyl- 11hydroxytetrahydrocannabinol. The abbreviation “HU” stands for Hebrew University.
86.2 Legal status 86.2.1 United States HU-210 is a schedule I controlled substance under the Controlled Substances Act. [14] To view national schedule, see: List of Schedule I drugs (US),
The (+) enantiomer of HU-210 has almost all of the cannabinoid activity, with the (−) enantiomer HU-211 86.2.2 New Zealand being inactive as a cannabinoid but instead acting as an Banned in New Zealand as of 8 May 2014. NMDA antagonist having neuroprotective effects.[8][9] HU-210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal neural stem and progenitor cells likely via a sequential activation of CB1 receptors, Gᵢ/ₒ proteins, and ERK signaling. It was also indicated by this increased neural growth to entail antianxiety and antidepressant effects.[10]
86.3 Other HU Cannabinoids • HU-211
HU-210, alongside other synthetic cannabinoids like WIN 55,212-2 and JWH-133, is implicated in preventing the inflammation caused by amyloid beta proteins involved in Alzheimer’s disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through the activation of cannabinoid receptors, which prevents microglial activation that elicits the inflammation. In addition, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.[11]
• HU-239
HU-210 is a potent analgesic with many of the same effects as natural THC.
• HU-336
• HU-243 • HU-308 • HU-320 • HU-331
• HU-345
86.1 Recreational use
[15]
86.4 See also
According to the U.S. Customs and Border Protection, HU-210 was discovered in Spice Gold incense products seized at the US border in January 2009. Over 100 pounds of Spice products were seized based on this finding.[12] HU-210 was also detected in three Spice products in the UK, as reported in June 2009.[13] 124
• Spice (drug) • 47,497 • JWH-018
86.6. EXTERNAL LINKS
86.5 References [1] http://www.deadiversion.usdoj.gov/drugs_concern/ spice/spice_hu210.htm [2] http://www.deadiversion.usdoj.gov/schedules/ orangebook/c_cs_alpha.pdf [3] Mechoulam, R., Lander, N., Breuer, A., Zahalka, J. Synthesis of the Individual, Pharmacologically Distinct, Enantiomers of a Tetrahydrocannabinol Derivative. Tetrahedron: Asymmetry. 1990. Vol 1, No 5. pp 315318. [4] Mechoulam, R., et al. (1988). “Enantiomeric cannabinoids: stereospecificity of psychotropic activity”. Experientia 44 (9): 762–764. doi:10.1007/BF01959156. PMID 3416993. [5] Little PJ, Compton DR, Mechoulam R, Martin BR. Stereochemical effects of 11-OH-Δ8-THC-dimethylheptyl in mice and dogs. Pharmacology, Biochemistry, and Behavior. 1989 Mar;32(3):661-666. [6] Järbe, T.; Hiltunen, A.; Mechoulam, R. (1989). “Stereospecificity of the discriminative stimulus functions of the dimethylheptyl homologs of 11-hydroxy-delta 8tetrahydrocannabinol in rats and pigeons”. The Journal of Pharmacology and Experimental Therapeutics 250 (3): 1000–1005. PMID 2550611. [7] Devane, W. A., et al. (1992). “A novel probe for the cannabinoid receptor”. Journal of Medical Chemistry 35 (11): 2065–2069. doi:10.1021/jm00089a018. PMID 1317925. [8] Howlett, A.; Champion, T.; Wilken, G.; Mechoulam, R. (1990). “Stereochemical effects of 11-OH-Δ8tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor”. Neuropharmacology 29 (2): 161. doi:10.1016/00283908(90)90056-W. PMID 2158635. [9] Darlington CL (October 2003). “Dexanabinol: a novel cannabinoid with neuroprotective properties”. IDrugs : the Investigational Drugs Journal 6 (10): 976–9. PMID 14534855. [10] Jiang, W., et al. (2005). “Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects”. The Journal of Clinical Investigation 115 (11): 3104– 3116. doi:10.1172/JCI25509. PMC 1253627. PMID 16224541. [11] Ramírez Bg, E. A. ; Blázquez, C.; Gómez Del Pulgar, T.; Guzmán, M.; De Ceballos, M. L. (2005). “Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation”. Journal of Neuroscience 25 (8): 1904–1913. doi:10.1523/JNEUROSCI.4540-04.2005. PMID 15728830. [12] “Lab Results Confirm CBP in Ohio Discover Synthetic Narcotics in Incense Packets - CBP.gov”.
125
[13] “EMCDDA Action on new drugs briefing paper: Understanding the ‘Spice’ phenomenon”. [14] “Spice Cannabinoid - HU-210”. [15] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are
86.6 External links • Comment in Nature on the article about neurogenesis.
Chapter 87
HU-243 HU-243 (AM-4056) is a synthetic cannabinoid drug that is a single enantiomer of the hydrogenated derivative of the commonly used reference agonist HU-210. It is a potent agonist at both the CB1 and CB2 receptors, with a binding affinity of 0.041nM at the CB1 receptor, making it marginally more potent than HU-210, which had an affinity of 0.061nM in the same assay.[1]
87.1 See also • AM-2389 • Nabidrox • Nabilone
87.2 References [1] Stern, E.; Lambert, D. M. (2007). “Medicinal Chemistry Endeavors around the Phytocannabinoids”. Chemistry & Biodiversity 4 (8): 1707–1728. doi:10.1002/cbdv.200790149. PMID 17712816.
126
Chapter 88
HU-308 HU-308 is a drug that acts as a cannabinoid agonist. It is highly selective for the CB2 receptor subtype, with a selectivity of over 5000x for CB2 vs CB1 .[1] The synthesis and characterization took place in the laboratory of Prof. Mechoulam at the Hebrew University of Jerusalem in the late 1990s. It has analgesic effects,[2] promotes proliferation of neural stem cells,[3] and protects both liver and blood vessel tissues against oxidative stress via inhibition of TNF-α.[4][5]
88.1 See also • HU-210 • HU-320
88.2 References [1] Hanus, L., et al. (1999). “HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor”. Proceedings of the National Academy of Sciences of the United States of America 96 (25): 14228–14233. Bibcode:1999PNAS...9614228H. doi:10.1073/pnas.96.25.14228. PMC 24419. PMID 10588688. [2] Labuda, C.; Koblish, M.; Little, P. (2005). “Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain”. European Journal of Pharmacology 527 (1–3): 172–174. doi:10.1016/j.ejphar.2005.10.020. PMID 16316653. [3] Palazuelos, J., et al. (2006). “Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 (13): 2405–2407. doi:10.1096/fj.06-6164fje. PMID 17015409. [4] Rajesh, M.; Pan, H.; Mukhopadhyay, P.; Batkai, S.; OseiHyiaman, D.; Hasko, G.; Liaudet, L.; Gao, B.; Pacher, P. (2007). “Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis”. Journal of leukocyte biology 82 (6): 1382–1389. doi:10.1189/jlb.0307180. PMC 2225476. PMID 17652447.
127
[5] Rajesh, M., et al. (2007). “CB2-receptor stimulation attenuates TNF-α-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion”. American journal of physiology. Heart and circulatory physiology 293 (4): H2210–H2218. doi:10.1152/ajpheart.00688.2007. PMC 2229632. PMID 17660390.
Chapter 89
HU-331 HU-331 is a quinone anticarcinogenic drug synthesized from cannabidiol, a cannabinoid in the Cannabis sativa plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible effect on the action of DNA topoisomerase I. The cannabinoid quinone HU331 is a very specific inhibitor of topoisomerase II, compared with most known anticancer quinones.[1] One of the main objectives of these studies is the development of a new quinone derived compound that produces antineoplastic activity while maintaining low toxicity at therapeutic doses.
89.1 Mechanism of action Inhibitors of topoisomerases can act at two different levels. First inhibiting topoisomerase, which stabilize the topoisomerase-DNA complex and thus introduce DNA breaks in the wires that lead to apoptosis, then inhibiting the catalytic activity of topoisomerase, which hinders the activity of these enzymes without introducing breaks into the DNA chains. HU-331 seems to be a catalytic inhibitor of topoisomerase II, probably by enzymatic ligation to the protein. This molecule does not cause damage to DNA, but protects cells from damage, natural, or induced by other inhibitors of topoisomerase II that act as inhibitors of topoisomerase. Even when 60% of the target cells are killed by treatment with HU-331, other cells’ nucleic content remains unharmed, with less breakage of DNA chains that control important cellular functions.[2] Doxorubicin, like other anticancer quinones, was used for chemotherapy in human cancers for many years. The mechanism of action of these drugs has been the subject of considerable controversy since chemotherapeutic drugs exert their cytotoxic effect on target cells by nonspecific mechanisms. The doxorubicin damages DNA by intercalation, the generation of reactive oxygen species and inhibition of DNA topoisomerase I and II. This leads to breaking the chains of DNA single and double strands. The protein associated with these ruptures are the topoisomerase II and DNA damage is catalyzed
by this enzyme.[2] Thus, while doxorubicin and other anthraquinones act through many mechanisms such as apoptosis, abrogation of the cell cycle cell, activation of caspases, generation of ROS, inhibition of both topoisomerases, activation of intracellular secondary messengers, etc. Hu-331 is more active and less toxic, since it generates reactive oxygen species in the heart and has a specific activity that gives great potential to develop as a new anticancer drug, according to Kogan et al.[2] Cannabinoids can act as anticancer compounds killing several oncogenic cells followed by direct interaction with cannabinoid receptors. The growth of glioma is inhibited by a selective activation of the CB2 cannabinoid receptor and endogenous cannabinoids such as anandamide inhibit the proliferation of cells involved in lung cancer. The reason behind the antitumor effect of HU-331 appears unknown as cannabinoid receptor antagonists do not inhibit HU-331, despite being mediated by a cannabinoid receptor. The HU-331 exerts an antiangiogenic effect accompanied by apoptosis of endothelial cells. Although in some studies. HU-331 has not caused the death of cells by oncogenic apoptosis. The conclusion that would lead cells to apoptosis based on treatment with the drug did not increase the proportion of cells containing DNA Lues in the sub-G1 phase and have not found the expression of caspase-3 in cancer cells.[2]
89.2 See also • HU-210 • HU-320 • HU-336
89.3 References
128
[1] Kogan N.M. et al. (2007). “HU-331, a novel cannabinoidbased anticancer topoisomerase II inhibitor”. Mol. Cancer Ther. 6 (1): 173–183. doi:10.1158/1535-7163.MCT06-0039. PMID 17237277. [2] Kogan N.M. et al. (2007). “A Cannabinoid Anticancer Quinone, HU-331, Is More Potent and Less Car-
89.3. REFERENCES
diotoxic Than Doxorubicin: A Comparative in Vivo Study”. J. Pharmacol. Exp. Ther. 322 (2): 646–653. doi:10.1124/jpet.107.120865. PMID 17478614.
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Chapter 90
11-Hydroxy-THC 11-Hydroxy-Δ9 -tetrahydrocannabinol, abbreviated as 11-OH-THC, is the main active metabolite of THC which is formed in the body after cannabis consumption.[1] 11-Hydroxy-THC has been shown to be active in its own right,[2] but the effects produced are not necessarily identical to those of THC.[3] This might partially explain the biphasic effects of cannabis, whereby some effects such as increased appetite tend to be delayed rather than occurring immediately when the drug is consumed.[4] 11-Hydroxy-THC is subsequently metabolised further to 11-nor-9-carboxy-THC, which is not psychoactive but might still play a role in the analgesic and antiinflammatory effects of cannabis.
90.1 References [1] Johnson JR, Jennison TA, Peat MA, Foltz RL (1984). “Stability of delta 9-tetrahydrocannabinol (THC), 11hydroxy-THC, and 11-nor-9-carboxy-THC in blood and plasma”. Journal of analytical toxicology 8 (5): 202–4. doi:10.1093/jat/8.5.202. PMID 6094914. [2] Turkanis SA, Karler R (1988). “Changes in neurotransmitter release at a neuromuscular junction of the lobster caused by cannabinoids”. Neuropharmacology 27 (7): 737–42. doi:10.1016/0028-3908(88)90083-4. PMID 2901683. [3] Hollister LE, Gillespie HK (1975). “Action of delta-9tetrahydrocannabinol. An approach to the active metabolite hypothesis”. Clin. Pharmacol. Ther. 18 (6): 714–9. PMID 1204277. [4] Lemberger, L; Martz, R; Rodda, B; Forney, R; Rowe, H (1973). “Comparative Pharmacology of Δ9Tetrahydrocannabinol and its Metabolite, 11-OH-Δ9Tetrahydrocannabinol”. The Journal of Clinical Investigation 52 (10): 2411–7. doi:10.1172/JCI107431. PMC 302499. PMID 4729039.
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Chapter 91
9-nor-9β-Hydroxyhexahydrocannabinol 9-nor−9β-Hydroxyhexahydrocannabinol (HHC), is a synthetic cannabinoid derivative which resulted from early modifications to the structure of THC, in a search for the simplest compound that could still fulfil the binding requirements to produce cannabis-like activity.[1][2] HHC is active in its own right with similar potency to THC, but further simplification and variation of this parent structure lead to more potent, yet structurally simpler derivatives such as 47,497 and 55,940,[3][4][5] which after several steps of modification have become quite structurally distinct from THC, while HHC on the other hand is still substantially similar in structure to THC. The discovery of this simplified class of cannabinoid derivatives was highly significant in of the widespread use of 55,940 for early scientific research into the cannabinoid receptors,[6] as well as later work using more complex compounds such as 55,244 to map the CB1 binding site in more detail, but aside from these specific applications, these compounds attracted little attention and no compounds from this series were developed for medical use despite favourable safety profiles in animal studies. Unexpectedly, some 25 years later, these compounds came back into prominence when an obscure derivative (C8)- 47,497 was found to have been sold as the active ingredient in the “herbal” cannabis substitute product Spice,[7] which ironically has led to a resurgence of interest into laboratory-conducted scientific research of this family of drugs.
91.1 See also • AM-2389 • HU-243
91.2 References [1] Johnson MR, et al. Potent Analgetics Derived From 9Nor-9β-Hydroxyhexahydrocannabinol. NIDA Research Monograph 34; 1980. pp 68-74.
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[2] Melvin LS, Johnson MR. Structure-Activity Relationships of Tricyclic and Nonclassical Bicyclic Cannabinoids. NIDA Research Monograph 79; 1987. pp 31-47. [3] Weissman, A; Milne, GM; Melvin Jr, LS (1982). “Cannabimimetic activity from -47,497, a derivative of 3-phenylcyclohexanol”. The Journal of Pharmacology and Experimental Therapeutics 223 (2): 516–23. PMID 6290642. [4] Melvin, LS, et al. (1984). “A cannabinoid derived prototypical analgesic”. Journal of Medical Chemistry 27 (1): 67–71. doi:10.1021/jm00367a013. PMID 6690685. [5] Compton, DR; Johnson, MR; Melvin, LS; Martin, BR (1992). “Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents”. The Journal of Pharmacology and Experimental Therapeutics 260 (1): 201–9. PMID 1309872. [6] Devane, WA, et al. (1988). “Determination and characterization of a cannabinoid receptor in rat brain”. Molecular Pharmacology 34 (5): 605–13. PMID 2848184. [7] Auwärter, V, et al. (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–7. doi:10.1002/jms.1558. PMID 19189348.
Chapter 92
Ibipinabant Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB1 antagonist.[1] It has potent anorectic effects in animals,[2] and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists.[3][4][5]
92.1 See also • Cannabinoid receptor antagonist
92.2 References [1] Lange, JH; Coolen, HK; Van Stuivenberg, HH; Dijksman, JA; Herremans, AH; Ronken, E; Keizer, HG; Tipker, K et al. (2004). “Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists”. Journal of Medical Chemistry 47 (3): 627–43. doi:10.1021/jm031019q. PMID 14736243. [2] Need, AB; Davis, RJ; Alexander-Chacko, JT; Eastwood, B; Chernet, E; Phebus, LA; Sindelar, DK; Nomikos, GG (2006). “The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats”. Psychopharmacology 184 (1): 26–35. doi:10.1007/s00213005-0234-x. PMID 16328376. [3] Lange, JH; Van Stuivenberg, HH; Veerman, W; Wals, HC; Stork, B; Coolen, HK; McCreary, AC; Adolfs, TJ; Kruse, CG (2005). “Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity”. Bioorganic & Medicinal Chemistry Letters 15 (21): 4794–8. doi:10.1016/j.bmcl.2005.07.054. PMID 16140010. [4] Srivastava, BK; Joharapurkar, A; Raval, S; Patel, JZ; Soni, R; Raval, P; Gite, A; Goswami, A et al. (2007). “Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: synthesis, biological evaluation, and molecular
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modeling in the homology model”. Journal of Medical Chemistry 50 (24): 5951–66. doi:10.1021/jm061490u. PMID 17979261. [5] Srivastava, BK; Soni, R; Joharapurkar, A; Sairam, KV; Patel, JZ; Goswami, A; Shedage, SA; Kar, SS et al. (2008). “Bioisosteric replacement of dihydropyrazole of 4S-(-)−3-(4-chlorophenyl)-N-methyl-N'(4-chlorophenyl)-sulfonyl-4-phenyl-4,5-dihydro-1Hpyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole”. Bioorganic & Medicinal Chemistry Letters 18 (3): 963–8. doi:10.1016/j.bmcl.2007.12.036. PMID 18207393.
Chapter 93
IDFP IDFP is an organophosphorus compound related to the nerve agent sarin. Like sarin, IDFP is an irreversible inhibitor for a number of different enzymes that normally serve to break down neurotransmitters, however the long alkyl chain of IDFP makes it dramatically weaker as an inhibitor of acetylcholinesterase (AChE), with an IC50 of only 6300nM, while it is a potent inhibitor of two enzymes monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG), and fatty acid amide hydrolase (FAAH), the primary enzyme that degrades the other main endocannabinoid anandamide. The IC50 of IDFP is 0.8nM at MAGL, and 3.0nM at FAAH. Inhibition of these two enzymes causes markedly increased levels of both anandamide and 2-AG in the brain, resulting in increased cannabinoid signalling and typical cannabinoid behavioral effects in animal studies, while its lack of potency at AChE means that no cholinergic symptoms are produced.[1][2][3][4] Despite its similar chemical structure to the banned nerve agents, the long alkyl chain of IDFP causes it to fall outside the definition of “toxic chemicals” under the Chemical Weapons Convention,[5] and since it also does not exhibit the potent AChE inhibition of related organophosphorus compounds, IDFP is not subject to the same stringent legal controls.
93.1 See also • Methoxy arachidonyl fluorophosphonate • 4-Nonylphenylboronic acid
93.2 References [1] Nomura, D. K.; Blankman, J. L.; Simon, G. M.; Fujioka, K.; Issa, R. S.; Ward, A. M.; Cravatt, B. F.; Casida, J. E. (2008). “Activation of the endocannabinoid system by organophosphorus nerve agents”. Nature Chemical Biology 4 (6): 373–378. doi:10.1038/nchembio.86. PMC 2597283. PMID 18438404. [2] Casida, J. E.; Nomura, D. K.; Vose, S. C.; Fujioka, K. (2008). “Organophosphate-sensitive lipases modulate
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brain lysophospholipids, ether lipids and endocannabinoids”. Chemico-Biological Interactions 175 (1–3): 355– 364. doi:10.1016/j.cbi.2008.04.008. PMC 2582404. PMID 18495101. [3] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.; Mangravite, L. M.; Chiu, S.; Casida, J. E.; Krauss, R. M. (2008). “Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins”. Proceedings of the National Academy of Sciences 105 (38): 14561–14566. doi:10.1073/pnas.0807232105. PMC 2567196. PMID 18794527. [4] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.; Barber, A.; Casida, J. E.; Krauss, R. M. (2011). Bartolomucci, Alessandro, ed. “Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes”. PLoS ONE 6 (11): e26415. doi:10.1371/journal.pone.0026415. PMC 3208546. PMID 22073164. [5] CWC Schedule 1 Part A. Toxic Chemicals
Chapter 94
2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4nonylphenyl)cyclohex-1-ene 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4nonylphenyl)cyclohex-1-ene is an analgesic compound which is a cannabinoid agonist. It is a ring-opened cannabinoid derivative, an analogue of cannabidiol. However, unlike cannabidiol, this compound produces potent cannabis-like effects in animals, suggesting it acts as a CB1 agonist.[1] It can be synthesized by Birch reduction from the nonylanalog of cannabidiol.[2]
94.1 References [1] Razdan, K. (1981). “The Total Synthesis of Cannabinoids”. In John Apsimon. The Total Synthesis of Natural Products. Wiley Interscience. p. 245. ISBN 978-0-47105460-3. OCLC 19487018. [2] Razdan RK, Pars HG, Thompson WR, Granchelli FE (1974). “Lithium-ammonia reduction of tetrahydrocannabinols”. Tetrahedron Letters 15 (49–50): 4315. doi:10.1016/S0040-4039(01)92152-5.
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Chapter 95
JTE 7-31 JTE 7-31 is a selective cannabinoid receptor agonist invented by Japan Tobacco.[1][2] It is a reasonably highly selective CB2 agonist, but still retains appreciable affinity at CB1 , with a Kᵢ of 0.088nM at CB2 vs 11nM at CB1 .
95.1 See also • A-834,735 • JTE-907 • MDA-19 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • S-444,823
95.2 References [1] WO patent 1997/029079, Inaba T, Kaya T, Iwamura H, “Novel compounds and pharmaceutical use thereof”, granted 1997-14-08 [2] US patent 6017919, Inaba T, Kaya T, Iwamura H, “Compounds and pharmaceutical use thereof”, granted 200001-25
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Chapter 96
JTE-907 JTE-907 is a drug used in scientific research that acts as a selective CB2 inverse agonist.[1][2] It has antiinflammatory effects in animal studies,[3] thought to be mediated by an interaction between the CB2 receptor and IgE.[4]
96.1 See also • JTE 7-31
96.2 References [1] Iwamura, H, et al. (2001). “In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor”. The Journal of Pharmacology and Experimental Therapeutics 296 (2): 420–5. PMID 11160626. [2] Raitio, KH, et al. (2006). “Synthesis and SAR studies of 2-oxoquinoline derivatives as CB2 receptor inverse agonists”. Journal of Medical Chemistry 49 (6): 2022–7. doi:10.1021/jm050879z. PMID 16539390. [3] Ueda, Y, et al. (2005). “Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE907, in cutaneous inflammation in mice”. European Journal of Pharmacology 520 (1–3): 164–71. doi:10.1016/j.ejphar.2005.08.013. PMID 16153638. [4] Ueda, Y; Miyagawa, N; Wakitani, K (2007). “Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice”. Life Sciences 80 (5): 414–9. doi:10.1016/j.lfs.2006.09.026. PMID 17055000.
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Chapter 97
JWH-015 JWH-015 is a chemical from the naphthoylindole family that acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8 nM, while its affinity for CB1 is 383 nM, meaning that it binds almost 28x more strongly to CB2 than CB1 [1] However it still displays some CB1 activity, and in some model systems can be very potent and efficacious at activating CB1 receptors,[2] and therefore it is not as selective as newer drugs such as JWH-133.[3] It has been shown to possess immunomodulatory effects,[4][5] and CB2 agonists may be useful in the treatment of pain and inflammation.[6][7] It was discovered and named after Dr. John W. Huffman.
[3] Marriott KS, Huffman JW (2008). “Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor”. Curr Top Med Chem 8 (3): 187–204. doi:10.2174/156802608783498014. PMID 18289088. [4] Ghosh S, Preet A, Groopman JE, Ganju RK (July 2006). “Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes”. Mol. Immunol. 43 (14): 2169–79. doi:10.1016/j.molimm.2006.01.005. PMID 16503355. [5] Montecucco F, Burger F, Mach F, Steffens S (March 2008). “CB2 cannabinoid receptor agonist JWH015 modulates human monocyte migration through defined intracellular signaling pathways”. Am. J. Physiol. Heart Circ. Physiol. 294 (3): H1145–55. doi:10.1152/ajpheart.01328.2007. PMID 18178718.
97.1 Metabolism
[6] Balter MB, Uhlenhuth EH (1992). “Prescribing and use of benzodiazepines: an epidemiologic perspective”. J Psychoactive Drugs 24 (1): 63–4. doi:10.1186/17422094-2-29. PMID 1352348.
JWH-015 has been shown in vitro to be metabolised primarily by hydroxylation and N-dealkylation, and also by epoxidation of the naphthalene ring,[8] similar to the metabolic pathways seen for other aminoalkylindole cannabinoids such as WIN 55,212-2.[9] Epoxidation of polycyclic aromatic hydrocarbons (see for example benzo(a)pyrene toxicity) can produce carcinogenic metabolites, although there is no evidence to show that JWH-015 or other aminoalkylindole cannabinoids are actually carcinogenic in vivo. A study published in the British Journal of Cancer shows that JWH-015 may signal certain cancers to shrink through a process called apoptosis.[10]
[7] Romero-Sandoval A, Eisenach JC (April 2007). “Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision”. Anesthesiology 106 (4): 787–94. doi:10.1097/01.anes.0000264765.33673.6c. PMID 17413917. [8] Zhang Q, Ma P, Cole RB, Wang G. Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS. Analytical and Bioanalytical Chemistry. 2006 Nov;386(5):1345-55. PMID 16955257
97.2 References [1] Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (August 2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 )receptor binding”. Drug Alcohol Depend 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [2] Murataeva N, Mackie K, Straiker A (November 2012). “The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons”. Pharmacol. Res. 66 (5): 437–42. doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID 22921769.
[9] Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang G (October 2002). “In vitro metabolism of R(+)[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist”. Drug Metab. Dispos. 30 (10): 1077–86. doi:10.1124/dmd.30.10.1077. PMID 12228183. [10] N Olea-Herrero, D Vara, S Malagarie-Cazenave, Díaz“Inhibition of human Laviada (18 August 2009). tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2”. British Journal of Cancer: 101, 940–950. doi:10.1038/sj.bjc.6605248. Retrieved 10 July 2014.
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Chapter 98
JWH-051 JWH-051 is an analgesic drug which is a cannabinoid agonist. Its chemical structure is closely related to that of the potent cannabinoid agonist HU-210, with the only difference being the removal of the hydroxyl group at position 1 of the aromatic ring. It was discovered and named after Dr. John W. Huffman. JWH-051 retains high affinity for the CB1 receptor, but is a much stronger agonist for CB2 , with a Ki value of 14nM at CB2 vs 19nM at CB1 .[1] It was one of the first CB2 -selective ligands developed, although its selectivity for CB2 is modest compared to newer compounds such as HU-308. It has similar effects to other cannabinoid agonists such as sedation and analgesia, but with a relatively strong antiinflammatory effect due to its strong activity at CB2 .[2][3][4]
98.1 References [1] Huffman, JW, Yu, S, Showalter, V, Abood, ME, Wiley, JL, Compton, DR, Martin, BR, Bramblett, RD, Reggio, PH (1996). “Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor”. Journal of Medical Chemistry 39 (20): 3875–7. doi:10.1021/jm960394y. PMID 8831752. [2] Huffman, JW (2000). “The search for selective ligands for the CB2 receptor”. Current pharmaceutical design 6 (13): 1323–37. doi:10.2174/1381612003399347. PMID 10903395. [3] Klein, TW, Newton, C, Friedman, H (1998). “Cannabinoid receptors and the cytokine network”. Advances in experimental medicine and biology. Advances in Experimental Medicine and Biology 437: 215–22. doi:10.1007/978-1-4615-5347-2_24. ISBN 978-0-30645838-5. PMID 9666274. [4] Griffin, G, Fernando, SR, Ross, RA, McKay, NG, Ashford, ML, Shire, D, Huffman, JW, Yu, S et al. (1997). “Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals”. European Journal of Pharmacology 339 (1): 53–61. doi:10.1016/S00142999(97)01336-8. PMID 9450616.
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Chapter 99
JWH-057 JWH-057, also known as deoxy-Δ8-THC-DMH, is a selective cannabinoid ligand, with a binding affinity of Kᵢ = 2.9 ± 1.6 nM for the CB2 subtype, and Kᵢ = 23 ± 7 nM for CB1 .[1]
99.1 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073
99.2 References [1] Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH (1996). “Synthesis and Pharmacology of a Very Potent Cannabinoid Lacking a Phenolic Hydroxyl with High Affinity for the CB2 Receptor”. J. Med. Chem. 39 (20): 3875–3877. doi:10.1021/JM960394Y.
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Chapter 100
JWH-120 JWH-120 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is the N-propyl analog of JWH-122. It is a potent and selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 6.1 ± 0.7 nM at this subtype, and 173 times selectivity over the CB1 subtype.[1]
100.1 See also • JWH-122 • JWH-193 • JWH-210 • JWH-398
100.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 101
JWH-122 JWH-122 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is a methylated analogue of JWH-018. It has a Kᵢ of 0.69 nM at CB1 and 1.2 nM at CB2 .[1]
101.1 See also • JWH-193 • JWH-210 • JWH-398
101.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 102
JWH-133 JWH-133 is a potent selective CB2 receptor agonist, with a Ki of 3.4nM and selectivity of around 200x for CB2 over CB1 receptors. It was discovered by, and named after, John W. Huffman.
102.3 External links
JWH-133, alongside WIN 55,212-2 and HU-210, is implicated in preventing the inflammation caused by Amyloid beta proteins involved in Alzheimer’s Disease, in addition to preventing cognitive impairment and loss of neuronal markers. This antiinflamatory action is induced through agonist action at cannabinoid receptors, which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
• JNeurosci.org Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation Also has been shown to block grown of tumors. More clinical studies and trials are needed.
It may be linked with anti-cancer properties, according to pre-trial data from a 2010 study in Madrid. [1]
102.1 Legal Status The substance commonly referred to as “JWH-133” is not a scheduled substance in the U.S., although its young age prevents it from having received the level of government attention as with the older, more widely used and well known chemicals. Low abuse potential makes it less likely for regulation a priori relative to its sister drugs such as JWH-018, as JWH-133 (chemical name (6aR,10aR)−3-(1,1-Dimethylbutyl)−6a,7,10,10atetrahydro −6,6,9-trimethyl-6H-dibenzo[b,d]pyran) is selective for the non-psychoactive CB2 receptor and hence devoid of any psychoactive side effects or abuse potential.[2]
102.2 References [1] http://www.enewspf.com/index. php/latest-news/health-and-fitness/ 18029-marijuana-compound-halts-breast-cancer-tumor-growth-
[2] http://www.usdoj.gov/dea/pubs/scheduling.html
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Chapter 103
JWH-148 JWH-148 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is the indole 2-methyl analog of JWH-120. It is a moderately selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 14.0 ± 1.0 nM at this subtype, and more than 8 times selectivity over the CB1 subtype.[1]
103.1 See also • JWH-120 • JWH-122 • JWH-193 • JWH-210 • JWH-398
103.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 104
JWH-149 JWH-149 is a synthetic cannabimimetic that was discovered by John W. Huffman. It is the N-pentyl analog of JWH-148. It is a potent but only moderately selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 0.73 ± 0.03 nM at this subtype, and more than 6 times selectivity over the CB1 subtype.[1]
104.1 See also • JWH-120 • JWH-122 • JWH-148 • JWH-193 • JWH-210 • JWH-398
104.2 References [1] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
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Chapter 105
JWH-161 JWH-161 is a cannabinoid derivative that was designed by Dr John W. Huffman's team as a hybrid between the dibenzopyran “classical” cannabinoid drugs and the novel indole derivatives, in an attempt to unravel the differences in their binding modes to the CB1 receptor. While retaining structural elements from both families, JWH-161 has a CB1 Kᵢ of 19.0nM, although it was found to be slightly weaker than THC in animal tests.[1]
105.1 References [1] Huffman JW, Padgett LW (2005). “Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes”. Current Medicinal Chemistry 12 (12): 1395–411. doi:10.2174/0929867054020864. PMID 15974991.
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Chapter 106
JWH-176 JWH-176 is an analgesic drug which acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is only 26.0nM, making it more potent than THC itself,[1] however JWH-176 is particularly notable in that it is a hydrocarbon containing no heteroatoms. This demonstrates that reasonably high-affinity cannabinoid binding and agonist effects can be produced by compounds with no hydrogen bonding capacity at all, relying merely on Van der Waals interactions to bind to the receptor.[2] It was discovered by, and named after, Dr. John W. Huffman.
106.1 See also • JWH-175
106.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. [2] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN 3-540-22565-X
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Chapter 107
JWH-359 JWH-359 is a dibenzopyran “classical” cannabinoid drug, which is a potent and selective CB2 receptor agonist, with a Kᵢ of 13.0nM and selectivity of around 220x for CB2 over CB1 receptors. It is related to other dibenzopyran CB2 agonists such as JWH-133 and L-759,656 but with a chiral side chain which has made it useful in mapping the shape of the CB2 binding site.[1][2] It was discovered by, and named after, Dr. John W. Huffman.
107.1 References [1] Huffman, J.; Bushell, S.; Joshi, S.; Wiley, J.; Martin, B. (2006). “Enantioselective synthesis of 1-methoxyand 1-deoxy-2'-methyl-delta8-tetrahydrocannabinols: new selective ligands for the CB2 receptor”. Bioorganic & Medicinal Chemistry 14 (1): 247–262. doi:10.1016/j.bmc.2005.08.013. PMID 16165365. [2] “Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor”. Curr Top Med Chem 8 (3): 187–204. 2008. doi:10.2174/156802608783498014. PMID 18289088.
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Chapter 108
JZL184 JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG).[1] It displays high selectivity for MAGL over other brain serine hydrolases, including the anandamidedegrading enzyme fatty acid amide hydrolase (FAAH), thereby making it a useful tool for studying the effects of endogenous 2-AG signaling, in vivo. istration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects.
108.1 See also • JZL195
108.2 References [1] Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF (November 2008). “Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects”. Nat. Chem. Biol. 5 (1): 37–44. doi:10.1038/nchembio.129. PMC 2605181. PMID 19029917.
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Chapter 109
JZL195 JZL195 is a potent inhibitor of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary enzymes responsible for degrading the endocannabinoids anandamide (AEA) and 2arachidonoylglycerol (2-AG), respectively.[1]
109.1 See also • JZL184
109.2 References [1] Long, J. Z.; Nomura, D. K.; Vann, R. E.; Walentiny, D. M.; Booker, L.; Jin, X.; Burston, J. J.; Sim-Selley, L. J.; Lichtman, A. H.; Wiley, J. L.; Cravatt, B. F. (2009). “Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo”. Proceedings of the National Academy of Sciences 106 (48): 20270. doi:10.1073/pnas.0909411106.
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Chapter 110
KM-233 KM-233 is a drug which is an analogue of Δ8tetrahydrocannabinol (THC), the less active but more stable isomer of the active component of Cannabis. km-233 differs from Δ8-THC by the pentyl side chain being replaced by a 1,1-dimethylbenzyl group. It has high binding affinity in vitro for both the CB1 and CB2 receptors, with a CB2 affinity of 0.91nM and 13x selectivity over the CB1 receptor.[1] In animal studies it has been found to be effective for the treatment of glioma, a form of brain tumor.[2] A large number of related analogues are known where the 1,1-dimethylbenzyl group is substituted or replaced by other groups, with a fairly well established structure-activity relationship.[3][4][5][6][7]
110.1 See also • AM-411 • AMG-36
110.2 References [1] Krishnamurthy M, Ferreira AM, Moore BM 2nd. Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids. Bioorganic and Medicinal Chemistry Letters. 2003 Oct 20;13(20):3487-90. PMID 14505654 [2] Duntsch C, et al. Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma. Journal of Neuro-oncology. 2006 Apr;77(2):143-52. PMID 16314952 [3] Nadipuram AK, et al. Synthesis and testing of novel classical cannabinoids: exploring the side chain ligand binding pocket of the CB1 and CB2 receptors. Bioorganic and Medicinal Chemistry. 2003 Jul 17;11(14):3121-32. PMID 12818675 [4] Durdagi S, et al. The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2. Journal of Medicinal Chemistry. 2007 Jun 14;50(12):2875-85. PMID 17521177
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[5] Krishnamurthy M, Gurley S, Moore BM 2nd. Exploring the substituent effects on a novel series of C1'-dimethylaryl Delta8-tetrahydrocannabinol analogs. Bioorganic and Medicinal Chemistry. 2008 Jul 1;16(13):6489-500. PMID 18524604 [6] Ferreira AM, et al. Quantitative structure-activity relationship (QSAR) for a series of novel cannabinoid derivatives using descriptors derived from semi-empirical quantum-chemical calculations. Bioorganic and Medicinal Chemistry. 2009 Mar 15;17(6):2598-606. PMID 19250829 [7] Brogi S, et al. Three-dimensional quantitative structureselectivity relationships analysis guided rational design of a highly selective ligand for the cannabinoid receptor 2. European Journal of Medicinal Chemistry. 2011 Feb;46(2):547-55. PMID 21183257
Chapter 111
L-759,633 L-759,633 is an analgesic drug that is a cannabinoid agonist. It is a fairly selective agonist for the CB2 receptor, with selectivity of 163x for CB2 over CB1 .[1] It produces some similar effects to other cannabinoid agonists such as analgesia, but with little or no sedative or psychoactive effects due to its weak CB1 activity, and a relatively strong antiinflammatory effect due to its strong activity at CB2 .[2][3]
111.1 See also • L-759,656 • L-768,242
111.2 References [1] Ross, RA, Brockie, HC, Stevenson, LA, Murphy, VL, Templeton, F, Makriyannis, A, Pertwee, RG (1999). “Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630”. British Journal of Pharmacology 126 (3): 665– 72. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID 10188977. [2] Huffman, JW (2000). “The search for selective ligands for the CB2 receptor”. Current pharmaceutical design 6 (13): 1323–37. doi:10.2174/1381612003399347. PMID 10903395. [3] Huffman, JW (2005). “CB2 receptor ligands”. Mini reviews in medicinal chemistry 5 (7): 641–9. doi:10.2174/1389557054368844. PMID 16026310.
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Chapter 112
L-759,656 L-759,656 is an analgesic drug that is a cannabinoid agonist. It is a highly selective agonist for the CB2 receptor, with selectivity of 414x for CB2 over CB1 ,[1] although it is still not as selective as newer agents such as HU-308. It produces some similar effects to other cannabinoid agonists such as analgesia, but with little or no sedative or psychoactive effects due to its weak CB1 activity, and a relatively strong antiinflammatory effect due to its strong activity at CB2 .[2][3]
112.1 See also • L-759,633 • L-768,242
112.2 References [1] Ross, R.; Brockie, H.; Stevenson, L.; Murphy, V.; Templeton, F.; Makriyannis, A.; Pertwee, R. (1999). “Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630”. British Journal of Pharmacology 126 (3): 665– 672. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID 10188977. [2] Huffman, J. W. (2000). “The search for selective ligands for the CB2 receptor”. Current pharmaceutical design 6 (13): 1323–1337. doi:10.2174/1381612003399347. PMID 10903395. [3] Huffman, J. W. (2005). “CB2 receptor ligands”. Mini reviews in medicinal chemistry 5 (7): 641–649. doi:10.2174/1389557054368844. PMID 16026310.
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Chapter 113
LASSBio-881 LASSBio-881 is a drug which acts as both a non-selective partial agonist of the CB1 and CB2 cannabinoid receptors, and also as an antagonist of the TRPV1 receptor, as well as having antioxidant effects. It has potent anti-inflammatory and anti-hyperalgesic effects in animal studies.[1][2][3]
113.1 References [1] Duarte CD, Tributino JL, Lacerda DI, Martins MV, Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP, Bertho AL, Miranda AL, Barreiro EJ, Fraga CA. Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenylN-acylhydrazone derivatives: Discovery of LASSBio881, a new ligand of cannabinoid receptors. Bioorganic and Medicinal Chemistry. 2007 Mar 15;15(6):2421-33. PMID 17275312 [2] Tributino JL, Santos ML, Mesquita CM, Lima CK, Silva LL, Maia RC, Duarte CD, Barreiro EJ, Fraga CA, Castro NG, Miranda AL, Guimaraes MZ. LASSBio-881: an Nacylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation. British Journal of Pharmacology. 2010 Apr;159(8):171623. PMID 20401963 [3] Santana P et al. NEUROACTIVE PROPERTIES OF THE MULTIFUNCTIONAL PROTOTYPE LASSBio881: FOCUS ON THE CANNABINOID SYSTEM
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Chapter 114
LBP-1 (drug) LBP-1 is a drug originally developed by Organon for the treatment of neuropathic pain,[1][2] and subsequently further developed by Merck after they acquired Organon’s patents following their merger with Schering-Plough.[3][4][5] It acts as a potent and selective cannabinoid receptor agonist, with high potency at both the CB1 and CB2 receptors, but low penetration of the blood–brain barrier. This makes LBP-1 peripherally selective, and while it was effective in animal models of neuropathic pain and allodynia, it did not produce cannabinoid-appropriate responding suggestive of central effects, at any dose tested.[6]
114.1 See also • Org 28312 • Org 28611
114.2 References [1] Julia Adam. Indole Derivatives. Patent WO 2008/101995 [2] Paul David Ratcliffe, Julia Adam-Worrall, Angus John Morrison, Stuart John Francis, Takao Kiyoi. Indole Derivatives. Patent US 7763732 [3] Morrison AJ, Adam JM, Baker JA, Campbell RA, Clark JK, Cottney JE, Deehan M, Easson AM, Fields R, Francis S, Jeremiah F, Keddie N, Kiyoi T, McArthur DR, Meyer K, Ratcliffe PD, Schulz J, Wishart G, Yoshiizumi K. Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor. Bioorganic and Medicinal Chemistry Letters. 2011 Jan 1;21(1):506-9. PMID 21075630 [4] Kiyoi T, Adam JM, Clark JK, Davies K, Easson AM, Edwards D, Feilden H, Fields R, Francis S, Jeremiah F, McArthur D, Morrison AJ, Prosser A, Ratcliffe PD, Schulz J, Wishart G, Baker J, Campbell R, Cottney JE, Deehan M, Epemolu O, Evans L. Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists. Bioorganic and Medicinal Chemistry Letters. 2011 Mar 15;21(6):1748-53. PMID 21316962
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[5] Ratcliffe P, Adam JM, Baker J, Bursi R, Campbell R, Clark JK, Cottney JE, Deehan M, Easson AM, Ecker D, Edwards D, Epemolu O, Evans L, Fields R, Francis S, Harradine P, Jeremiah F, Kiyoi T, McArthur D, Morrison A, ier P, Pick J, Schnabel PG, Schulz J, Steinbrede H, Walker G, Westwood P, Wishart G, de Haes JU. Design, synthesis and structure-activity relationships of (indo-3yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate. Bioorganic and Medicinal Chemistry Letters. 2011 Apr 15;21(8):2541-6. PMID 21411321 [6] Adam JM, Clark JK, Davies K, Everett K, Fields R, Francis S, Jeremiah F, Kiyoi T, Maidment M, Morrison A, Ratcliffe P, Prosser A, Schulz J, Wishart G, Baker J, Boyce S, Campbell R, Cottney JE, Deehan M, Martin I. Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain. Bioorganic and Medicinal Chemistry Letters. 2012 Apr 15;22(8):2932-7. PMID 22421020
Chapter 115
Leelamine Leelamine is a diterpene amine that has weak affinity for the cannabinoid receptors CB1 and CB2 , as well as being an inhibitor of pyruvate dehydrogenase kinase.[1] Optically active leelamine is also used as a chiral resolving agent for carboxylic acids.[2][3]
115.1 See also • THC • Resin acid
115.2 References [1] “Leelamine - Dehydroabietylamine - Cayman Chemical”. Retrieved May 20, 2013. [2] US patent 3454626 [3] US patent 4559178
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Chapter 116
Levonantradol Levonantradol ( 50,556-1) is a synthetic cannabinoid analog of dronabinol (Marinol) developed by Pfizer in the 1980s. It is around 30x more potent than THC, and exhibits antiemetic and analgesic effects via activation of CB1 and CB2 cannabinoid receptors.[1] Levonantradol is not currently used in medicine as dronabinol or nabilone are felt to be more useful for most conditions, however it is widely used in research into the potential therapeutic applications of cannabinoids.[2][3][4]
drug must be dissolved in 5% ethanol, 5% emulphur, and 90% sterile saline. Synthetic cannabinoids like Levonantradol readily cross the blood-brain barrier because they are highly lipophilic and have low molecular weights. Levonantradol’s bioavailability is variable due to the first metabolism.
116.1 Pharmacodynamics
Levonantradol has been clinically tested in cancer patients for its pain relief and antiemetic benefits. Cancer patients that endure chemotherapy often develop intense nausea, and Levonantradol has been tested to reduce these emetic symptoms. It is often used instead of THC because it has a higher efficacy. Levonantradol also acts on pain pathways in the central nervous system, which enables the drug to alleviate pain. Studies have shown an absence of emetic side effects within the half-life of the Levonantradol istered. Other studies suggest that cannabinoid agonists can synergize opioid anti-nociception. Cannabinoid receptors are located in nociceptive pathways, and CBs can promote signal transduction in TRP channels. Although Levonantradol relieves nociceptive and postoperative pain, decreases nausea, and improves spasticity in addition to being more effective than placebos, it has yet to be approved as legal medicine. Researchers have concluded that Levonantradol is no more effective than Codeine, which is why they do not recommend expansion into clinical practice.
Levonantradol is a full CB1 receptor agonist. Cannabinoid receptors belong to the superfamily of G-protein coupled receptors (GPCRs), and endogenous cannabinoids naturally activate GPCRs. GPCRs modulate the inhibition of adenylyl cyclase and accumulation of the second messenger, cyclic adenosine monophosphate (cAMP). The CB1 receptor is the most common GPCR in the central nervous system. The activation of CB1 Rs decrease calcium conductance and increase potassium conductance in the brain. CB signaling naturally modulates synaptic transmission and mediates psychoactivity, and synthetic cannabinoids mimic these same actions. Although the efficacy of Levonantradol is dependent on the level of GR activity, Full agonists like Levonantradol have the ability to activate GPCRs and convert Gα into a high affinity state for GTP or low affinity state for GDP. Previous studies suggest that Levonantradol has a higher binding affinity and efficacy than other similar synthetic cannabinoids (e.g. Δ9 -THC).
116.3 Treatment
116.4 Side effects 116.2 Pharmacokinetics Although Levonantradol has been extensively tested on animals including cats, rodents, and non-human primates. It has also been tested among cancer patient populations in clinical trials. Levonantradol is most commonly istered intramuscularly (I.M.), however it can also be istered orally. The dosage can range from 0.25 mg3.0 mg every 2–4 hours, and the half-life is 1–2 hours. In order to ister Levonantradol intramuscularly, the
The side effects for Levonantradol include ptosis, sedation, and ataxia in non-human primates. In rodents, the symptoms include dysphoria, memory impairment, motor incoordination, reduced concentration, and disorientation. Levonantradol also decreases startle response. In humans, side effects include dry mouth, drowsiness, dizziness, altered perception, mild sedation, and lack of concentration. It can cause an increase in heart rate and decrease in blood pressure. Euphoric symptoms rarely occurred in subjects.
156
116.7. REFERENCES
116.5 See also • 47,497
116.6 Notes [1] Little PJ, et al. Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. Journal of Pharmacology and Experimental Therapeutics 1988; 247:1046–1051. [2] Tramer MR, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. British Medical Journal 2001 Jul 7;323(7303):16-21. [3] Campbell FA, et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. British Medical Journal. 2001 Jul 7;323(7303):13-6. [4] Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. Journal of Ethnopharmacology. 2006 Apr 21;105(1-2):1-25.
116.7 References • Childers, SR (Mar 10, 2006). “Activation of Gproteins in brain by endogenous and exogenous cannabinoids.”. The AAPS journal 8 (1): E112–7. doi:10.1208/aapsj080113. PMC 2751429. PMID 16584117. • Hosking, R.D.; Zajicek, J.P. (2008). “Therapeutic potential of cannabis in pain medicine”. British Journal of Anaesthesia 101 (1): 59–68. doi:10.1093/bja/aen119. • McCarthy, LE; Borison, HL (Aug–Sep 1981). “Antiemetic activity of N-methyllevonantradol and nabilone in cisplatin-treated cats.”. Journal of clinical pharmacology 21 (8–9 Suppl): 30S–37S. doi:10.1002/j.1552-4604.1981.tb02570.x. PMID 6271834. • Milewich, L; Gant, NF; Schwarz, BE; Chen, GT; MacDonald, PC (Mar 15, 1979). “5 alphaReductase activity in human placenta.”. American journal of obstetrics and gynecology 133 (6): 611– 7. PMID 34324.
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Chapter 117
List of AM cannabinoids Alexandros Makriyannis is a professor in the Department of Medicinal Chemistry at Northeastern University, where his research group has synthesized many new compounds with cannabinoid activity. Some of those are: • AM-087 — an analgesic CB1 agonist derived from Δ8 THC substituted with a side chain on the 3position, it has a Kᵢ of 0.43nM making it roughly 100x as potent as THC. • AM-251 — an inverse agonist at the CB1 cannabinoid receptor that is structurally related to SR141716A (rimonabant), but has a higher binding affinity with a Kᵢ value of 7.5nM.[1] • AM-281 — N-(morpholin-4-yl)−1-(2,4dichlorophenyl)−5-(4-iodophenyl)−4-methyl1H-pyrazole-3-carboxamide[1] • AM-356 — a synthetically created stable chiral analog of anandamide, it acts on the cannabinoid receptors with a Kᵢ of 17.9nM at CB1 and 868nM at CB2 .[2] • AM-374 — palmitylsulfonyl fluoride[3] • AM-381 — stearylsulfonyl fluoride • AM-404 — an active metabolite of paracetamol (acetaminophen) and a likely inhibitor of fatty acid amide hydrolase (FAAH) • AM-411 — an adamantyl-substituted derivative of Δ8 THC, it is a potent and fairly selective CB1 full agonist with a Kᵢ of 6.80nM. It is also a moderately potent CB2 agonist with a Kᵢ of 52.0nM. • AM-630 — a potent and selective inverse agonist for the cannabinoid receptor CB2 , with a Kᵢ of 32.1nM at CB2 and 165x selectivity over CB1 , at which it acts as a weak partial agonist. • AM-661 — 1-(N-methyl-2-piperidine)methyl-2methyl-3-(2-iodo)benzoylindole[4] • AM-678 — another name for JWH-018, it is a full agonist at both cannabinoid receptors with some selectivity for CB2 . 158
• AM-679 — an iodobenzoylindole which acts as a moderately potent agonist for the cannabinoid receptors, with a Kᵢ of 13.5nM at CB1 and 49.5nM at CB2 . • AM-694 — an iodobenzoylindole which acts as a potent and selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 0.08nM at CB1 and 18x selectivity over the related CB2 receptor (1.44nM).[5] • AM-735 — 3-bornyl-Δ8-THC, a mixed CB1 / CB2 agonist with Kᵢ of 8.9nM at CB1 and 7.4nM at CB2 .[6] • AM-855 — an analgesic derivative of Δ8 tetrahydrocannabinol, it is an agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 22.3nM at CB1 and 58.6nM at CB2 . • AM-881 — a chlorine-substituted stereoisomer of anandamide whose Kᵢ = 5.3nM at CB1 and 95nM at CB2 .[2] • AM-883 — an allyl-substituted stereoisomer of anandamide whose Kᵢ = 9.9nM at CB1 and 226nM at CB2 .[2] • AM-905 — a potent and reasonably selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 1.2nM at CB1 and 5.3nM at CB2 . • AM-906 — a potent and dodecally selective agonist for the CB1 cannabinoid receptor, with a Kᵢ of 0.8nM at CB1 and 9.5nM at CB2 . • AM-919 — a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 2.2nM at CB1 and 3.4nM at CB2 . It is a derivative of HU-210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-926 — a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 2.2nM at CB1 and 4.3nM at CB2 . It is a derivative of HU-210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-938 — a potent agonist at both CB1 and CB2 with quadruple selectivity for CB2 , with a Kᵢ of
117.1. SEE ALSO 1.2nM at CB1 and 0.3nM at CB2 . It is a derivative of HU-210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-1116 — a dimethylated stereoisomer of anandamide whose Kᵢ = 7.4nM at CB1 .[2] • AM-1172 — an endocannabinoid analog specifically designed to be a potent and selective inhibitor of AEA uptake that is resistant to FAAH hydrolysis. • AM-1220 — a potent and selective analgesic CB1 agonist (as racemate) with a Kᵢ of 3.88nM at CB1 and 73.4nM at CB2 , giving it 19x selectivity for CB1 . (R) enantiomer has around 1000x higher affinity for CB1 than (S) enantiomer.[7][8] • AM-1221 — a potent and selective CB2 agonist with a Kᵢ of 0.28nM at CB2 and 52.3nM at CB1 , giving it a selectivity of almost 187x. • AM-1235 — a moderately CB1 selective agonist, with a Kᵢ of 1.5nM at CB1 and 20.4nM at CB2 , giving it a selectivity of around 13x.[9] • AM-1241 — a potent and selective analgesic CB2 agonist with a Kᵢ of 3.4nM at CB2 and 80x selectivity over CB1 .[10] • AM-1248 — a moderately potent agonist with some selectivity for CB1 , containing an unusual 3(adamant-1-oyl) substitution on the indole ring.
159 • AM-3102 — an analog of oleoylethanolamide, the endogenous agonist for proliferator-activated receptor α (PPARα). It also acts as a weak cannabinoid agonist with Kᵢ values of 33µM at CB1 and 26µM at CB2 . • AM-4030 — a potent agonist at both CB1 and CB2 , it is dodecally selective for CB1 , with a Kᵢ of 0.7nM at CB1 and 8.6nM at CB2 . It is a derivative of HU210 and represents a hybrid structure between the classical and nonclassical cannabinoid families. • AM-4054 — a potent but slow-onset agonist with CB1 affinity of 2.2nM and a 40x selectivity for CB1 over CB2 .[18][19] • AM-4113 — a CB1 selective neutral antagonist.[20] • AM-6545 — a peripherally selective silent antagonist of CB1 receptors.
117.1 See also • List of JWH cannabinoids • List of HU cannabinoids • List of cannabinoids
117.2 Further reading
• AM-1710 — a CB2 selective cannabilactone with A more complete list can be found here 54x selectivity over CB1 .[11] • AM-1714 — a CB2 selective cannabilactone with 490x selectivity over CB1 .[11] • AM-2201 — a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a Kᵢ of 1.0nM at CB1 and 2.6nM at CB2 . • AM-2212 — a potent agonist at both CB1 and CB2 with dodecal selectivity for CB1 , with a Kᵢ of 1.4nM at CB1 and 18.9nM at CB2 .[4] • AM-2213 — a potent agonist at both CB1 and CB2 with 10x selectivity for CB1 , with a Kᵢ of 3.0M at CB1 and 30nM at CB2 .[4] • AM-2232 — a potent agonist at both CB1 and CB2 , with a Kᵢ of 0.28nM at CB1 and 1.48nM at CB2 .[9]
117.3 References [1] Lan, Ruoxi; Lu, Qian; Fan, Pusheng; Gatley, John; Volkow, Nora D.; Fernando, Susanthi R.; Pertwee, Roger; Makriyannis, Alexandros (1999). “Design and synthesis of the CB1 selective cannabinoid antagonist AM281: A potential human SPECT ligand”. AAPS PharmSci 1 (2): 39–45. doi:10.1208/ps010204. [2] Selwood, D. (2009). “The Cannabinoid Receptors. Edited by Patricia H. Reggio”. ChemMedChem 4: 1949. doi:10.1002/cmdc.200900286. [3] Pacher, P.; Bátkai, S; Kunos, G (2006). “The Endocannabinoid System as an Emerging Target of Pharmacotherapy”. Pharmacological Reviews 58 (3): 389– 462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
• AM-2233 — (R) enantiomer is potent and selective CB1 agonist used in 131 I radiolabelled form to map distribution of CB1 receptors in brain.[12][13][14][15][16][17]
[4] Hongfeng Deng. Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and other heterocyclic analogs. PhD Dissertation, University of Connecticut, 2000.
• AM-2389 — classical cannabinoid derivative with 26x selectivity for CB1 .
[5] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-0607
160
[6] Lu D, Guo J, Duclos RI Jr, Bowman AL, Makriyannis A. Bornyl- and isobornyl-Delta8-tetrahydrocannabinols: a novel class of cannabinergic ligands. Journal of Medicinal Chemistry. 2008 Oct 23;51(20):6393-9. PMID 18826296 [7] D'ambra, T. (1996). “C-Attached aminoalkylindoles: potent cannabinoid mimetics”. Bioorganic & Medicinal Chemistry Letters 6: 17–14. doi:10.1016/0960894X(95)00560-G. [8] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D. B.; Mukhin, A. G.; Horti, A. G. (2005). “Synthesis and Structure−Activity Relationship of a Novel Series of Aminoalkylindoles with Potential for Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography”. Journal of Medicinal Chemistry 48 (18): 5813. doi:10.1021/jm0502743. PMID 16134948. [9] US patent 7241799, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200707-10 [10] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473. [11] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur GA, Malan TP Jr, Porreca F, Veerappan V, Tian X, George C, Parrish DA, Papahatjis DP, Makriyannis A. Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. Journal of Medicinal Chemistry. 2007 Dec 27;50(26):6493-500. PMID 18038967 [12] Deng H, Gifford AN, Zvonok AM, Cui G, Li X, Fan P, Deschamps JR, Flippen-Anderson JL, Gatley SJ, Makriyannis A (October 2005). “Potent cannabinergic indole analogues as radioiodinatable brain imaging agents for the CB1 cannabinoid receptor”. Journal of Medicinal Chemistry 48 (20): 6386–92. doi:10.1021/jm050135l. PMID 16190764. [13] Hanuš, L. R. O.; Mechoulam, R. (2005). “Cannabinoid chemistry: an overview”. “Cannabinoids as Therapeutics”. Milestones in Drug Therapy MDT. p. 23. doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6. [14] Shen , Xiao JC, Armstrong H, Hagmann W, Fong TM (February 2006). “F200A substitution in the third transmembrane helix of human cannabinoid CB1 receptor converts AM2233 from receptor agonist to inverse agonist”. European Journal of Pharmacology 531 (1–3): 41– 6. doi:10.1016/j.ejphar.2005.12.026. PMID 16438957. [15] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.; Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gifford, A. N. (2006). “Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233”. Synapse 60 (2): 93–101. doi:10.1002/syn.20277. PMID 16715483.
CHAPTER 117. LIST OF AM CANNABINOIDS
[16] Leung K (Dec 12, 2006). “R-2-[131I]Iodophenyl(1-(1-methylpiperidin-2-ylmethyl)−1H-indol-3yl)methanone”. Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. PMID 20641836. [17] Pei, Y., et al. (2008). “Ligand-Binding Architecture of Human CB2 Cannabinoid Receptor: Evidence for Receptor Subtype-Specific Binding Motif and Modeling GPCR Activation”. Chemistry & Biology 15: 1207. doi:10.1016/j.chembiol.2008.10.011. [18] [Paronis CA, Thakur GA, Vemuri K, Makriyannis A, Bergman J. Effects of a Selective Cannabinoid Agonist and Antagonist on Body Temperature in Rats. The FASEB Journal. April 2007 21 (Meeting Abstract Supplement) A409. http://www.fasebj.org/cgi/content/ meeting_abstract/21/5/A409] [19] Paronis, C. A.; Thakur, G. A.; Bajaj, S.; Nikas, S. P.; Vemuri, V. K.; Makriyannis, A.; Bergman, J. (2012). “Diuretic effects of cannabinoids”. Journal of Pharmacology and Experimental Therapeutics 344 (1): 8–14. doi:10.1124/jpet.112.199331. PMID 23019138. [20] Seely KA, Prather PL, James LP, Moran JH. Marijuanabased drugs: innovative therapeutics or designer drugs of abuse? Molecular Interventions. 2011 Feb;11(1):36-51. PMID 21441120
Chapter 118
List of JWH cannabinoids The John W. Huffman research group at Clemson University synthesized over 450 cannabinoids. Some of those are:
• JWH-057 — a 1-deoxy analog of Δ8-THC that has very high affinity for the CB2 receptor, but also has high affinity for the CB1 receptor.[2]
• JWH-007 — an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 receptor and CB2 receptors, with some selectivity for CB2 with a Kᵢ of 2.9nM ± 2.6 and 9.5nM ± 4.5 at CB1 .[1]
• JWH-073 — an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB1 subtype with a Kᵢ of 8.9nM. It is found in some forms of synthetic cannabis.
• JWH-015 — a chemical from the naphthoylindole family, which acts as a subtype-selective cannabinoid agonist. Its affinity for CB2 receptors is 13.8nM, while its affinity for CB1 is 383nM, meaning that it binds almost 28x more strongly to CB2 than CB1 .[1] • JWH-018 — an analgesic chemical from the naphthoylindole family, which acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2 with a Kᵢ of 2.9nM ± 2.6 and 9nM ± 5 at CB1 .[1] It is found in some forms of synthetic cannabis. • JWH-019 — an agonist at both CB1 and CB2 receptors, it has 1.77x selectivity for CB2 with a Kᵢ of 5.55nM ± 2 and 9.8nM ± 2 at CB1 . • JWH-030 — an analgesic chemical from the naphthoylpyrrole family, it is a partial agonist at CB1 receptors, with a Kᵢ of 87nM, making it roughly half the potency of THC. • JWH-047 — a potent and selective agonist for the CB2 receptor with a Kᵢ of 0.9 nM, and a Kᵢ of 59 ± 3 nM at CB1 , it has a 65x selectivity for CB2 .[1] • JWH-048 — a potent and selective agonist for the CB2 receptor with a Kᵢ of 0.49 nM ± 0.1, and a Kᵢ of 10.7 nM ± 1.0 at CB1 , it has a 22x selectivity for CB2 .[1] • JWH-051 — an analgesic, it has high affinity for the CB1 receptor, but is a much stronger agonist for CB2 , with a Kᵢ value of 0.03nM at CB2 vs 1.20nM at CB1 . It was one of the first CB2 -selective ligands developed, although its selectivity for CB2 is modest compared to newer compounds such as HU-308. 161
• JWH-081 — an analgesic chemical from the naphthoylindole family, which acts as an agonist at both the cannabinoid receptors with a Kᵢ of 1.2nM ± 0.03 at CB1 [3] and 12.4nM ± 2.2 at the CB2 receptors. It is fairly selective for the CB1 subtype with approximately 10x the affinity for CB2 . It is found in some forms of synthetic cannabis. • JWH-098 — a potent and fairly selective CB2 agonist with a Kᵢ of 1.9nM ± 0.3 at CB2 and 4.5nM ± 0.1 at CB1 ,[3] giving it about 2.4x selectivity for CB2 . • JWH-116 — a CB1 ligand with a Kᵢ of 52 ± 5 nM[3] • JWH-120 — a potent and 173-fold selective CB2 agonist with a Kᵢ of 6.1nM ± 0.7, it is the N-propyl homolog of JWH-122.[2] • JWH-122 — a potent and fairly selective CB1 agonist with a Kᵢ of 0.69nM ± 0.5 at CB1 and 1.2nM ± 1.2 at CB2 . It is found in some forms of synthetic cannabis. • JWH-133 — a potent and highly selective CB2 receptor agonist with a Kᵢ of 3.4nM and selectivity of around 200x for CB2 over CB1 receptors.[1] • JWH-139 — 3-(1,1-dimethylpropyl)−6,6,9trimethyl-6a,7,10,10a-tetrahydro-6Hbenzo[c]chromene[4] • JWH-147 — an analgesic drug from the naphthoylpyrrole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Kᵢ of 11.0nM at CB1 vs 7.1nM at CB2 .
162 • JWH-148 — a moderately selective ligand for the CB2 receptor, with a binding affinity of Kᵢ = 14.0 ± 1.0 nM at this subtype, and more than 8 times selectivity over the CB1 subtype.[5] • JWH-149 — a potent and fairly selective CB2 agonist with a Kᵢ of 0.73nM ± 0.03 and 5.0nM ± 2.1 at CB1 ,[3] giving it about 6.8x selectivity for CB2 . • JWH-161 — a CB1 ligand with Kᵢ of 19.0nM • JWH-164 — a potent cannabinoid agonist with a Kᵢ of 6.6nM ± 0.7 at CB1 and 6.9nM ± 0.2 at CB2 . • JWH-166 — a potent and highly selective CB2 agonist with a Kᵢ of 1.9nM ± 0.08 at CB2 and 44nM ± 10 at CB1 giving it 23x selectivity for CB2 .[1] • JWH-167 — a weak cannabinoid agonist from the phenylacetylindole family with 1.77x selectivity for CB1 with a Kᵢ of 90nM ± 17 at CB1 and 159nM ± 14 at CB2 .[6] • JWH-171 — an analgesic drug which acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is only 51nM, making it slightly less potent than THC itself. • JWH-175 — (1-pentylindol-3-yl)naphthalen-1ylmethane, 22nM at CB1 [3] • JWH-176 — 1-([(1E)−3-pentylinden-1ylidine]methyl)naphthalene, 26nM at CB1 [3] • JWH-181 — a potent cannabinoid agonist with 2.1x selectivity for CB2 with a Kᵢ of 0.62nM ± 0.04 and 1.3nM ± 0.1 at CB1 . • JWH-182 — a potent cannabinoid agonist with some selectivity for CB1 with a Kᵢ of 0.65nM ± 0.03 and 1.1nM ± 0.1 at CB2 . • JWH-184 — 1-pentyl-1H-indol-3-yl-(4-methyl-1naphthyl)methane, 23nM at CB1 [3] • JWH-185 — 1-pentyl-1H-indol-3-yl-(4-methoxy1-naphthyl)methane, 17nM at CB1 [3] • JWH-192 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methylnaphthalen-1-ylmethane, 41nM at CB1 [3] • JWH-193 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methylnaphthalen-1-ylmethanone, 6nM at CB1 [3] • JWH-194 — 2-methyl-1-pentyl-1H-indol-3-yl-(4methyl-1-naphthyl)methane, 127nM at CB1 [3] • JWH-195 — (1-(2-morpholin-4-ylethyl)indol-3yl)-naphthalen-1-ylmethane, 113nM at CB1 [3] • JWH-196 — 2-methyl-3-(1naphthalenylmethyl)−1-pentyl-1H-Indole, 151nM ± 18 at CB1
CHAPTER 118. LIST OF JWH CANNABINOIDS • JWH-197 — 2-methyl-1-pentyl-1H-indol-3-yl-(4methoxy-1-naphthyl)methane, 323nM at CB1 [3] • JWH-198 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methoxynaphthalen-1-ylmethanone, 10nM at CB1 [3] • JWH-199 — (1-(2-morpholin-4-ylethyl)indol-3yl)−4-methoxynaphthalen-1-ylmethane, 20nM at CB1 [3] • JWH-200 — an analgesic chemical from the aminoalkylindole family, which acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is 42nM, around the same as that of THC, but interestingly, its analgesic potency in vivo was higher than that of other analogues with stronger CB1 binding affinity in vitro, around 3 times that of THC but with less sedative effect, most likely reflecting favorable pharmacokinetic characteristics. It is found in some forms of synthetic cannabis. • JWH-203 — an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist with approximately equal affinity at both the CB1 and CB2 receptors, having a Kᵢ of 8.0nM at CB1 and 7.0nM at CB2 . Similar to the related 2'-methoxy compound JWH-250, JWH203 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds, and is the most potent compound found in the phenylacetyl group.[6] It is found in some forms of synthetic cannabis. • JWH-205 — 1-(2-methyl-1-pentylindol-3-yl)−2phenylethanone, CB1 : 124nM ± 23 CB2 : 180nM ± 9 CB2 selectivity: 1.45x[6] • JWH-210 — an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both the CB1 and CB2 receptors, with Kᵢ values of 0.46nM at CB1 and 0.69nM at CB2 . It is one of the most potent 4-substituted naphthoyl derivatives in the naphthoylindole series, having a higher binding affinity (i.e. lower Kᵢ) at CB1 than both its 4-methyl and 4-n-propyl homologues (JWH-122 and JWH-182 respectively), and than the 4-methoxy compound JWH-081.[1] It is found in some forms of synthetic cannabis. • JWH-213 — a potent and fairly selective CB2 agonist with a Kᵢ of 0.42nM ± 0.05 at CB2 and 1.5nM ± 0.2 at CB1 giving it 3.6x selectivity over CB1 .[1] • JWH-220 — 19nM at CB1 • JWH-229 — 1-methoxy-3-(1',1'-dimethylhexyl)Δ8 -THC, a dibenzopyran “classical” cannabinoid drug with a Kᵢ of 4.6nM ± 2.0, it is a potent CB2 agonist.
118.1. SEE ALSO • JWH-234 — a cannabinoid agonist that has 2.2x selectivity for CB2 with a Kᵢ value of 8.4nM ± 1.8 at CB2 and 3.8nM ± 0.6 at CB1 . • JWH-249 — CB1 : 8.4nM ± 1.8 CB2 : 20nM ± 2 selectivity for CB1 : 2.38x[6] • JWH-250 — an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors, with a Kᵢ of 11nM at CB1 and 33nM at CB2 .[6] It is found in some forms of synthetic cannabis. • JWH-251 — (1-pentyl-3-(229nM ± 3 methylphenylacetyl)indole) CB1 : CB2 : 146nM ± 36 selectivity for CB1 : 5x[6] • JWH-253 — • JWH-258 — a potent and mildly selective CB1 agonist with a Kᵢ of 4.6nM ± 0.6 and 10.5nM ± 1.3 at CB2 .[1] • JWH-300 — CB1 : 116nM CB2 : 5.3nM[2] • JWH-302 — (1-pentyl-3-(3methoxyphenylacetyl)indole) CB1 : 17nM ± 2 CB2 : 89nM ± 15 selectivity for CB1 : 5.26x[6] • JWH-307 — an analgesic drug from the naphthoylpyrrole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Kᵢ of 7.7nM at CB1 vs 3.3nM at CB2 . • JWH-336 — CB1 : ~1.2nM CB2 : 36nM[2]
163
118.1 See also • List of AM cannabinoids • List of HU cannabinoids • List of cannabinoids • List of miscellaneous designer cannabinoids
118.2 References [1] Huffman, JW, Zengin, G, Wu, MJ, Lu, J, Hynd, G, Bushell, K, Tartal, C, Hurst, DP, Reggio, PH, Selley, DE, Cassidy, MP, Wiley, JL, Martin, BR (2005). “Structureactivity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists”. Bioorganic & Medicinal Chemistry Letters 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455. [2] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473. [3] Huffman, JW, Mabon, R, Wu, MJ, Lu, J, Hart, R, Hurst, DP, Reggio, PH, Wiley, JL, Martin, BR (2003). “3Indolyl-1-naphthylmethanes: New Cannabimimetic Indoles Provide Evidence for Aromatic Stacking Interactions with the CB1 Cannabinoid Receptor”. Bioorganic & Medicinal Chemistry Letters 11 (4): 539–549. doi:10.1016/S0968-0896(02)00451-0. PMID 12538019.
• JWH-350 — a 11-nor-1-methoxy-3-(1',1'dimethylheptyl)−9α-hydroxyhexahydrocannabinol with 33-fold selectivity for the CB2 receptor and high CB2 receptor affinity (Kᵢ=12nM ± 1) has the desirable combination of excellent CB2 affinity combined with little affinity for the CB1 receptor.[2]
[4] Howlett, A. C.; Barth, F; Bonner, TI; Cabral, G; Casellas, P; Devane, WA; Felder, CC; Herkenham, M; MacKie, K (2002). “International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors”. Pharmacological Reviews 54 (2): 161–202. doi:10.1124/pr.54.2.161. PMID 12037135.
• JWH-359 — a dibenzopyran “classical” cannabinoid drug with a Kᵢ of 13.0nM and selectivity of around 220x for CB2 , it is a potent and selective CB2 receptor agonist.
[5] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
• JWH-387 — 1-pentyl-3-(4-bromo-1naphthoyl)indole, an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both receptors with a Kᵢ of 1.2nM at CB1 and 1.1nM at CB2 . • JWH-398 — an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both receptors with a Kᵢ of 2.3nM at CB1 and 2.8nM at CB2 .[7] • JWH-424 — a potent and moderately selective CB2 agonist with a Kᵢ of 5.44nM at CB2 and 20.9nM at CB1 .
[6] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [7] “The Cannabinoid Receptors”. doi:10.1007/978-159745-503-9. Retrieved 28 August 2013.
Chapter 119
LY-2183240 LY-2183240 is a drug which acts both as a potent inhibitor of the reuptake of the endocannabinoid anandamide and as an inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading anandamide. This leads to markedly elevated anandamide levels in the brain, and LY-2183240 has been shown to produce both analgesic and anxiolytic effects in animal models.[1][2][3][4]
Simmons RM, Li D, Iyengar S, Felder CC. Identification of a high-affinity binding site involved in the transport of endocannabinoids. 2005 Dec; 102(49):17852-7. PMID 16314570
2.Jump up ^ Dickason-Chesterfield AK, Kidd SR, Moore SA, Schaus JM, Liu B, Nomikos GG, Felder CC. Pharmacological characterization of endocannabinoid transport and fatty acid amide hydrolase inhibitors. Cellular and Molecular Neurobiology. 2006 Jul-Aug;26(46):407-23. PMID 16736384 3.Jump up ^ Alexander 119.1 See also JP, Cravatt BF. The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and • PF-04457845 several other brain serine hydrolases. Journal of the American Chemical Society. 2006 Aug 2;128(30):9699• URB-597 704. PMID 16866524 4.Jump up ^ Maione S, Morera E, Marabese I, Ligresti A, Luongo L, Ortar G, Di Marzo V. Antinociceptive effects of tetrazole inhibitors 119.2 References of endocannabinoid inactivation: cannabinoid and noncannabinoid receptor-mediated mechanisms. British [1] Dickason-Chesterfield AK, Kidd SR, Moore SA, Schaus Journal of Pharmacology. 2008 Nov;155(5):775-82. JM, Liu B, Nomikos GG, Felder CC. Pharmacological PMID 18660824 5.Jump up ^ Powers MS, Barrenha GD, characterization of endocannabinoid transport and fatty Mlinac NS, Barker EL, Chester JA. Effects of the novel acid amide hydrolase inhibitors. Cellular and Molecu- endocannabinoid uptake inhibitor, LY2183240, on fearlar Neurobiology. 2006 Jul-Aug;26(4-6):407-23. PMID potentiated startle and alcohol-seeking behaviors in mice 16736384 selectively bred for high alcohol preference. Psychophar[2] Alexander JP, Cravatt BF. The putative endocannabi- macology (Berlin). 2010 Dec;212(4):571-83. PMID noid transport blocker LY2183240 is a potent inhibitor 20838777 of FAAH and several other brain serine hydrolases. Journal of the American Chemical Society. 2006 Aug 2;128(30):9699-704. PMID 16866524 [3] Maione S, Morera E, Marabese I, Ligresti A, Luongo L, Ortar G, Di Marzo V. Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: cannabinoid and non-cannabinoid receptormediated mechanisms. British Journal of Pharmacology. 2008 Nov;155(5):775-82. PMID 18660824 [4] Powers MS, Barrenha GD, Mlinac NS, Barker EL, Chester JA. Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference. Psychopharmacology (Berlin). 2010 Dec;212(4):571-83. PMID 20838777
1. Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L, 164
Chapter 120
LY-320,135 LY-320,135 is a drug used in scientific research which acts as a selective antagonist of the cannabinoid receptor CB1 . It was developed by Eli Lilly and Company in the 1990s. LY-320,135 displays fairly good selectivity, with a binding affinity for CB1 around 70x stronger than for CB2 ,[1] but both its potency and selectivity are modest compared to newer agents, and at higher doses it also binds to a range of non-cannabinoid receptors. However LY-320,135 is still fairly widely used in research, particularly for elucidating the mechanisms by which many CB1 antagonists act as inverse agonists at higher doses.[2]
120.1 References [1] Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ, Cullinan GJ, Hunden DC, Johnson DW, Chaney MO, Koppel GA, Brownstein M. LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. Journal of Pharmacology and Experimental Therapeutics. 1998 Jan;284(1):291-7. PMID 9435190 [2] Pertwee RG. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sciences. 2005 Feb 4;76(12):1307-24. PMID 15670612
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Chapter 121
MAM-2201 MAM-2201 (4'-methyl-AM-2201, 5"-fluoro-JWH122) is a drug that presumably acts as a potent agonist for the cannabinoid receptors. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in the Netherlands and in June 2011 as an ingredient in synthetic cannabis smoking blends.[1][2][3] Like RCS-4 and AB001, MAM-2201 thus appears to be a novel compound invented by "research chemical" suppliers specifically for grey-market recreational use. Structurally, MAM-2201 is a hybrid of two known cannabinoid compounds JWH122 and AM-2201, both of which had previously been used as active ingredients in synthetic cannabis blends before being banned in many countries. MAM-2201 has been banned by being added to the temporary class drug schedule in New Zealand, effective from 13 July 2012.[4]
121.2 References
[2] Moosmann, B., et al. (2012). “Separation and structural characterization of the synthetic cannabinoids JWH-412 and 1-(5-fluoropentyl)−1H-indol-3yl]-(4methylnaphthalen-1-yl)methanone using GC–MS, NMR analysis and a flash chromatography system”. Forensic Science International 220 (1–3): e17–e22. doi:10.1016/j.forsciint.2011.12.010. PMID 22264627. [3] Simolka, K., et al. (2012). “Analysis of synthetic cannabinoids in “spice-like” herbal highs: Snapshot of the German market in summer 2011”. Analytical and Bioanalytical Chemistry 404 (1): 157–171. doi:10.1007/s00216012-6122-4. PMID 22710567. [4] Temporary Class Drug Notice, 5 July 2012. NZ Department of Internal Affairs.
121.1 Pharmacology Nothing has been published on the pharmacology of MAM-2201, though it presumably has similar properties to the closely related AM-2201 and JWH-122, which are both full agonists and unselectively bind to CB1 and CB2 cannabinoid receptors with low nanomolar affinity.
121.1.1
[1] EMCDDA–Europol 2011 Annual Report on the implementation of Council Decision 2005/387/JHA
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 is generally applicable to MAM-2201. The pharmacokinetics of MAM-2201 has not been studied, but its metabolism likely differs only slightly from that of JWH-018, with the main metabolic pathway being hydroxylation at various positions, followed by glucuronidation of the hydroxylated metabolites. Ndealkylation is also likely to occur, producing fluoroalkyl metabolites and ultimately 3-fluoropropanoic acid, though the odd-numbered alkyl chain of MAM2201 would not be expected to produce fluoroacetate as a metabolite. Also metabolism of the related compound AM-694 has shown hydrolytic defluorination of the alkyl chain, meaning any fluoroalkyl metabolites formed are likely to be further metabolised themselves.[5] 166
[5] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012). “The detection of the urinary metabolites of 1-(5fluoropentyl)−1H-indol-3-yl]-(2-iodophenyl)methanone (AM-694), a high affinity cannabimimetic, by gas chromatography - mass spectrometry”. Drug Testing and Analysis 5 (2): 110–5. doi:10.1002/dta.1336. PMID 22522907.
Chapter 122
MDA-19 MDA-19 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2 , with reasonable selectivity over the psychoactive CB1 receptor, though with some variation between species. In animal studies it was effective for the treatment of neuropathic pain, but failed to produce cannabis-like behavioural effects.[1][2]
122.1 See also • AM-1221 • JTE 7-31 • JWH-019 • JWH-133 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
122.2 References [1] Diaz P, et al. Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of neuropathic pain. Journal of Medicinal Chemistry. 2008 Aug 28;51(16):4932-47. PMID 18666769 [2] Xu JJ, et al. Pharmacological characterization of a novel cannabinoid ligand, MDA19, for treatment of neuropathic pain. Anesthesia and Analgesia. 2010 Jul;111(1):99-109. PMID 20522703
167
Chapter 123
Menabitan Menabitan (INN; SP-204), or menabitan hydrochloride (USAN), is a synthetic drug which acts as a potent cannabinoid receptor agonist.[1][2] It is closely related to natural cannabinoids of the tetrahydrocannabinol (THC) group, differing mainly by its longer and branched side chain, and the replacement of the 9-position carbon with a nitrogen.[1] It was studied as an analgesic in the 1970s and was found to possess antinociceptive effects in both humans and animals but was never marketed.[1][3][4]
123.1 See also • A-40174 (SP-1) • Dimethylheptylpyran
123.2 References [1] Green K, Kim K (February 1977). “Acute dose response of intraocular pressure to topical and oral cannabinoids”. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 154 (2): 228–31. doi:10.3181/00379727-154-39643. PMID 402656. [2] David J. Triggle (1996). Dictionary of Pharmacological Agents. Boca Raton: Chapman & Hall/CRC. p. 1271. ISBN 978-0-412-46630-4. [3] Reggio PH (1987). “Molecular determinants for cannabinoid activity: refinement of a molecular reactivity template”. NIDA Research Monograph 79: 82–95. PMID 2830539. [4] Gabriel G. Nahas (5 April 1999). Marihuana and Medicine. Humana Press. p. 46. ISBN 978-0-89603593-5. Retrieved 9 May 2012.
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Chapter 124
Methanandamide Methanandamide (AM-356) is a synthetically created stable chiral analog of anandamide.[1] Its effects have been observed to act on the cannabinoid receptors (specifically on CB1 receptors, which are part of the central nervous system) found in different organisms such as mammals, fish, and certain invertebrates (e.g. Hydra).
124.1 References [1] Abadji, V, et al. (1994). "(R)-methanandamide: A chiral novel anandamide possessing higher potency and metabolic stability”. Journal of Medical Chemistry 37 (12): 1889–93. doi:10.1021/jm00038a020. PMID 8021930.
169
Chapter 125
MK-9470 MK-9470 is a synthetic compound, which binds to the CB1 cannabinoid receptor and functions as an inverse agonist.[1]
125.1 References [1] Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ (2007). "[18 F]MK9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid1 receptor”. Proc. Natl. Acad. Sci. U.S.A. 104 (23): 9800–5. Bibcode:2007PNAS..104.9800B. doi:10.1073/pnas.0703472104. PMC 1877985. PMID 17535893.
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Chapter 126
N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide 7-methoxy-1-(2-morpholinoethyl)-N-((1S,4R)−1,3,3trimethylbicyclo[2.2.1]heptan-2-yl)−1H-indole-3carboxamide (N-[(S)-fenchyl]−1-[2-(morpholin-4yl)ethyl]−7-methoxyindole-3-carboxamide, UR-12, MN-25) is a drug invented by Bristol-Myers Squibb,[1] that acts as a reasonably selective agonist of peripheral cannabinoid receptors.[2] It has moderate affinity for CB2 receptors with a Kᵢ of 11nM, but 22x lower affinity for the psychoactive CB1 receptors with a Kᵢ of 245nM. The indole 2-methyl derivative has the ratio of affinities reversed however, with a Kᵢ of 8nM at CB1 and 29nM at CB2 ,[3][4] which contrasts with the usual trend of 2-methyl derivatives having increased selectivity for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).[5][6] Chemically, it is closely related to another indole-3carboxamide synthetic cannabinoid, Org 28611, but with a different cycloalkyl substitution on the carboxamide, and the cyclohexylmethyl group replaced by morpholinylethyl, as in JWH-200 or A-796,260. Early compounds such as these have subsequently led to the development of a large number of related indole-3carboxamide cannabinoid ligands.[7][8][9][10]
126.1 See also • A-834,735 • AB-001 • AM-1221
2-methyl derivative
126.2 References
• JTE 7-31
[1] CANNABINOID RECEPTOR MODULATORS, THEIR PROCESSES OF PREPARATION, AND USE OF CANNABINOID RECEPTOR MODULATORS IN TREATING RESPIRATORY AND NON-RESPIRATORY DISEASES. WO 2001/58869
• JWH-203 • MDA-19 • SR-144,528
[2] Rulin Zhao, et al. Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)−1Hindole-3-carboxylic acid, key intermediate in the synthesis
• UR-144 171
172
CHAPTER 126. N-(S)-FENCHYL-1-(2-MORPHOLINOETHYL)−7-METHOXYINDOLE-3-CARBOXAMIDE
3. Chin CL, et al. (January 2008). “Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI”. British Journal of [3] Hynes, J., et al. (2002). “C-3 Amido-Indole cannabinoid Pharmacology 153 (2): 367–79. doi :10.1038/ sj.bjp receptor modulators”. Bioorganic & Medicinal Chemistry Letters 12 (17): 2399–402. doi:10.1016/S0960- .0707506. PMC 2219521. PMID 17965748 of novel 3-amidoindole and indolopyridone cannabinoid ligands. ARKIVOC 2010 (vi):89-95.
894X(02)00466-3. PMID 12161142. [4] Wrobleski, Stephen T., et al. (2003). “Rational Design and Synthesis of an Orally Active Indolopyridone as a Novel Conformationally Constrained Cannabinoid Ligand Possessing Antiinflammatory Properties”. Journal of Medicinal Chemistry 46 (11): 2110–6. doi:10.1021/jm020329q. PMID 12747783. [5] Huffman, J. W.; Padgett, L. W. (2005). “Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes”. Current Medicinal Chemistry 12 (12): 1395–1411. doi:10.2174/0929867054020864. PMID 15974991. [6] Manera, C.; Tuccinardi, T.; Martinelli, A. (2008). “Indoles and Related Compounds as Cannabinoid Ligands”. Mini Reviews in Medicinal Chemistry 8 (4): 370–387. doi:10.2174/138955708783955935. PMID 18473928. [7] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a. [8] Kiyoi T, et al. (August 2010). “Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (16): 4918–21. doi:10.1016/j.bmcl.2010.06.067. PMID 20634067. [9] Moir EM, et al. (December 2010). “Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (24): 7327–30. doi:10.1016/j.bmcl.2010.10.061. PMID 21074434. [10] Blaazer, A. R. et al. (2011). “Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure–activity relationships, physicochemical properties and biological activity”. European Journal of Medicinal Chemistry 46 (10): 5086–5098. doi:10.1016/j.ejmech.2011.08.021. PMID 21885167.
126.3 Further reading 1. John Hynes., et al. C3 AMIDO-INDOLE CANNABINOID RECEPTOR MODULATORS. Bioorganic and Medical Chemistry Letters. Volume 12 issue 17, 2 September 2002 pages 2399-2402 2. Frost, J. M., et al. (2010). “Indol −3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity”. Journal of Medicinal Chemistry 53 (1): 295. doi :10.1021/ jm901214q. PMID 19921781
Chapter 127
Nabazenil Nabazenil (SP-175) is a synthetic cannabinoid receptor agonist, which has anticonvulsant properties.[1]
127.1 References [1] Concise dictionary of pharmacological agents: properties and synonyms. p188. ISBN 0-7514-0499-3
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Chapter 128
Nabilone Main article: Medical cannabis
vealed that patients taking cisplatin chemotherapy preferred metoclopramide, while patients taking carboplatin chemotherapy preferred nabilone to control nausea and Nabilone is a synthetic cannabinoid with therapeutic [5] use as an antiemetic and as an adjunct analgesic for vomiting. neuropathic pain. It mimics the main chemical com- One study compared the efficacy and tolerability of pound of cannabis (THC), the active ingredient found in nabilone with that of dihydrocodeine in the treatment of naturally occurring Cannabis sativa L.[1] neuropathic pain.[6] The authors found that nabilone was In Canada, the United States, the United Kingdom and not as effective as dihydrocodeine in controlling pain, and Mexico, nabilone is marketed as Cesamet. It was ap- caused a higher incidence of minor adverse drug reactions proved in 1985 by the U.S. Food and Drug is- than did dihydrocodeine. One critic of the study has sugtration (FDA) for treatment of chemotherapy-induced gested that nabilone might be best suited for the treatment nausea and vomiting (CINV) that has not responded to of patients suffering from central and spasticity-related conventional antiemetics. Though it was approved by pain, for which there is stronger evidence for the benethe FDA in 1985, the drug only began marketing in the fits of cannabinoid therapy; however, these patients made United States in 2006. In Austria Nabilone is marketed up only a small fraction of the study’s population, and the study was not designed to identify subgroups which as Canemes and got its approval for CINV in 2013.[2] might have responded more favorably to treatment than Although it doesn't have any indication officially (except others.[7] in Mexico), nabilone is widely used as an adjunct therapy for chronic pain management. Numerous trials and A clinical trial performed in Canada reviewed the use of nabilone to treat nightmares in individuals suffering case studies have demonstrated modest effectiveness for from post-traumatic stress syndrome.[8] The study found [3] [4] relieving fibromyalgia and multiple sclerosis. that nighttime istration of nabilone reduced the Nabilone is a racemic mixture consisting of the (S,S) and frequency and/or intensity of nightmares in 34 out of the (R,R) isomers ("trans"). 47 (72%) of patients, with 28 reporting complete cessation of nightmares.[8] This study is limited to the extent that there was no placebo control, but warrants future investigation into the use of cannabinoid therapy 128.1 Medical uses in the treatment of post-traumatic stress syndrome and other disorders involving recurrent nightmares. As enNabilone has shown modest effectiveness in relieving docannabinoids play a significant role in regulating longfibromyalgia.[3] term depression, perhaps downregulating the CB1 sysThe main settings that have seen published clinical tem can help remove the highly potentiated, hippocamtrials of nabilone include movement disorders such pal/amydygalia memories of the fear. At the very least, as Parkinson’s syndrome, chronic pain, dystonia and CB1 agonists make one less likely to a dream, spasticity neurological disorders, multiple sclerosis, and or even make REM sleep happen without significant inthe nausea of cancer chemotherapy. Nabilone is also ef- volvement of the limbic system. fective in the treatment of inflammatory bowel disease, especially ulcerative colitis. Medical marijuana patients report that nabilone is more similar in effect to CBD than 128.2 Adverse effects THC, indicating that it has more of a therapeutic effect on the body than a “high” effect on the mind. Nabilone can increase, rather than decrease, postA study comparing nabilone with metoclopramide, operative pain; in the treatment of fibromyalgia, adconducted before the development of modern 5- verse effects limits the useful dose.[3] Adverse effects of HT3 antagonist anti-emetics such as ondansetron, re- nabilone include, but are not limited to dizziness/vertigo, 174
128.4. REFERENCES euphoria, drowsiness, dry mouth, ataxia, sleep disturbance, dysphoria, headache, nausea, disorientation, depersonalization, asthenia and increased appetite.[9]
128.3 See also • Dronabinol
128.4 References [1] “How to use Cesamet”. Artek LLC. 2008. [2] “Canemes (nabilone)". [3] Fine PG, Rosenfeld MJ (2013). “The endocannabiRamnoid system, cannabinoids, and pain”. bam Maimonides Med J (Review) 4 (4): e0022. doi:10.5041/RMMJ.10129. PMC 3820295. PMID 24228165. [4] Wissel J, et al. (2006). “Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial”. J Neurol. (Research article) 253 (10): 1337–41. doi:10.1007/s00415-006-0218-8. PMID 16988792. [5] Cunningham D, et al. (1988). “A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogues”. Eur J Cancer Clin Oncol (Randomized controlled trial) 24 (4): 685–9. doi:10.1016/0277-5379(88)90300-8. PMID 2838294. [6] Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D (January 2008). “Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study”. BMJ (Randomized controlled trial) 336 (7637): 199–201. doi:10.1136/bmj.39429.619653.80. PMC 2213874. PMID 18182416. [7] Cohen SP (January 2008). “Cannabinoids for chronic pain”. BMJ (Research article) 336 (7637): 167– 8. doi:10.1136/bmj.39434.444583.80. PMC 2213791. PMID 18182415. [8] Fraser, GA (2009). “The Use of a Synthetic Cannabinoid in the Management of Treatment-Resistant Nightmares in Posttraumatic Stress Disorder (PTSD)". CNS Neurosci Ther (Trial report) 15 (1): 84–88. doi:10.1111/j.17555949.2008.00071.x. PMID 19228182. [9] “Cesamet (nabilone) Prescribing Information”. http:// www.cesamet.com/pdf/Cesamet_PI_50_count.pdf. Meda Pharmaceuticals Inc. Retrieved 16 July 2014.
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Chapter 129
Nabitan Nabitan (Nabutam, Benzopyranoperidine, SP-106, Abbott 40656) is a synthetic cannabinoid analog of dronabinol (Marinol).[1] It exhibits antiemetic and analgesic effects, most likely by binding to and activating the CB1 and CB2 cannabinoid receptors, and reduced intraocular pressure in animal tests, making it potentially useful in the treatment of glaucoma.[2] Nabitan has the advantage of being water soluble unlike most cannabinoid derivatives, and was researched for potential use as an analgesic or sedative,[3] although it was never developed for clinical use and is not currently used in medicine, as dronabinol or nabilone were felt to be more useful. However it is sometimes used in research into the potential therapeutic applications of cannabinoids.
129.1 References [1] Razdan RK. The Total Synthesis of Cannabinoids. WileyInterscience 1980 [2] Razdan RK, Howes JF. “Drugs related to tetrahydrocannabinol.” Medicinal Research Reviews 1983; 3(2):119146. PMID 6134882 [3] Archer RA. “The cannabinoids: therapeutic potentials.” Annual Reports in Medicinal Chemistry 1974; 9: 253-259. PMID 12307093
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Chapter 130
Nabiximols tiate the marketing rights in other countries in European Union and selected other countries around the world.” In April 2011, GW licensed to Novartis the rights to commercialise nabiximols in Asia (excluding China and Japan), Africa and the Middle East (excluding Israel). [3]
130.1 Availability
Canadian packaging of a case of Sativex vials
Nabiximols (USAN,[1] trade name Sativex) is a patented cannabinoid oromucosal mouth spray developed by the UK company GW Pharmaceuticals for multiple sclerosis (MS) patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.[2] Nabiximols is distinct from all other pharmaceutically produced cannabinoids currently available because it is a mixture of compounds derived from Cannabis plants, rather than a mono-molecular synthetic product. The drug is a pharmaceutical product standardised in composition, formulation, and dose, although it is still effectively a tincture of the cannabis plant. Its principal active cannabinoid components are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD). The product is formulated as an oromucosal spray which is istered by spraying into the mouth. Each spray delivers a near 1:1 ratio of CBD to THC, with a fixed dose of 2.7 mg THC and 2.5 mg CBD. Nabiximols is also being developed in Phase III trials as a potential treatment to alleviate pain due to cancer. It has also been researched in various models of peripheral and central neuropathic pain. In May 2003 GW Pharmaceuticals and Bayer entered into an exclusive marketing agreement for GW’s cannabis-based medicinal extract product, to be marketed under the brand name Sativex. “Bayer has obtained exclusive rights to market Sativex in the UK. In addition, Bayer has the option for a limited period of time to nego-
In June 2010, the Medicines and Healthcare products Regulatory Agency of the United Kingdom licensed nabiximols as a prescription-only medicine for the treatment of spasticity due to multiple sclerosis. This regulatory authorization represents the world’s first full regulatory approval for the medicine. The spray is being marketed in the UK by Bayer Schering Pharma. Many MS patients cannot receive nabiximols due to local National Health Service (NHS) resistance to its funding.[4][5] but, in August 2014, the NHS in Wales agreed to fund Sativex for people with multiple sclerosis.[6] Nabiximols was also approved in Spain for MS spasticity in the second half of 2010 and was launched in that country in March 2011. It was approved in the Czech Republic in April 2011, in in May 2011, in Denmark in June 2011 and in Sweden in January 2012 to MS patients who have not responded adequately to other medication for spasticity.[7] It has also been recommended for approval in Italy and Austria with formal approvals expected in these countries during 2011. In Spain and other European markets (excluding the UK), nabiximols will be marketed by Almirall. In Canada, nabiximols has been approved by Health Canada for the treatment of MS spasticity. It has also received a licence with conditions (NOC/c) for two additional uses: as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis,[8] and also for pain due to cancer.[9][10] Nabiximols is available in a number of countries as an unlicensed medicine, which enables doctors to prescribe the product to individual patients who they consider may benefit. The product has been exported from the UK to a total of 28 countries to date. In February 2007, GW and Otsuka Pharmaceutical an-
177
178 nounced an exclusive agreement for Otsuka to develop and market the drug in the United States. The first large scale US Phase IIb trial, Spray Trial, for cancer patients reported positive results in March 2010. GW and Otsuka have now commenced the Phase III development of nabiximols in cancer pain. In 2013, legalized the use of cannabinoids in medicine, Sativex is the first one to be sold under prescription.
130.2 Effectiveness Of the two preliminary Phase III studies investigating the treatment of MS patients, one showed a reduction of spasticity of 1.2 points on the 0–10 points rating scale (versus 0.6 points under placebo), the other showed a reduction of 1.0 versus 0.8 points. Only the first study reached statistical significance. The Phase III approval study consisted of a run-in phase where the response of individuals to the drug was determined. The responders (42% of patients) showed a significant effect in the second, placebo controlled, phase of the trial.[11] A 2009 meta-analysis of six studies found large variations of effectiveness, with a – statistically non-significant – trend towards a reduction of spasticity.[12]
130.3 Side effects
CHAPTER 130. NABIXIMOLS • Dronabinol • GW Pharmaceuticals • Hortapharm B.V.
130.6 References [1] United States Adopted Names Coincil: Statement on a nonproprietary name [2] http://www.gwpharm.com/SPC.aspx [3] “GW signs Sativex cannabis-based drug deal with Novartis”. The Telegraph. 11 April 2011. Retrieved 12 July 2012. [4] Ryan, Siobhan (4 June 2011). “Sussex MS sufferers call for drug funding”. Argus (Sussex,UK). Retrieved 8 June 2011. [5] “Sativex rejected by healthcare provider”. Lincolnshire. 20 June 2011. Retrieved 20 June 2011. [6] “Wales NHS to offer MS cannabis drug Sativex”. 15 August 2014. Retrieved 18 August 2014. [7] Sativex (nabiximols), Swedish Medical Products Agency [8] GW Pharmaceuticals. "Multiple Sclerosis". Accessed 24 July 2011. [9] GW Pharmaceuticals. "Cancer Pain" Accessed 24 July 2011. [10] “Sativex - Investigational Cannabis-Based Treatment for Pain and Multiple Sclerosis Drug Development Technology”. www.drugdevelopment-technology.com. Retrieved 2008-08-08.
In early clinical trials, nabiximols has generally been well tolerated.[13][14][15] The most common adverse effects in Phase III trials were dizziness (25%), drowsiness (8.2%) and disorientation (4%). 12% of patients stopped taking [11] Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel the drug because of the side effects. No investigations 2011/2012 (German) regarding the potential for dependence are available, but such a potential is unlikely considering the pharmacolog- [12] Lakhan, Shaheen E; Rowland, Marie (2009). “Whole plant cannabis extracts in the treatment of spasticity in ical properties of the two components.[11]
130.4 Controversy
multiple sclerosis: a systematic review”. BMC Neurol 9: 59. doi:10.1186/1471-2377-9-59. PMC 2793241. PMID 19961570.
[13] Wade D, Makela P, Robson P, House H, Bateman C (2004). “Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients”. Mult Scler 10 (4): 434–41. doi:10.1191/1352458504ms1082oa. PMID 15327042.
GW Pharmaceuticals were issued a unique license to cultivate cannabis for the manufacturing of Sativex in the UK, granting them the sole legal right to research in aerosolized cannabis derived therapeutics, which in April 2013 became commercially viable when the UK Govern[14] Wade D, Makela P, House H, Bateman C, Robson P ment scheduled the Sativex formulation to part IV of the (2006). “Long-term use of a cannabis-based medicine UK Drugs Act.[16] in the treatment of spasticity and other symptoms in multiple sclerosis”. Mult Scler 12 (5): 639–45. doi:10.1177/1352458505070618. PMID 17086911.
130.5 See also • Medical cannabis • Nabilone
[15] Wade D, Robson P, House H, Makela P, Aram J (2003). “A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms”. Clin Rehabil 17 (1): 21–9. doi:10.1191/0269215503cr581oa. PMID 12617376.
130.7. EXTERNAL LINKS
[16] http://www.gwpharm.com/GW%20Pharmaceuticals% 20cannabinoid-medicine%20Sativex%20moved% 20to%20Schedule%204%20of%20UK%20Drugs% 20Act.aspx
130.7 External links • GW Pharmaceuticals Website
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Chapter 131
Naboctate Naboctate (SP-325) is a synthetic cannabinoid receptor agonist, which has antiemetic, sedative, anxiolytic and anti-glaucoma properties.[1]
131.1 References [1] Concise dictionary of pharmacological agents: properties and synonyms. p188. ISBN 0-7514-0499-3
180
Chapter 132
NESS-0327 NESS-0327 is a drug used in scientific research which acts as an extremely potent and selective antagonist of the cannabinoid receptor CB1 . It is much more potent an antagonist, and more selective for the CB1 receptor over CB2 , than the more commonly used ligand rimonabant, with a Kᵢ at CB1 of 350fM (i.e. 0.00035nM) and a selectivity of over 60,000x for CB1 over CB2 .[1] Independently, two other groups have described only modest nanomolar CB1 affinity for this compound (125nM[2] and 18.4nM[3] ). Also unlike rimonabant, NESS-0327 does not appear to act as an inverse agonist at higher doses, instead being a purely neutral antagonist which blocks the CB1 receptor but does not produce any physiological effect of its own.[4]
132.1 See also • Discovery and development of Cannabinoid Receptor 1 Antagonists • NESS-040C5
132.2 References [1] Ruiu S, Pinna GA, Marchese G, Mussinu JM, Saba P, Tambaro S, Casti P, Vargiu R, Pani L. Synthesis and characterization of NESS 0327: a novel putative antagonist of the CB1 cannabinoid receptor. Journal of Pharmacology and Experimental Therapeutics. 2003 Jul;306(1):363-70. PMID 12663689 [2] A.R. Stoit, J.H.M. Lange, A.P. den Hartog, E. Ronken, K. Tipker, H.H. van Stuivenberg, J.A.R. Dijksman, H.C. Wals, C.G. Kruse, Chem. Pharm. Bull. 50 (2002) 11091113 [3] Y. Zhang, J.P. Burgess, M. Brackeen, A. Gilliam, S.W. Mascarella, K. Page, H.H. Seltzman, B.F. Thomas, J. Med. Chem. 51 (2008) 3526-3539 [4] Tambaro S, Mongeau R, Dessi C, Pani L, Ruiu S. Modulation of ATP-mediated contractions of the rat vas deferens through presynaptic cannabinoid receptors. European Journal of Pharmacology. 2005 Nov 21;525(1-3):150-3. PMID 16271359
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Chapter 133
NESS-040C5 NESS-040C5 is a potent cannabinoid agonist which was developed for the treatment of glaucoma.[1] It has reasonable selectivity for the CB2 receptor subtype, having a CB2 affinity of 0.4nM, and 25x selectivity over the related CB1 receptor.[2]
133.1 See also • AB-FUBINACA • NESS-0327 • SR-144,528
133.2 References [1] Paolo Lazzari et al. Pharmaceutical Compounds. US Patent 8106218 [2] Hanus LO, Mechoulam R. Novel natural and synthetic ligands of the endocannabinoid system. Current Medicinal Chemistry. 2010;17(14):1341-59. PMID 20166928
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Chapter 134
NMP-7 NMP-7 is a drug which acts as both a non-selective agonist of the CB1 and CB2 cannabinoid receptors, and also as a blocker of T-type calcium channels, the target of anticonvulsant drugs such as ethosuximide. NMP-7 has an agonist EC50 of 96.9nM at CB1 and 10.5nM at CB2 , and an IC50 of 1.84μM for blocking Cav3.2 T-type calcium channels. In animal studies it produces potent analgesic effects in a variety of different tests.[1]
134.1 References [1] You H, Gadotti VM, Petrov RR, Zamponi GW, Diaz P. Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands. Molecular Pain. 2011 Nov 17;7:89. PMID 22093952
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Chapter 135
Nonabine Nonabine (BRL-4664) is a drug which is a cannabinoid derivative, which was developed for the prevention of nausea and vomiting associated with cancer chemotherapy.[1] It has strong antiemetic effects equivalent to those of chlorpromazine, and also produces some mild sedative effects, along with dry mouth and EEG changes typical of cannabinoid agonists, but with minimal changes in mood or perception, suggesting the abuse potential is likely to be low.[2][3]
135.1 References [1] Staquet M, Bron D, Rozencweig M, Kenis Y. Clinical studies with a THC analog (BRL-4664) in the prevention of cisplatin-induced vomiting. Journal of Clinical Pharmacology. 1981 Aug-Sep;21(8-9 Suppl):60S-63S. PMID 7197692 [2] Archer CB, Amlot PL, Trounce JR. Antiemetic effect of nonabine in cancer chemotherapy: a double blind study comparing nonabine and chlorpromazine. British Medical Journal (Clinical Research Edition). 1983 Jan 29;286(6362):350-1. PMID 6402096 [3] McClelland GR, Sutton JA. Pilot investigation of the quantitative EEG and clinical effects of ketazolam and the novel antiemetic nonabine in normal subjects. Psychopharmacology (Berlin). 1985;85(3):306-8. PMID 2860687
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Chapter 136
11-nor-9-Carboxy-THC Not to be confused with Tetrahydrocannabinolic acid. 11-nor−9-Carboxy-THC, also known as 11-nor−9carboxy-delta-9-tetrahydrocannabinol, 11-nor9-carboxy-delta-9-THC, 11-COOH-THC, THCCOOH, and THC-11-oic acid, is the main secondary metabolite of THC which is formed in the body after Cannabis is consumed. 11-COOH-THC is formed in the body by oxidation of the active metabolite 11-Hydroxy-THC (also known as 11OH-THC) by liver enzymes. It is then metabolized further by conjugation with glucuronide,[2] forming a watersoluble congener which can be more easily excreted by the body.[3]
While 11-COOH-THC does not have any psychoactive effects in its own right, it may still have a role in the analgesic and antiinflammatory effects of cannabis,[10][11][12] and has also been shown to moderate the effects of THC itself which may help explain the difference in subjective effects seen between occasional and regular s of cannabis.[13][14]
136.1 References
11-COOH-THC is not psychoactive itself, but has a long half-life in the body of up to several days (or even weeks in very heavy s),[4][5][6] making it the main metabolite tested for when blood or urine testing for cannabis use. More selective tests are able to distinguish between 11-OH-THC and 11-COOH-THC, which can help determine how recently cannabis was consumed;[7][8] if only 11-COOH-THC is present then the cannabis was used some time ago and any impairment in cognitive ability or motor function will have dissipated, whereas if both 11-OH-THC and 11-COOH-THC are present then the cannabis was consumed more recently and motor impairment may still be present. Some jurisdictions where cannabis use is decriminalized or permitted under some circumstances use such tests when determining whether drivers were legally intoxicated and therefore unfit to drive, with the comparative levels of THC, 11-OH-THC and 11-COOH-THC being used to derive a “blood cannabis level” analogous to the blood alcohol level used in prosecuting impaired drivers.[9] On the other hand in jurisdictions where cannabis is completely illegal, any detectable levels of 11COOH-THC may be deemed to constitute driving while intoxicated, even though this approach has been criticized as tantamount to prohibition of “driving whilst being a recent of cannabis” regardless of the presence or absence of any actual impairment that might impact on driving performance.
185
[1] http://www.clinchem.org/cgi/content/full/55/12/2180 [2] Skopp, G; Pötsch, L (2002). “Stability of 11-nor-delta(9)carboxy-tetrahydrocannabinol glucuronide in plasma and urine assessed by liquid chromatography-tandem mass spectrometry”. Clinical chemistry 48 (2): 301–6. PMID 11805011. [3] Law, B; Mason, PA; Moffat, AC; King, LJ (1984). “Confirmation of cannabis use by the analysis of delta 9tetrahydrocannabinol metabolites in blood and urine by combined HPLC and RIA”. Journal of analytical toxicology 8 (1): 19–22. doi:10.1093/jat/8.1.19. PMID 6323852. [4] Huestis, MA; Mitchell, JM; Cone, EJ (1995). “Detection times of marijuana metabolites in urine by immunoassay and GC-MS”. Journal of analytical toxicology 19 (6): 443–9. doi:10.1093/jat/19.6.443. PMID 8926739. [5] Pope Jr, HG; Gruber, AJ; Hudson, JI; Huestis, MA; Yurgelun-Todd, D (2001). “Neuropsychological performance in long-term cannabis s”. Archives of General Psychiatry 58 (10): 909–15. doi:10.1001/archpsyc.58.10.909. PMID 11576028. [6] Dietz, L; Glaz-Sandberg, A; Nguyen, H; Skopp, G; Mikus, G; Aderjan, R (2007). “The urinary disposition of intravenously istered 11-nor-9carboxy-delta-9-tetrahydrocannabinol in humans”. Therapeutic drug monitoring 29 (3): 368–72. doi:10.1097/FTD.0b013e31805ba6fd. PMID 17529896. [7] Huestis, MA; Henningfield, JE; Cone, EJ (1992). “Blood cannabinoids. II. Models for the prediction of time of marijuana exposure from plasma concentrations of delta 9-tetrahydrocannabinol (THC) and 11-nor9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH)".
186
CHAPTER 136. 11-NOR-9-CARBOXY-THC
Journal of analytical toxicology 16 (5): doi:10.1093/jat/16.5.283. PMID 1338216.
283–90.
[8] Huestis, MA; Elsohly, M; Nebro, W; Barnes, A; Gustafson, RA; Smith, ML (2006). “Estimating time of last oral ingestion of cannabis from plasma THC and THCCOOH concentrations”. Therapeutic drug monitoring 28 (4): 540–4. doi:10.1097/00007691-20060800000009. PMID 16885722. [9] Ménétrey, A; Augsburger, M; Favrat, B; Pin, MA; Rothuizen, LE; Appenzeller, M; Buclin, T; Mangin, P; Giroud, C (2005). “Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral istration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC”. Journal of analytical toxicology 29 (5): 327–38. doi:10.1093/jat/29.5.327. PMID 16105257. [10] Burstein, SH; Hull, K; Hunter, SA; Latham, V (1988). “Cannabinoids and pain responses: a possible role for prostaglandins”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 (14): 3022–6. PMID 2846397. [11] Doyle, SA; Burstein, SH; Dewey, WL; Welch, SP (1990). “Further studies on the antinociceptive effects of delta 6THC-7-oic acid”. Agents and actions 31 (1–2): 157–63. doi:10.1007/bf02003237. PMID 2178317. [12] Ujváry, I; Grotenhermen, F (2014). “11-Nor-9-carboxyΔ9-tetrahydrocannabinol – a ubiquitous yet underresearched cannabinoid. A review of the literature”. Cannabinoids 9 (1): 1–8. [13] Burstein, S; Hunter, SA; Latham, V; Renzulli, L (1987). “A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic effect in mice”. Experientia 43 (4): 402–3. doi:10.1007/BF01940427. PMID 3032669. [14] Burstein, S; Hunter, SA; Latham, V; Renzulli, L (1986). “Prostaglandins and cannabis--XVI. Antagonism of delta 1-tetrahydrocannabinol action by its metabolites”. Biochemical pharmacology 35 (15): 2553–8. doi:10.1016/0006-2952(86)90053-5. PMID 3017356.
Chapter 137
O-1057 O-1057 is an analgesic cannabinoid derivative created by Organix Inc. for use in scientific research. Unlike most cannabinoids discovered to date, it is water soluble, which gives it considerable advantages over many related cannabinoids. It has moderate affinity for both CB1 and CB2 receptors, with Kᵢ values of 8.36nM at CB1 and 7.95nM at CB2 .[1]
137.1 See also • AM-2232 • O-774 • O-1812 • O-2694
137.2 References [1] Pertwee RG, et al. O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. British Journal of Pharmacology. 2000 Apr;129(8):1577-84. PMID 10780961
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Chapter 138
O-1125 O-1125 (3-(1,1-dimethylhexyl-6dimethylcarboxamide)-Δ8-tetrahydrocannabinol) is a drug which is a cannabinoid derivative. It has analgesic effects and is used in scientific research. It is a potent CB1 full agonist with a Ki of 1.16nM.[1]
138.1 References [1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649
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Chapter 139
O-1238 O-1238 is a drug which is a cannabinoid derivative that is used in scientific research. It is a partial agonist at the cannabinoid receptor CB1 ,[1] producing a maximal stimulation of 58.3%[2] with a Ki of 8.45nM.[3]
139.1 References [1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649 [2] Griffin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ, Saha B, Razdan RK, Martin BR, Abood ME. An investigation into the structural determinants of cannabinoid receptor ligand efficacy. British Journal of Pharmacology. 1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469 PMID 10323589 [3] Ross RA, Gibson TM, Stevenson LA, Saha B, Crocker P, Razdan RK, Pertwee RG. Structural determinants of the partial agonist-inverse agonist properties of 6'azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabinoid receptors. British Journal of Pharmacology. 1999 Oct;128(3):735-43. PMID 10516656
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Chapter 140
O-1269 O-1269 is a drug that is a diarylpyrazole derivative, related to potent cannabinoid antagonist drugs such as rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full or partial agonists at the cannabinoid receptors rather than antagonists, and so produce the usual effects expected of cannabinoid agonists in animal tests, such as sedation and analgesic effects. The N-heptyl homologue O-1270 and the N-propyl homologue O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker binding affinity at cannabinoid receptors compared to the pentyl homologue O-1269.[1][2][3] Agonist-like and atypical cannabinoid activity has also been observed with a number of related compounds.[4][5]
140.1 References [1] Billy R. Martin, Raj K. Razdan, Anu Mahadevan. Pyrazole cannabinoid agonist and antagonists. US Patent 6509367, filed Sep 22, 2001, issued Jan 21, 2003. [2] Shim JY, Welsh WJ, Cartier E, Edwards JL, Howlett AC. Molecular interaction of the antagonist N-(piperidin1-yl)−5-(4-chlorophenyl)−1- (2,4-dichlorophenyl)−4methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor. Journal of Medicinal Chemistry. 2002 Mar 28;45(7):1447-59. PMID 11906286 [3] Francisco ME, Seltzman HH, Gilliam AF, Mitchell RA, Rider SL, Pertwee RG, Stevenson LA, Thomas BF. Synthesis and structure-activity relationships of amide and hydrazide analogues of the cannabinoid CB(1) receptor antagonist N-(piperidinyl)- 5-(4-chlorophenyl)−1-(2,4dichlorophenyl)−4-methyl-1H-pyrazole-3-carboxamide (SR141716). Journal of Medicinal Chemistry. 2002 Jun 20;45(13):2708-19. PMID 12061874 [4] Thomas, B. F.; Francisco, M. E. Y.; Seltzman, H. H.; Thomas, J. B.; Fix, S. E.; Schulz, A. K.; Gilliam, A. F.; Pertwee, R. G.; Stevenson, L. A. (2005). “Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist N-(piperidinyl)−5(4-chlorophenyl)−1-(2,4-dichlorophenyl)−4-methyl1H-pyrazole-3-carboxamide (SR141716) with unique binding selectivities and pharmacological activities”. Bioorganic & Medicinal Chemistry 13 (18): 5463–5474. doi:10.1016/j.bmc.2005.06.005. PMID 15994087.
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[5] Wiley, J. L.; Selley, D. E.; Wang, P.; Kottani, R.; Gadthula, S.; Mahadeven, A. (2011). “3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB1) Receptor Antagonist Rimonabant: Cannabinoid AgonistLike Effects in Mice via Non-CB1, Non-CB2 Mechanism”. Journal of Pharmacology and Experimental Therapeutics 340 (2): 433–444. doi:10.1124/jpet.111.187815. PMC 3263966. PMID 22085649.
Chapter 141
O-1602 O-1602 is a synthetic compound most closely related to abnormal cannabidiol, and more distantly related in structure to cannabinoid drugs such as THC. O-1602 does not bind to the classical cannabinoid receptors CB1 or CB2 with any significant affinity, but instead is an agonist at several other receptors which appear to be related to the cannabinoid receptors, particularly GPR18 and GPR55. These previously orphan receptors have been found to be targets for a number of endogenous and synthetic cannabinoid compounds, and are thought to be responsible for most of the non-CB1 , non-CB2 mediated effects that have become evident in the course of cannabinoid research. O-1602 produces some effects shared with classical cannabinoid compounds such as analgesic and antiinflammatory effects and appetite stimulation, but it does not produce sedation or psychoactive effects, and has several actions in the gut and brain that are not shared with typical cannabinoid agonists.[1][2][3][4][5][6][7]
141.1 See also • Cannabidiol
17 (8): 1651–1664. doi:10.1002/ibd.21538. 3116968. PMID 21744421.
PMC
[4] Díaz-Arteaga, A.; Vázquez, M. J.; Vazquez-Martínez, R.; Pulido, M. R.; Suarez, J.; Velásquez, D. A.; López, M.; Ross, R. A.; De Fonseca, F. R.; Bermudez-Silva, F. J.; Malagón, M. M.; Diéguez, C.; Nogueiras, R. (2012). “The atypical cannabinoid O-1602 stimulates food intake and adiposity in rats”. Diabetes, Obesity and Metabolism 14 (3): 234–243. doi:10.1111/j.14631326.2011.01515.x. PMID 21981246. [5] Kargl, J.; Haybaeck, J.; Stančić, A.; Andersen, L.; Marsche, G.; Heinemann, A.; Schicho, R. (2012). “O1602, an atypical cannabinoid, inhibits tumor growth in colitis-associated colon cancer through multiple mechanisms”. Journal of Molecular Medicine 91 (4): 449–58. doi:10.1007/s00109-012-0957-1. PMC 3529923. PMID 22965195. [6] McHugh, D.; Wager-Miller, J.; Page, J.; Bradshaw, H. B. (2012). “SiRNA knockdown of GPR18 receptors in BV2 microglia attenuates N-arachidonoyl glycine-induced cell migration”. Journal of Molecular Signaling 7 (1): 10. doi:10.1186/1750-2187-7-10. PMC 3493281. PMID 22834922. [7] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Bradshaw, H.; Kelly, M. E.; Straiker, A. (2013). “A GPR18-based signaling system regulates IOP in murine eye”. British Journal of Pharmacology 169 (4): 834– 43. doi:10.1111/bph.12136. PMC 3687663. PMID 23461720.
• O-1918
141.2 References [1] Ashton, J. C. (2012). “The atypical cannabinoid o-1602: Targets, actions, and the central nervous system”. Central nervous system agents in medicinal chemistry 12 (3): 233–239. doi:10.2174/187152412802430156. PMID 22831390. [2] Schuelert, N.; McDougall, J. J. (2011). “The abnormal cannabidiol analogue O-1602 reduces nociception in a rat model of acute arthritis via the putative cannabinoid receptor GPR55”. Neuroscience Letters 500 (1): 72–76. doi:10.1016/j.neulet.2011.06.004. PMID 21683763. [3] Schicho, R.; Bashashati, M.; Bawa, M.; McHugh, D.; Saur, D.; Hu, H. M.; Zimmer, A.; Lutz, B.; MacKie, K.; Bradshaw, H. B.; McCafferty, D. M.; Sharkey, K. A.; Storr, M. (2011). “The atypical cannabinoid O1602 protects against experimental colitis and inhibits neutrophil recruitment”. Inflammatory Bowel Diseases
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Chapter 142
O-1812 O-1812 is an eicosanoid derivative related to anandamide that acts as a potent and highly selective agonist for the cannabinoid receptor CB1 , with a Kᵢ of 3.4nM at CB1 and 3870nM at CB2 .[1] Unlike most related compounds, O-1812 is metabolically stable against rapid breakdown by enzymes, and produces a cannabinoid-like discriminative effect in rats, which is similar but not identical to that produced by cannabinoid drugs of other chemical classes.[2][3][4][5]
142.1 See also • AM-1235 • AM-2232 • AM-2389 • Methanandamide • O-774 • O-1057
142.2 References [1] Di Marzo V, et al. (February 2001). “Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor “hybrid” ligands”. Biochemical and Biophysical Research Communications 281 (2): 444–51. doi:10.1006/bbrc.2001.4354. PMID 11181068. [2] Baskfield CY, Martin BR, Wiley JL (April 2004). “Differential effects of delta9-tetrahydrocannabinol and methanandamide in CB1 knockout and wild-type mice”. The Journal of Pharmacology and Experimental Therapeutics 309 (1): 86–91. doi:10.1124/jpet.103.055376. PMID 14718593. [3] Wiley JL, et al. (August 2004). “A comparison of the discriminative stimulus effects of delta(9)tetrahydrocannabinol and O-1812, a potent and metabolically stable anandamide analog, in rats”. Experimental and Clinical Psychopharmacology 12 (3): 173–9. doi:10.1037/1064-1297.12.3.173. PMID 15301634.
192
[4] Wiley JL, Smith FL, Razdan RK, Dewey WL (March 2005). “Task specificity of cross-tolerance between Delta9-tetrahydrocannabinol and anandamide analogs in mice”. European Journal of Pharmacology 510 (12): 59–68. doi:10.1016/j.ejphar.2005.01.006. PMID 15740725. [5] Breivogel CS, et al. (July 2008). “Sensitivity to delta9tetrahydrocannabinol is selectively enhanced in betaarrestin2 -/- mice”. Behavioural Pharmacology 19 (4): 298–307. doi:10.1097/FBP.0b013e328308f1e6. PMC 2751575. PMID 18622177.
Chapter 143
O-1871 O-1871 is a potent cannabinoid agonist which was invented by Billy R Martin and Raj K Razdan in 2002. It has a CB1 receptor affinity of 2.0nM and a CB2 receptor affinity of 0.3nM.[1] Structurally, O-1871 is a cyclohexylphenol derivative related to 47,497, and so is illegal in most jurisdictions where 47,497 and its derivatives are banned. However the 3,3dimethylcyclohexyl substituent of O-1871 can be replaced by various other groups, producing other potent compounds such as the cycloheptyl derivative O-1656 and the 2-adamantyl derivative O-1660, as well as the corresponding 3,5-dichlorophenyl derivative,[2] which are not cyclohexylphenol derivatives.
143.1 See also • 55,940 • Cannabidiol • Cannabicyclohexanol
143.2 References [1] Billy R Martin, Raj K Razdan. CANNABINOIDS. Patent WO 2003/091189 [2] Xin-Zhong Lai, Dai Lu, Alexandros Makriyannis. Novel biphenyl and biphenyl-like cannabinoids. Patent US 2004/0087590
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Chapter 144
O-1918 O-1918 is a synthetic compound related to cannabidiol, which is an antagonist at two former orphan receptors GPR18 and GPR55, that appear to be related to the cannabinoid receptors. O-1918 is used in the study of these receptors, which have been found to be targets for a number of endogenous and synthetic cannabinoid compounds, and are thought to be responsible for most of the non-CB1 , non-CB2 mediated effects that have become evident in the course of cannabinoid research.[1][2][3][4][5]
144.1 See also • Abnormal cannabidiol • O-1602
144.2 References [1] Offertáler, L.; Mo, F. M.; Bátkai, S.; Liu, J.; Begg, M.; Razdan, R. K.; Martin, B. R.; Bukoski, R. D.; Kunos, G. (2003). “Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor”. Molecular Pharmacology 63 (3): 699–705. doi:10.1124/mol.63.3.699. PMID 12606780. [2] Zakrzeska, A.; Schlicker, E.; Baranowska, M.; Kozłowska, H.; Kwolek, G.; Malinowska, B. (2010). “A cannabinoid receptor, sensitive to O-1918, is involved in the delayed hypotension induced by anandamide in anaesthetized rats”. British Journal of Pharmacology 160 (3): 574–584. doi:10.1111/j.1476-5381.2009.00579.x. PMC 2931558. PMID 20105178. [3] Schuelert, N.; McDougall, J. J. (2011). “The abnormal cannabidiol analogue O-1602 reduces nociception in a rat model of acute arthritis via the putative cannabinoid receptor GPR55”. Neuroscience Letters 500 (1): 72–76. doi:10.1016/j.neulet.2011.06.004. PMID 21683763. [4] Szczesniak, A. M.; Maor, Y.; Robertson, H.; Hung, O.; Kelly, M. E. M. (2011). “Nonpsychotropic Cannabinoids, Abnormal Cannabidiol and CanabigerolDimethyl Heptyl, Act at Novel Cannabinoid Receptors to Reduce Intraocular Pressure”. Journal of Ocular Pharmacology and Therapeutics 27 (5): 427–435. doi:10.1089/jop.2011.0041. PMID 21770780.
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[5] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Bradshaw, H.; Kelly, M. E.; Straiker, A. (2013). “A GPR18-based signaling system regulates IOP in murine eye”. British Journal of Pharmacology 169 (4): 834– 43. doi:10.1111/bph.12136. PMC 3687663. PMID 23461720.
Chapter 145
O-2050 O-2050 is a drug that is a classical cannabinoid derivative, which acts as a silent antagonist for the CB1 receptor. This gives it an advantage in research over many commonly used cannabinoid antagonists such as rimonabant, which at higher doses act as inverse agonists at CB1 as well as showing off-target effects. However while O2050 acts as a silent antagonist in vitro, some tests in vivo have suggested it may show agonist activity under certain circumstances.[1][2][3][4][5][6]
145.1 See also • O-2113
145.2 References [1] Martin B, et al. Agonists and silent antagonists in a series of cannabinoid sulfonamides. 12th Annual Symposium on the Cannabinoids, 2002 [2] Martin et al. SULFONAMIDE CANNABINOID AGONISTS AND ANTAGONISTS. US Patent 7279500, Oct 9 2007 [3] Gardner A, Mallet PE. Suppression of feeding, drinking, and locomotion by a putative cannabinoid receptor 'silent antagonist'. European Journal of Pharmacology. 2006 Jan 13;530(1-2):103-6. PMID 16380113 [4] Higuchi S, Irie K, Mishima S, Araki M, Ohji M, Shirakawa A, Akitake Y, Matsuyama K, Mishima K, Mishima K, Iwasaki K, Fujiwara M. The cannabinoid 1receptor silent antagonist O-2050 attenuates preference for high-fat diet and activated astrocytes in mice. Journal of Pharmacological Sciences. 2010;112(3):369-72. PMID 20168044 [5] Higuchi S, Ohji M, Araki M, Furuta R, Katsuki M, Yamaguchi R, Akitake Y, Matsuyama K, Irie K, Mishima K, Mishima K, Iwasaki K, Fujiwara M. Increment of hypothalamic 2-arachidonoylglycerol induces the preference for a high-fat diet via activation of cannabinoid 1 receptors. Behavioural Brain Research. 2011 Jan 1;216(1):477-80. PMID 20817042 [6] Wiley JL, Breivogel CS, Mahadevan A, Pertwee RG, Cascio MG, Bolognini D, Huffman JW, Walentiny DM, Vann
195
RE, Razdan RK, Martin BR. Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB(1) receptor antagonist. European Journal of Pharmacology. 2011 Jan 25;651(1-3):96-105. PMID 21114999
Chapter 146
O-2113 O-2113 is a drug that is a classical cannabinoid derivative, which acts as a potent agonist for cannabinoid receptors, producing sedation, hypothermia and analgesia in animal studies.[1]
146.1 See also • O-2050 • O-2372 • O-2545
146.2 References [1] Martin, et al. SULFONAMIDE CANNABINOID AGONISTS AND ANTAGONISTS. US Patent 7279500, Oct 9 2007
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Chapter 147
O-2372 O-2372 is an analgesic cannabinoid derivative created by Organix Inc. for use in scientific research. It has high affinity for both CB1 and CB2 receptors, with Kᵢ values of 1.3nM at CB1 and 0.57nM at CB2 , but is only moderately soluble in water compared to other related compounds such as O-2694, which it is a metabolite of.[1]
147.1 See also • O-2113 • O-2545 • O-2694
147.2 References [1] Martin BR, et al. Pharmacological characterization of novel water-soluble cannabinoids. Journal of Pharmacology and Experimental Therapeutics. 2006 Sep;318(3):1230-9. PMID 16757541
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Chapter 148
O-2545 O-2545 is an analgesic cannabinoid derivative created by Organix Inc. for use in scientific research. Unlike most cannabinoids discovered to date, it is water soluble, which gives it considerable advantages over many related cannabinoids. It has high affinity for both CB1 and CB2 receptors, with Kᵢ values of 1.5nM at CB1 and 0.32nM at CB2 .[1]
148.1 See also • O-2113 • O-2372 • Tropoxane
148.2 References [1] Martin BR, et al. Pharmacological characterization of novel water-soluble cannabinoids. Journal of Pharmacology and Experimental Therapeutics. 2006 Sep;318(3):1230-9. PMID 16757541
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Chapter 149
O-2694 O-2694 is a drug that is a cannabinoid derivative. It has analgesic effects and is used in scientific research. Unlike most cannabinoids discovered to date, it is highly watersoluble, which gives it considerable advantages over many related drugs. It has high affinity for both CB1 and CB2 receptors, with Kᵢ values of 3.7nM at CB1 and 2.8nM at CB2 . However, it has complex pharmacokinetics as most of the istered dose is metabolised by hydrolysis of the ester link to the water-insoluble compound O-2372, thus producing a biphasic effects profile that is less suitable for research purposes than the related compound O2545.[1]
149.1 See also • O-1057 • O-2372
149.2 References [1] Martin BR, et al. Pharmacological characterization of novel water-soluble cannabinoids. Journal of Pharmacology and Experimental Therapeutics. 2006 Sep;318(3):1230-9. PMID 16757541
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Chapter 150
O-774 O-774 is a classical cannabinoid derivative which acts as a potent agonist for the cannabinoid receptors, with a Kᵢ of 0.6 nM at CB1 , and very potent cannabinoid effects in animal studies.[1][2]
150.1 See also • AM-2232 • O-1057 • O-1812
150.2 References [1] Singer M, et al. Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8tetrahydrocannabinol. Journal of Medicinal Chemistry. 1998 Oct 22;41(22):4400-7. PMID 9784115 [2] The Cannabinoid Receptors. Part I. Cannabinoid Receptor Ligands and Structure-Activity Relationships. pp 6-9. Edited by Patricia H Reggio. Humana Press 2009. ISBN 978-1-58829-712-9
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Chapter 151
O-806 O-806 is a drug which is a cannabinoid derivative that is used in scientific research. It is described as a mixed agonist/antagonist at the cannabinoid receptor CB1 , meaning that it acts as an antagonist when co-istered alongside a more potent CB1 agonist, but exhibits weak partial agonist effects when istered by itself.[1][2]
151.1 References [1] Griffin, G.; Wray, E.; Rorrer, W.; Crocker, P.; Ryan, W.; Saha, B.; Razdan, R.; Martin, B.; Abood, M. (1999). “An investigation into the structural determinants of cannabinoid receptor ligand efficacy”. British Journal of Pharmacology 126 (7): 1575–1584. doi:10.1038/sj.bjp.0702469. PMC 1565939. PMID 10323589. [2] Griffin, G.; Wray, E.; Martin, B.; Abood, M. (1999). “Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum”. British Journal of Pharmacology 128 (3): 684–688. doi:10.1038/sj.bjp.0702806. PMC 1571656. PMID 10516649.
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Chapter 152
O-823 O-823 is a drug which is a cannabinoid derivative that is used in scientific research. It is described as a mixed agonist/antagonist at the cannabinoid receptor CB1 , meaning that it acts as an antagonist when co-istered alongside a more potent CB1 agonist, but exhibits weak partial agonist effects when istered by itself.[1][2][3]
152.1 References [1] Pertwee RG, Fernando SR, Griffin G, Ryan W, Razdan RK, Compton DR, Martin BR. Agonistantagonist characterization of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol in two isolated tissue preparations. European Journal of Pharmacology. 1996 Nov 14;315(2):195-201. PMID 8960884 [2] Griffin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ, Saha B, Razdan RK, Martin BR, Abood ME. An investigation into the structural determinants of cannabinoid receptor ligand efficacy. British Journal of Pharmacology. 1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469 PMID 10323589 [3] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology. 1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806 PMID 10516649
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Chapter 153
Org 27569 Org 27569 is a drug which acts as a potent and selective allosteric modulator of the cannabinoid CB1 receptor. Studies in vitro suggest that it binds to a regulatory site on the CB1 receptor target, causing a conformational change that increases the binding affinity of CB1 agonists such as 55,940, while decreasing the binding affinity of CB1 antagonists or inverse agonists such as rimonabant. However while Org 27569 increases the ability of CB1 agonists to bind to the receptor, it decreases their efficacy at stimulating second messenger signalling once bound, and so in practice behaves as an insurmountable antagonist of CB1 receptor function.[1]
153.1 References [1] Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, McLean A, McIntosh L, Goodwin G, Walker G, Westwood P, Marrs J, Thomson F, Cowley P, Christopoulos A, Pertwee RG, Ross RA (November 2005). “Allosteric modulation of the cannabinoid CB1 receptor”. Molecular Pharmacology 68 (5): 1484–95. doi:10.1124/mol.105.016162. PMID 16113085.
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Chapter 154
Org 28312 Org 28312 is a drug developed by Organon International which acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors. It was developed with the aim of finding a water soluble cannabinoid agonist suitable for intravenous use as an analgesic, but did not proceed to human trials, with the related compound Org 28611 chosen instead due to its better penetration into the brain.[1] The structure-activity relationships of these compounds have subsequently been investigated further leading to the development of a number of more potent analogues, derived by cyclisation around the indole or piperazine rings.[2][3]
154.1 See also • LBP-1 • Org 28611
154.2 References [1] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a. [2] Kiyoi T, York M, Francis S, Edwards D, Walker G, Houghton AK, Cottney JE, Baker J, Adam JM (August 2010). “Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (16): 4918–21. doi:10.1016/j.bmcl.2010.06.067. PMID 20634067. [3] Moir EM, Yoshiizumi K, Cairns J, Cowley P, Ferguson M, Jeremiah F, Kiyoi T, Morphy R, Tierney J, Wishart G, York M, Baker J, Cottney JE, Houghton AK, Mhail P, Osprey A, Walker G, Adam JM (December 2010). “Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists”. Bioorganic & Medicinal Chemistry Letters 20 (24): 7327–30. doi:10.1016/j.bmcl.2010.10.061. PMID 21074434.
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Chapter 155
Org 28611 Org 28611 (SCH-900,111) is a drug developed by Organon International which acts as a potent cannabinoid receptor full agonist at both the CB1 and CB2 receptors. It was developed with the aim of finding a water soluble cannabinoid agonist suitable for intravenous use as an analgesic,[1] and while it achieved this aim and has progressed as far as Phase II clinical trials in humans as both a sedative and an analgesic, results against the comparison drugs (midazolam and morphine respectively) were not particularly favourable in initial testing.[2][3]
155.1 See also • LBP-1 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • Org 28312
155.2 References [1] Adam, J. M., et al. (2010). “Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists”. MedChemComm 1: 54. doi:10.1039/c0md00022a. [2] Zuurman L, ier PC, de Kam M, Kleijn HJ, Cohen AF, van Gerven JM (August 2009). “Pharmacodynamic and pharmacokinetic effects of the intravenously istered CB1 receptor agonist Org 28611 in healthy male volunteers”. Journal of Psychopharmacology (Oxford, England) 23 (6): 633–44. doi:10.1177/0269881108091551. PMID 18635703. [3] A Comparison of Analgesic Efficacy Between a Single Dose of ORG 28611, Morphine, and Placebo After Dental Impaction Surgery
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Chapter 156
Otenabant Otenabant (-945,598) is a drug which acts as a potent and highly selective CB1 antagonist.[1] It was developed by Pfizer for the treatment of obesity,[2] but development for this application has been discontinued following the problems seen during clinical use of the similar drug rimonabant.[3]
156.1 See also • Cannabinoid receptor antagonist
156.2 References [1] Kim, M., et al. (2008), Design, chemical synthesis, and biological evaluation of novel triazolyl analogues of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist, Tetrahedron 64 (48): 10802–10809, doi:10.1016/j.tet.2008.09.057 [2] Woods SC. The endocannabinoid system: novel pathway for cardiometabolic Risk-factor reduction. Journal of the American Academy of Physician Assistants. 2007 Nov;Suppl Endocannabinoid:7-10. PMID 18047036 [3] http://www.pfizer.com
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Chapter 157
Parahexyl Parahexyl (Synhexyl, n-hexyl-Δ3 THC) is a synthetic homologue of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9 -THC, one of the active components of cannabis. [1][2] Parahexyl is similar in both structure and activity to THC, differing only in the position of one double bond, and the lengthening of the 3-pentyl chain by one CH2 group to n-hexyl. [3] Parahexyl produces classic cannabis agonist effects in animals. It has a somewhat higher oral bioavailability than THC itself but is otherwise very similar. [4] Presumably it acts as a CB1 agonist in the same way as THC but as there has been no research published using Parahexyl since the discovery of the CB1 receptor this has not been definitively confirmed.
157.2 See also • Tetrahydrocannabivarin • Tetrahydrocannabinol-C4
157.3 References
Parahexyl was made illegal under UN convention in 1982 on the basis of its structural similarity and similar effects profile to THC, despite never having had any recorded instances of abuse by humans or illicit sale. Parahexyl was placed into the most restrictive Schedule 1 as a compound with no medical use.
157.1 Isomerism
Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6Hbenzo[c]chromen-1-ol. See also: Tetrahydrocannabinol#Isomerism. 207
[1] Adams R, Harfenist M, Loewe S (1949). “New Analogs of Tetrahydrocannabinol. XIX”. J. Am. Chem. Soc. 71 (5): 1624–1628. doi:10.1021/ja01173a023. [2] Ask Dr. Shulgin Online March 7, 2001 [3] Ono M, Shimamine M, Takahashi K, Inoue T (1974). "[Studies on hallucinogens. VII Synthesis of parahexyl]". Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences (in Japanese) 49 (92): 46–50. PMID 4477495. [4] Fairchild MD, Jenden DJ, Mickey MR, Yale C (1980). “EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline”. Pharmacol. Biochem. Behav. 12 (1): 99–105. doi:10.1016/00913057(80)90422-0. PMID 6102770.
Chapter 158
UR-144 UR-144 (TM-018, KM-X1, MN-001, YX-17) is a drug invented by Abbott Laboratories,[1] that acts as a selective full agonist of the peripheral cannabinoid receptor CB2 , but with much lower affinity for the psychoactive CB1 receptor.
drug screens has been developed by Tulip Biolabs, Inc. An Homogeneous Immunoassay that runs on most Clinical Chemistry Analyzers and detects several UR and XLR synthetic cannabinoids has been developed and introduced by Immunalysis Inc. Pomona USA.
158.1 Pharmacology
158.4 See also • AB-001
UR-144 has high affinity for the CB2 receptor with a Kᵢ of 1.8 nM but 83x lower affinity for the CB1 receptor with a Kᵢ of 150 nM.[2] Although a later study found its CB1 affinity to be much higher than previously expected, with a Kᵢ of 28.9nM and an EC50 of 1295nM. Chemically it is closely related to other 2,2,3,3-tetramethylcyclopropyl synthetic cannabinoids like A-796,260 and A-834,735 but with a different substitution on the 1-position of the indole core, in these compounds its 1-pentyl group is replaced with alkylheterocycles like 1-(2-morpholinoethyl) and 1-(tetrahydropyran-4-ylmethyl).
• AM-1221 • 4-HTMPIPO • JTE 7-31 • JWH-018 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide • XLR-11
158.5 References
158.2 History of use UR-144 has been detected as an ingredient of synthetic cannabis smoking blends in New Zealand, and subsequently banned from sale as a temporary class drug on 6 April 2012.[3] It has also been encountered in smoking blends and subsequently banned in Russia.[4] The chemical UR-144 has also been banned in the UK in 2013 along with RCS-4 and AM-2201. This is due to two people in Glasgow being itted to hospital after taking a legal high with the chemicals in it. Another person was itted to Brighton hospital after overdosing on the drug.
158.3 Detection A forensic standard of UR-144 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[5] An ELISA immunoassay technique for detecting UR-144 in urine as part of general 208
[1] WO application 2006069196, Pace JM, Tietje K, Dart MJ, Meyer MD, “3-Cycloalkylcarbonyl indoles as cannabinoid receptor ligands”, published 2006-06-29, assigned to Abbott Laboratories [2] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (January 2010). “Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity”. J. Med. Chem. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781. [3] Temporary Class Drug Notices. New Zealand Ministry of Health [4] Sobolevsky T, Prasolov I, Rodchenkov G (October 2012). “Detection of urinary metabolites of AM-2201 and UR144, two novel synthetic cannabinoids”. Drug Test Anal. doi:10.1002/dta.1418. PMID 23042760. [5] Southern Association of Forensic Scientists http://forendex.southernforensic.org/index.php/detail/ index/1218
158.6. FURTHER READING
158.6 Further reading • Poso A, Huffman JW (January 2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. Br. J. Pharmacol. 153 (2): 335–46. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473. • Chin CL, Tovcimak AE, Hradil VP, Seifert TR, Hollingsworth PR, Chandran P, Zhu CZ, Gauvin D, Pai M, Wetter J, Hsieh GC, Honore P, Frost JM, Dart MJ, Meyer MD, Yao BB, Cox BF, Fox GB (January 2008). “Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI”. Br. J. Pharmacol. 153 (2): 367–79. doi:10.1038/sj.bjp.0707506. PMC 2219521. PMID 17965748. • Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Miller LN, Li L, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (March 2008). “Indol3-yl-tetramethylcyclopropyl ketones: effects of indole ring substitution on CB2 cannabinoid receptor activity”. J. Med. Chem. 51 (6): 1904–12. doi:10.1021/jm7011613. PMID 18311894.
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Chapter 159
Perrottetinene Perrottetinene is a naturally occurring cannabinoid compound found in the New Zealand liverwort plant Radula marginata and other species from the Radula genus,[1] along with a number of similar compounds. Its chemical structure closely resembles that of THC, the main active component of marijuana, and it is thought that perrottetinene may also be an active cannabinoid agonist although detailed pharmacological investigation of the compound has yet to be reported.[2][3] Stereoselective synthesis of perrottinene has also been carried out to investigate the activity of its different enantiomers.[4]
159.1 References [1] Cullmann F, Becker H. Prenylated bibenzyls from the liverwort Radula laxiramea. Zeitschrift Fur Naturforschung. 1999; 54(3-4): 147-150. ISSN 09395075 [2] Toyota M, Kinugawa T, Asakawa Y. Bibenzyl Cannabinoid and Bisbibenzyl Derivative from the Liverwort Radula perrottetii. Phytochemistry 1994; 37(3):859-862. [3] Toyota M, Shimamura T, Ishii H, Renner M, Braggins J, Asakawa Y. New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata. Chemical and Pharmaceutical Bulletin (Tokyo). 2002 Oct;50(10):1390-2. PMID 12372871 [4] Song Y, Hwang S, Gong P, Kim D, Kim S. Stereoselective total synthesis of (-)-perrottetinene and assignment of its absolute configuration. Organic Letters. 2008 Jan 17;10(2):269-71. PMID 18085788
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Chapter 160
PF-03550096 PF-03550096 is a drug that acts as a potent agonist for the CB2 cannabinoid receptor, with good selectivity over CB1 having Kᵢ values of 7nM at CB2 and 1500nM at CB1 . It was originally developed by Pfizer in 2008 as a medication for irritable bowel syndrome,[1] but has only progressed to animal studies.[2]
160.1 See also • AB-FUBINACA • AB-PINACA
160.2 References [1] Ando K et al, BENZIMIDAZOLONE DERIVATIVES. WO 2008/032164 [2] Kikuchi, A.; Ohashi, K.; Sugie, Y.; Sugimoto, H.; Omura, H. (2008). “Pharmacological evaluation of a novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro and in vivo by using a rat model of visceral hypersensitivity”. Journal of pharmacological sciences 106 (2): 219– 224. doi:10.1254/jphs.FP0071599. PMID 18270474.
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Chapter 161
PF-514273 PF-514273 is a drug developed by Pfizer, which acts as an extremely selective antagonist for the CB1 receptor, with approximately 10,000x selectivity over the closely related CB2 receptor. This very high selectivity makes it useful for scientific research into these receptors, as many commonly used cannabinoid receptor antagonists also block the CB2 receptor to some extent.[1]
161.1 References [1] Dow RL, Carpino PA, Hadcock JR, Black SC, Iredale PA, DaSilva-Jardine P, Schneider SR, Paight ES, Griffith DA, Scott DO, O'Connor RE, Nduaka CI. Discovery of 2-(2-chlorophenyl)−3-(4-chlorophenyl)−7(2,2-difluoropropyl)−6,7-dihydro-2H-pyrazolo[3,4f][1,4]oxazepin-8(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity. Journal of Medicinal Chemistry. 2009 May 14;52(9):2652-5. PMID 19351113
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Chapter 162
PipISB PipISB is a drug used in scientific research which acts as a potent and selective inverse agonist of the cannabinoid receptor CB1 . It is highly selective for the CB1 receptor over CB2 , with a K at CB1 of 1.5nM vs over 7000nM at CB2 , has good blood-brain barrier penetration, and can be conveniently radiolabelled with either 11 C or 18 F, making it useful for mapping the distribution of CB1 receptors in the brain.[1][2]
162.1 References [1] Donohue, Sean R.; Halldin, Christer; Schou, Magnus; Hong, Jinsoo; Phebus, Lee; Chernet, Eyassu; Hitchcock, Stephen A.; Gardinier, Kevin M.; Ruley, Kevin M.; Krushinski, Joseph H.; Schaus, John; Pike, Victor W. (2008). “Radiolabeling of a high potency cannabinoid subtype-1 receptor inverse agonist, N-(4-fluoro-benzyl)−4-(3-(piperidin-1-yl-indole-1sulfonyl)benzamide (PipISB), with carbon-11 or fluorine18”. Journal of Labelled Compounds and Radiopharmaceuticals 51 (3): 146. doi:10.1002/jlcr.1491. [2] Finnema, S. J.; Donohue, S. R.; Zoghbi, S. S.; Brown, A. K.; Gulyás, B. Z.; Innis, R. B.; Halldin, C.; Pike, V. W. (2009). “Evaluation of \11C]PipISB and \18F]PipISB in monkey as candidate radioligands for imaging brain cannabinoid type-1 receptors in vivo”. Synapse 63 (1): 22–30. doi:10.1002/syn.20578. PMC 2587077. PMID 18925657.
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Chapter 163
Pirnabine Pirnabine (SP-304) is a synthetic cannabinoid receptor ligand, which was developed for the treatment of glaucoma.[1]
163.1 References [1]
214
Chapter 164
PSB-SB-1202 PSB-SB-1202 is a coumarin derivative which is an agonist at the cannabinoid receptors CB1 and CB2 , with a CB1 Ki of 32nM and a CB2 Ki of 49nM.[1] It is also a weak antagonist at the related receptor GPR55, with an IC50 of 6350nM, but has no significant affinity for GPR18.[2]
164.1 See also • PSB-SB-487
164.2 References [1] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I, Nieger M, Wenzel W, Bräse S, Müller CE. 7-Alkyl-3benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists. Journal of Medicinal Chemistry. 2012 Sep 27;55(18):7967-77. PMID 22916707 [2] Rempel, V.; Volz, N.; Gläser, F.; Nieger, M.; Bräse, S.; Müller, C. E. (2013). “Antagonists for the orphan G protein-coupled receptor GPR55 based on a coumarin scaffold”. Journal of Medicinal Chemistry 56 (11): 130516144836005. doi:10.1021/jm4005175. PMID 23679955.
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Chapter 165
PSB-SB-487 PSB-SB-487 is a coumarin derivative which is an antagonist at the former orphan receptor GPR55. Unlike older GPR55 antagonists such as O-1918, PSB-SB-487 has good selectivity over the related receptor GPR18, with an IC50 of 113nM at GPR55 vs 12500nM at GPR18.[1] However it has poorer selectivity over other related receptors, acting as a weak antagonist at CB1 with a Ki of 1170nM, and a partial agonist at CB2 with a Ki of 292nM.[2]
165.1 See also • PSB-SB-1202
165.2 References [1] Rempel, V.; Volz, N.; Gläser, F.; Nieger, M.; Bräse, S.; Müller, C. E. (2013). “Antagonists for the orphan G protein-coupled receptor GPR55 based on a coumarin scaffold”. Journal of Medicinal Chemistry 56 (11): 130516144836005. doi:10.1021/jm4005175. PMID 23679955. [2] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I, Nieger M, Wenzel W, Bräse S, Müller CE. 7-Alkyl-3benzylcoumarins: a versatile scaffold for the development of potent and selective cannabinoid receptor agonists and antagonists. Journal of Medicinal Chemistry. 2012 Sep 27;55(18):7967-77. PMID 22916707
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Chapter 166
QUCHIC QUCHIC (BB-22 or 1-(cyclohexylmethyl)−1Hindole-3-carboxylic acid 8-quinolinyl ester) is a designer drug offered by online vendors as a cannabimimetic agent, and was first detected being sold in synthetic cannabis products in Japan in early 2013,[1] and subsequently also in New Zealand.[2] The structure of QUCHIC appears to utilise an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. QUCHIC, along with QUPIC, represents a structurally unique synthetic cannabinoid chemotype since it contains an ester linker at the indole 3-position rather than the precedented ketone of JWH-018 and its analogues, or the amide of SDB-001 and its analogues. No information regarding the in vitro or in vivo activity of QUCHIC has been published, and only anecdotal reports are known of its pharmacology in humans or other animals.
166.1 See also • 5F-PB-22 • JWH-018 • PB-22 • QUPIC • SDB-001
166.2 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Dunne bans further two substances found in K2. Press Release: New Zealand Government. Tuesday, 30 April 2013
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Chapter 167
QUPIC QUPIC (PB-22 or 1-pentyl-1H-indole-3-carboxylic acid 8-quinolinyl ester) is a designer drug offered by online vendors as a cannabimimetic agent, and detected being sold in synthetic cannabis products in Japan in 2013.[1] The structure of QUPIC appears to use an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. QUPIC represents a structurally unique synthetic cannabinoid chemotype, since it contains an ester linker at the indole 3-position, rather than the precedented ketone of JWH-018 and its analogs, or the amide of SDB-001 and its analogs. No information regarding the in vitro activity of QUPIC has been published, however one in vivo study found PB-22 to cause seizures in humans and dogs.[2] QUPIC is an analog of JWH-018 which differs by having 8-hydroxyquinoline replacing the naphthalene group of JWH-018. QUPIC is now found in many herbal incense and potpourri products.
• SDB-001
167.4 References [1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; KikuraHanajiri, R.; Goda, Y. (2013). “Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products”. Forensic Toxicology. doi:10.1007/s11419013-0182-9. [2] Gugelmann, H; Gerona, R; Li, C; Tsutaoka, B; Olson, KR; Lung, D (2014). "'Crazy Monkey' Poisons Man and Dog: Human and canine seizures due to PB-22, a novel synthetic cannabinoid.”. Clinical Toxicology 52 (6): 635–8. doi:10.3109/15563650.2014.925562. PMID 24905571. [3] Forendex entry, Southern Association of Forensic Scientists
167.1 Detection A forensic standard of PB-22 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[3]
[4] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G; Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C (2014). “Four Postmortem Case Reports with Quantitative Detection of the Synthetic Cannabinoid, 5F-PB-22”. Journal of analytical toxicology. doi:10.1093/jat/bku048. PMID 24876364.
167.2 Legal status
[5] “PB-22 and 5F-PB-22”. Drug Enforcement istration, Office of Diversion Control.
As of 9 May 2014, PB-22 is no longer legal in New Zealand.
[6] Jeremy Pelzer (April 17, 2014). “Ohio bans two synthetic marijuana drugs sold as “herbal incense"". cleveland.com.
In January 2014, QUPIC was designated as a Schedule I controlled substance in the United States.[4][5]
[7] “Statutes & Constitution :View Statutes : Online Sunshine”. Leg.state.fl.us. 1997-05-06. Retrieved 2014-0712.
In Ohio, QUPIC is illegal.[6] Florida also has banned QUPIC/P-22.[7]
167.3 See also • 5F-PB-22 • QUCHIC 218
Chapter 168
Rimonabant Rimonabant (also known as SR141716; trade name Acomplia) is an anorectic antiobesity drug that has been withdrawn from the market due to potentially serious side effects. It was approved for use in Europe and other countries, but never approved in the United States. Rimonabant is an inverse agonist for the cannabinoid receptor CB1.[3] Its main effect is reduction in appetite.
168.1 History
the anti-obesity treatment for approval.[2] Subsequently, Sanofi-Aventis announced it was suspending the new drug application (NDA) for rimonabant, and that it would resubmit an application at some point in the future. The EU’s approval was not a blanket approval, nor did it approve Acomplia for nonobesity-related problems, such as smoking cessation, although off-label use of the drug was still possible. The approval was, in combination with diet and exercise, for the treatment of obese patients (BMI greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.
See also: Discovery and development of Cannabinoid In October 2008, the European Medicines Agency's Receptor 1 Antagonists Committee for Medicinal Products for Human Use (CHMP) had determined that the risks of Acomplia outRimonabant was the first selective CB1 receptor blocker weighed its benefits. The Agency subsequently recomto be approved for use anywhere in the world. In Europe, mended that the product be suspended from the UK marit was indicated for use in conjunction with diet and ex- ket, and that doctors not prescribe the drug due to the risk ercise for patients with a body mass index (BMI) greater of serious psychiatric problems, and even suicide. Sanofithan 30 kg/m², or patients with a BMI greater than 27 Aventis then suspended sale of the drug.[1][6][7] Approval kg/m² with associated risk factors, such as type 2 diabetes of the drug was officially withdrawn by the European or dyslipidaemia. In the UK, it was available beginning Medicines Agency on 16 January 2009.[8] in July 2006. As of 2008, the drug was available in 56 India has prohibited the manufacture and sale of the countries. drug.[9] On 21 June 2006, the European Commission approved the sale of rimonabant in the then-25-member European Union. Pharmaceutical company Sanofi-Aventis, (which changed its name to Sanofi in 2011) announced the first country in which Acomplia would be sold was the United Kingdom as a prescription drug. Sales began in July 2006. Sanofi-Aventis also projected that the drug would 168.2 Uses/potential uses be sold shortly thereafter in Denmark, Ireland, , Finland, and Norway. It was expected in Belgium[4] and Sweden in 2007. Ordinary obesity would, according to 168.2.1 Obesity official medical recommendations, not be enough to acquire the prescription in Sweden; there would be ad- In a 2006 (2 year) study reported in JAMA, “Compared ditional requirements concerning abnormal blood lipid with the placebo group, the 20 mg of rimonabant group levels.[5] produced greater mean (SEM) reductions in weight (−6.3 Rimonabant was submitted to the Food and Drug istration (FDA) for approval in the United States. However, in 2007, the FDA’s Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending
[0.2] kg vs −1.6 [0.2] kg; P<.001), waist circumference (−6.1 [0.2] cm vs −2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, −5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001).” [10]
219
220
168.2.2
CHAPTER 168. RIMONABANT
Smoking cessation
Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapy. The Studies with Rimonabant and Tobacco Use (STRATUS) program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy. According to a Cochrane Collaboration review in 2007, rimonabant “may increase the odds of quitting approximately 11/2-fold”.[11]
168.4 Negative side effects Shortly after market introduction, press reports and independent studies suggested that side effects occurred more intensely and more commonly than had been found by the manufacturer in their clinical studies. Reports of severe depression and suicidal thoughts were frequent.[18] As the drug’s target CB1 receptors are fairly ubiquitous throughout the central nervous system, it is not currently understood where the inverse agonist is acting to cause these side-effects. In 2007, it was reported that the committee advising the U.S. FDA had voted not to recommend the drug’s approval because of concerns over suicidality, depression, and other related side effects associated with use of the drug.[19]
168.5 Preparation 168.2.3
Addiction behaviors
Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans: priming and cues. It may also reduce ethanol- and opiate-seeking behavior.[12]
168.2.4
The chemical synthesis of rimonabant is described as follows:[20]
Short-term memory
Tetrahydrocannabinol (THC) is known to impair shortterm memory. It was therefore hypothesised that rimonabant may reduce or inhibit the atrophic effects of cannabinoids. Indeed, in animal studies, it significantly improved the ability of rats to encode information into short-term memory.[13]
168.2.5
Blockage of cannabis effects
Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9 -tetrahydrocannabinol (THC) in humans without affecting the pharmacokinetics.[14] Rimonabant has been described colloquially as “reverse marijuana”, having a depressing effect on appetite inverse to the increased appetite created by cannabinoids.[15]
168.3 Other effects Rimonabant reduces voluntary wheel running in laboratory mice.[16] Rimonabant significantly increased human sperm motility and viability in vitro.[17]
168.6 Brand names Brand names for rimonabant include Acomplia, Bethin, Monaslim, Remonabent, Riobant, Slimona, and Rimoslim. The proposed brand name if it had been approved for use in the United States was Zimulti.
168.7 References [1] “Anti-obesity drug use suspended”. BBC News. 23 October 2008. Retrieved 4 March 2010.
168.7. REFERENCES
[2] “Zimulti Acomplia Report - Diet Drug Acomplia / Zimulti Gets Thumbs Down From FDA ”. Acompliareport.com. 2007-06-13. Retrieved 2010-03-19. [3] Fong TM, Heymsfield SB (September 2009). “Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions”. Int J Obes (Lond) 33 (9): 947–55. doi:10.1038/ijo.2009.132. PMID 19597516.
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[16] Keeney BK, et al. (2008). “Differential response to a selective cannabinoid receptor antagonist (SR141716: rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behavior”. Behavioural Pharmacology 19 (8): 812– 820. doi:10.1097/FBP.0b013e32831c3b6b. PMID 19020416.
[4] Auteur: Femke Gebruers. “Article from the Belgian newspaper De Standaard”. Standaard.be. Retrieved 2010-03-19.
[17] Aguila S, et al. (2010). “Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm”. Br J Pharmacol 159 (4): 831–41. doi:10.1111/j.1476-5381.2009.00570.x. PMC 2829209. PMID 20067470.
[5] “Article from the Swedish TV station TV 4 website”. Tv4.se. 2008-03-06. Retrieved 2010-03-19.
[18] “Kassen müssen nicht für “Acomplia” zahlen”. tagesschau.de. 2006-10-17. Retrieved 2007-06-13.
[6] “European Medicines Agency”. Ema.europa.eu/ema/. 2010-02-15. Retrieved 2010-03-19.
[19] “Suicide risk fears over diet pill”. BBC News. 15 June 2007. Retrieved 4 March 2010.
[7] “Sanofi-aventis - A diversified healthcare company, focused on patients’ needs”. En.sanofi-aventis.com. Retrieved 2010-03-19.
[20] Yoshioka, T., et al. (1989). “Studies on hindered phenols and analogs. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation”. Journal of Medicinal Chemistry 32 (2): 421. doi:10.1021/jm00122a022. PMID 2913302.
[8] “Microsoft Word - Zimulti _Rimonabant_ Public Statement” (PDF). Retrieved 2010-03-19. [9] “Drugs banned in India”. Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Retrieved 2013-09-17. [10] JAMA. 2006 Feb 15;295(7):761-75. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J; RIO-North America Study Group. PMID 16478899 [11] Cahill K, Ussher M (2007). Cahill, Kate, ed. “Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation”. Cochrane database of systematic reviews (Online) (4): CD005353. doi:10.1002/14651858.CD005353.pub3. PMID 17943852. [12] Maldonado R, Valverde O, Berrendero F (2006). “Involvement of the endocannabinoid system in drug addiction”. Trends Neurosci. 29 (4): 225–32. doi:10.1016/j.tins.2006.01.008. PMID 16483675. [13] Deadwyler SA, Goonawardena AV, Hampson RE (2007). “Short-term memory is modulated by the spontaneous release of endocannabinoids: evidence from hippocampal population codes”. Behavioural Pharmacology 18 (5–6): 571–80. doi:10.1097/FBP.0b013e3282ee2adb. PMID 17762525. [14] Huestis MA, et al. (2001). “Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716”. Arch. Gen. Psychiatry 58 (4): 322–8. doi:10.1001/archpsyc.58.4.322. PMID 11296091. [15] Stephan Guyenet, PhD (9 March 2012) Seduced by Food: Obesity and the Human Brain Boing Boing
Chapter 169
Rosonabant Rosonabant (INN; E-6776) is a drug acting as a CB1 receptor antagonist/inverse agonist that was under investigation by Esteve as an appetite suppressant for the treatment of obesity.[1][2] Development of the drug for clinical use was apparently halted shortly after the related CB1 antagonist rimonabant was discontinued, likely due to the reports of severe psychiatric adverse effects such as anxiety, depression, and suicidal ideation associated with it and with similarly-acting agents.[3][4]
169.1 See also • Cannabinoid receptor antagonist
169.2 References [1] Janero DR, Makriyannis A (March 2009). “Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis”. Expert Opinion on Emerging Drugs 14 (1): 43–65. doi:10.1517/14728210902736568. PMID 19249987. [2] Tim C. Kirkham; S. J. Cooper (2007). Appetite and Body Weight: Integrative Systems and the Development of AntiObesity Drugs. Academic Press. p. 325. ISBN 978-0-12370633-1. Retrieved 12 May 2012. [3] Heal DJ, Gosden J, Smith SL (December 2009). “Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders”. British Journal of Clinical Pharmacology 68 (6): 861–74. doi:10.1111/j.13652125.2009.03549.x. PMC 2810797. PMID 20002080. [4] Lee HK, Choi EB, Pak CS (2009). “The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents”. Current Topics in Medicinal Chemistry 9 (6): 482–503. doi:10.2174/156802609788897844. PMID 19689362.
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Chapter 170
S-444,823 S-444,823 is a drug developed by Shionogi which is a cannabinoid agonist.[1] It was developed as an antipruritic, and has moderate selectivity for the CB2 subtype, having a CB2 affinity of 18nM, and 32x selectivity over the CB1 receptor. In animal studies it showed analgesic effects and strongly reduced itching responses, but without producing side effects such as sedation and catalepsy that are seen with centrally acting CB1 agonists.[2]
170.1 See also • JTE 7-31
170.2 References [1] Arimura A. Novel Use of Cannabinoid Receptor Agonist. Patent WO 2005/016351 [2] Odan M, et al. Discovery of S-444823, a potent CB1/CB2 dual agonist as an antipruritic agent. Bioorganic and Medicinal Chemistry Letters. 2012 Apr 15;22(8):2898901. PMID 22421019
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Chapter 171
SDB-001 This article is about the cannabinoid drug. For the South Korean girl band, see 2NE1. For the metabotropic glutamate receptor antagonist, see APICA (drug). SDB-001 (2NE1, APICA, N-(1-adamantyl)−1pentyl-1H-indole-3-carboxamide) is a drug that acts as a potent agonist for the cannabinoid receptors. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in Japan in March 2012 as an ingredient in synthetic cannabis smoking blends, along with a related compound APINACA (sold as “AKB48”).[1] Structurally it closely resembles cannabinoid compounds from patent WO 2003/035005 but with an indole core instead of indazole, and a simple pentyl chain on the indole 1-position. Pharmacological testing determined SDB-001 to have an IC50 of 175nM at CB1 , only slightly less potent than JWH-018 which had an IC50 of 169nM, but over four times more tightly binding than AKB48, which had an IC50 of 824nM.[2] The first published synthesis and pharmacological evaluation of SDB-001 revealed that it acts as a full agonist at CB1 (EC50 = 34 nM) and CB2 receptors (EC50 = 29 nM).[3] Furthermore, SDB-001 possesses cannabis-like effects in rats, and appears to be less potent than JWH-018 but more potent than THC.[3]
171.1 See also • AB-001 • QUCHIC • JWH-018 • SDB-006 • STS-135 (drug)
171.2 References [1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “Identification of two newtype synthetic cannabinoids, N-(1-adamantyl)−1pentyl-1H-indole-3-carboxamide (APICA) and N-(1-
224
adamantyl)−1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products”. Forensic Toxicology 30 (2): 114. doi:10.1007/s11419-012-01367. [2] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.; Goda, Y. (2012). “URB-754: A new class of designer drug and 12 synthetic cannabinoids detected in illegal products”. Forensic Science International 227 (1– 3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID 23063179. [3] Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. (2013). “The synthesis and pharmacological evaluation of adamantanederived indoles: Novel cannabimimetic drugs of abuse”. ACS Chemical Neuroscience 4 (7): 130403084729007. doi:10.1021/cn400035r.
Chapter 172
SDB-006 SDB-006 is a drug that acts as a potent agonist for the cannabinoid receptors, with an EC50 for CB1 activation of 19nM, and 7x selectivity for CB1 over CB2 . It was discovered during research into the related compound SDB001 which had been sold illicitly as “2NE1”.[1]
172.1 See also • APINACA • SDB-001 • STS-135_(drug)
172.2 References [1] Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. (2013). “The synthesis and pharmacological evaluation of adamantanederived indoles: Novel cannabimimetic drugs of abuse”. ACS Chemical Neuroscience 4 (7): 130403084729007. doi:10.1021/cn400035r.
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Chapter 173
SER-601 SER-601 (COR-167) is a drug which acts as a potent and selective cannabinoid CB2 receptor agonist, based on a quinolone−3-carboxylic acid core structure, with 190x selectivity for CB2 over the related CB1 receptor. It has analgesic effects in animal studies, as well as neuroprotective effects,[1] but without cannabis-like behavioural effects due to its low affinity for CB1 .[2] A number of related compounds are known, almost all of which have high selectivity for CB2 .[3]
173.1 See also • A-836,339 • CBS-0550
173.2 References [1] Contartese, A.; Valoti, M.; Corelli, F.; Pasquini, S.; Mugnaini, C.; Pessina, F.; Aldinucci, C.; Sgaragli, G.; Frosini, M. (2012). “A novel CB2 agonist, COR167, potently protects rat brain cortical slices against OGD and reperfusion injury”. Pharmacological Research 66 (6): 555–563. doi:10.1016/j.phrs.2012.08.003. PMID 23036353. [2] Pasquini S,et al. (August 2008). “Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo”. Journal of Medicinal Chemistry 51 (16): 5075–84. doi:10.1021/jm800552f. PMID 18680276. [3] Pasquini S,et al. (August 2010). “Investigations on the 4-quinolone-3-carboxylic acid motif. 3. Synthesis, structure-affinity relationships, and pharmacological characterization of 6-substituted 4-quinolone-3carboxamides as highly selective cannabinoid-2 receptor ligands”. Journal of Medicinal Chemistry 53 (16): 5915– 28. doi:10.1021/jm100123x. PMID 20718492.
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Chapter 174
Serinolamide A Serinolamide A is a naturally occurring eicosanoid derivative related to anandamide, which has been isolated from the marine cyanobacteria Lyngbya majuscula and related species in the Oscillatoria family. Testing established that serinolamide A is an active cannabinoid agonist with moderate potency, having a Ki of 1300nM at CB1 and 5x selectivity over the related CB2 receptor.[1]
174.1 See also • Methanandamide • O-1812 • Perrottetinene
174.2 References [1] Gutiérrez, M.; Pereira, A. R.; Debonsi, H. M.; Ligresti, A.; Di Marzo, V.; Gerwick, W. H. (2011). “Cannabinomimetic Lipid from a Marine Cyanobacterium”. Journal of Natural Products 74 (10): 2313– 2317. doi:10.1021/np200610t. PMC 3325759. PMID 21999614.
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Chapter 175
SR-144,528 SR144528 is a drug that acts as a potent and highly selective CB2 receptor inverse agonist, with a Kᵢ of 0.6nM at CB2 and 400nM at the related CB1 receptor.[1][2] It is used in scientific research for investigating the function of the CB2 receptor,[3][4][5] as well as for studying the effects of CB1 receptors in isolation, as few CB1 agonists that do not also show significant activity as CB2 agonists are available.[6][7][8] It has also been found to be an inhibitor of acyl-coenzymeA:cholesterol acyltransferase, an effect that appears to be independent from its action on CB2 receptors.[9]
175.1 See also
747–57. doi:10.1016/S0306-4522(03)00126-X. PMID 12809695. [5] Páldy E, et al. (December 2008). “CB(2) cannabinoid receptor antagonist SR144528 decreases mu-opioid receptor expression and activation in mouse brainstem: role of CB(2) receptor in pain”. Neurochemistry International 53 (6-8): 309–16. doi:10.1016/j.neuint.2008.08.005. PMID 18804501. [6] Lay L, Angus JA, Wright CE (March 2000). “Pharmacological characterisation of cannabinoid CB(1) receptors in the rat and mouse”. European Journal of Pharmacology 391 (1-2): 151–61. doi:10.1016/S0014-2999(00)000625. PMID 10720647. [7] Germanò MP, et al. (February 2001). “Cannabinoid CB1-mediated inhibition of stress-induced gastric ulcers in rats”. Naunyn-Schmiedeberg’s Archives of Pharmacology 363 (2): 241–4. doi:10.1007/s002100000360. PMID 11218077.
• NESS-040C5 • SR141716 • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
[8] Abalo R, et al. (June 2010). “The cannabinoid antagonist SR144528 enhances the acute effect of WIN 55,212-2 on gastrointestinal motility in the rat”. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society 22 (6): 694– e206. doi:10.1111/j.1365-2982.2009.01466.x. PMID 20132133.
175.2 References [1] Rinaldi-Carmona M, et al. (February 1998). “SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor”. The Journal of Pharmacology and Experimental Therapeutics 284 (2): 644–50. PMID 9454810. [2] Portier M, et al. (February 1999). “SR 144528, an antagonist for the peripheral cannabinoid receptor that behaves as an inverse agonist”. The Journal of Pharmacology and Experimental Therapeutics 288 (2): 582–9. PMID 9918562. [3] Gouldson P, et al. (July 2000). “Mutational analysis and molecular modelling of the antagonist SR 144528 binding site on the human cannabinoid CB(2) receptor”. European Journal of Pharmacology 401 (1): 17–25. doi:10.1016/S0014-2999(00)00439-8. PMID 10915832. [4] Nackley AG, Makriyannis A, Hohmann AG (2003). “Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation”. Neuroscience 119 (3):
228
[9] Thewke D, et al. (April 2009). “AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors”. Biochemical and Biophysical Research Communications 381 (2): 181–6. doi:10.1016/j.bbrc.2009.02.020. PMC 2665256. PMID 19338772.
Chapter 176
Stearoylethanolamide Stearoylethanolamide (SEA) is an endocannabinoid neurotransmitter.
176.1 References Binding, degradation and apoptotic activity stearoylethanolamide in rat C6 glioma cells
of
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Chapter 177
STS-135 (drug) STS-135 (N-(adamantan-1-yl)−1-(5fluoropentyl)−1H-indole-3-carboxamide) is a designer drug offered by online vendors as a cannabimimetic agent. The structure of STS-135 appears to utilise an understanding of structure-activity relationships within the indole class of cannabimimetics, although its design origins are unclear. STS-135 is the terminally-fluorinated analogue of SDB-001, just as AM-2201 is the terminally-fluorinated analogue of JWH-018, and XLR-11 is the terminally-fluorinated analogue of UR-144. No information regarding the in vitro or in vivo activity of STS-135 has been published, and only anecdotal reports are known of its pharmacology in humans or other animals.
177.1 Detection A forensic standard of STS-135 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[1]
177.2 See also • AB-001 • APINACA • AM-2201 • JWH-018 • SDB-001
177.3 References [1] Southern Association of Forensic Scientists
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Chapter 178
Surinabant Surinabant (SR147778) is a cannabinoid receptor type 1 antagonist developed by Sanofi-Aventis.[1] It is being investigated as a potential treatment for nicotine addiction, to assist smoking cessation. It may also be developed as an anorectic drug to assist with weight loss, however there are already several CB1 antagonists or inverse agonists on the market or under development for this application,[2] so surinabant is at present mainly being developed as an anti-smoking drug,[3] with possible application in the treatment of other addictive disorders such as alcoholism.[4][5] Other potential applications such as treatment of ADHD have also been proposed.[6]
178.1 See also • Cannabinoid receptor antagonist • O-1269
178.2 References [1] Rinaldi-Carmona M, Barth F, Congy C, Martinez S, Oustric D, Pério A, Poncelet M, Maruani J, Arnone M, Finance O, Soubrié P, Le Fur G. SR147778 [5-(4-bromophenyl)−1-(2,4-dichlorophenyl)−4-ethylN-(1-piperidinyl)−1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization. Journal of Pharmacology and Experimental Therapeutics. 2004 Sep;310(3):905-14. PMID 15131245 [2] Doggrell SA. Will the new CB1 cannabinoid receptor antagonist SR-147778 have advantages over rimonabant? Expert Opinion on Investigational Drugs. 2005 Mar;14(3):339-42. PMID 15833065 [3] Lamota L, Bermudez-Silva FJ, Marco EM, Llorente R, Gallego A, Rodríguez de Fonseca F, Viveros MP. Effects of adolescent nicotine and SR 147778 (Surinabant) istration on food intake, somatic growth and metabolic parameters in rats. Neuropharmacology. 2008 Jan;54(1):194-205. PMID 17720206 [4] Gessa GL, Serra S, Vacca G, Carai MA, Colombo G. Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational prop-
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erties of alcohol in alcohol-preferring sP rats. Alcohol and Alcoholism. 2005 Jan-Feb;40(1):46-53. PMID 15582988 [5] Lallemand F, De Witte P. SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats. Alcohol. 2006 Jul;39(3):125-34. PMID 17127132 [6] Louis C, Terranova JP, Decobert M, Bizot JC, Francon D, Alonso R, Cohen C, Griebel G. Surinabant, a new CB1 receptor antagonist, displays efficacy in animal models of attention deficit/hyperactivity disorder. Behavioural Pharmacology 2005; 16:S42.
Chapter 179
Taranabant Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 inverse agonist being investigated as a potential treatment for obesity due to its anorectic effects.[1][2] It was discovered by Merck & Co. In October 2008, Merck has stopped its phase III clinical trials with the drugs due to high level of central side effects, mainly depression and anxiety.[3][4][5][6]
179.1 See also • Cannabinoid receptor antagonist
179.2 References [1] Armstrong HE, Galka A, Lin LS, Lanza TJ Jr, Jewell JP, Shah SK, et al. “Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists.” Bioorganic & Medicinal Chemistry Letters. 2007 Apr 15;17(8):21847. PMID 17293109. doi:10.1016/j.bmcl.2007.01.087 [2] Fong TM, Guan XM, Marsh DJ, Shen , Stribling DS, Rosko KM, et al. “Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)−3-(4-chlorophenyl)−2-(3-cyanophenyl)−1methylpropyl]−2-methyl-2-[[5-(trifluoromethyl)pyridin2-yl]oxy]propanamide (MK-0364), in rodents.” Journal of Pharmacology and Experimental Therapeutics. 2007 Jun;321(3):1013-22. PMID 17327489. doi:10.1124/jpet.106.118737 [3] “Press release by Merck”. Retrieved October 2008. [4] Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N, Suryawanshi S, Molony C, Sieberts S, Nayee J, Meehan AG, Shapiro D, Heymsfield SB, Kaufman KD, Amatruda JM (May 2010). “A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study”. International Journal of Obesity (2005) 34 (5): 919–35. doi:10.1038/ijo.2010.21. PMID 20157323. [5] Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T, Erondu N, Shentu Y, Lu K, Suryawanshi S, Chou M, Johnson-Levonas AO, Heymsfield SB, Shapiro D, Kaufman KD, Amatruda JM (June 2010). “A one-year study
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to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes”. Diabetes, Obesity & Metabolism 12 (6): 517–31. doi:10.1111/j.1463-1326.2009.01188.x. PMID 20518807. [6] Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q, Suryawanshi S, Jones ME, Johnson-Levonas AO, Heymsfield SB, Kaufman KD, Amatruda JM (August 2010). “A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study”. International Journal of Obesity (2005) 34 (8): 1243–54. doi:10.1038/ijo.2010.38. PMID 20212496.
Chapter 180
Tedalinab Tedalinab (GRC-10693) is a drug developed by Glenmark Pharmaceuticals for the treatment of osteoarthritis and neuropathic pain, which acts as a potent and selective cannabinoid CB2 receptor agonist. It has a very high selectivity of 4700x for CB2 over the related CB1 receptor, has good oral bioavailability and has shown promising safety results and effective analgesic and antiinflammatory actions in early clinical trials.[1] A large number of related compounds are known, most of which also show high CB2 selectivity.[2]
180.1 See also • CBS-0550 • SER-601
180.2 References [1] Glenmark’s Molecule for Neuropathic Pain, Osteoarthritis - GRC 10693, Successfully Completes Phase I Trials. April 13, 2009. [2] Glenmark Pharmaceuticals. NOVEL CANNABINOID RECEPTOR LIGANDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS FOR THEIR PREPARATION, Filed June 1st, 2006. WO 2006/129178.
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Chapter 181
Tetrad test The tetrad test is a series of behavioral paradigms in which rodents treated with cannabinoids such as THC show effects.[1] It is widely used for screening drugs that induce cannabinoid receptor-mediated effects in rodents. The four behavioral components of the tetrad are spontaneous activity, catalepsy, hypothermia, and analgesia. Common assays for these behavioral paradigms are as follows:
181.1 References
• Spontaneous activity (or hypomotility) is determined by an open field test, in which a mouse is placed in a cage with perpendicular grid lines, usually spaced by approx. 1 inch. An experimenter counts the number of line crossings by the mouse in a given amount of time. • Catalepsy is determined by the bar test. The mouse is placed on a bar oriented parallel to and approximately 1 inch off of the ground. If the mouse remains immobile on the bar for typically more than 20 seconds, it is considered cataleptic. • Hypothermia is determined by using a rectal probe to measure the rectal temperature. • Analgesia is usually determined by the hot plate or tail immersion test. In the hot plate test, the mouse is placed on a heated plate, typically between 54 and 58°C. An experimenter measures the time it takes for the mouse to jump off of the hot plate. In the tail immersion test, the mouse is immobilized and its tail is placed into a warm water bath, typically also between 54 and 58°C. An experimenter measures the time it takes for the mouse to remove its tail from the water bath. Direct CB1 agonists, such as THC (the psychoactive component of marijuana), or WIN 55,212-2, have effects in all components of the tetrad and induce hypomotility, catalepsy, hypothermia, and analgesia in rodents. Accordingly, all true “tetrad effects” are not observed following treatment with antagonists of CB1 such as rimonabant. 234
[1] Little, P.J.; Compton, D.R.; Johnson, M.R.; Melvin, L.S.; Martin, B.R. (1988). Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. J Pharmacol Exp Ther 247: 1046–51.
Chapter 182
Tetrahydrocannabinol “THC” redirects here. For other uses, see THC (disam- the periaqueductal gray.[16] Other effects include relaxbiguation). ation, alteration of visual, auditory, and olfactory senses, fatigue, and appetite stimulation. THC has marked antiemetic properties. It may acutely reduce aggression Tetrahydrocannabinol (THC), or more precisely and increase aggression during withdrawal.[17] 9 its main isomer (−)-trans-Δ -tetrahydrocannabinol ( (6aR,10aR)-delta-9-tetrahydrocannabinol), is the principal psychoactive constituent (or cannabinoid) of the cannabis plant. First isolated in 1964 by Israeli scientists Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science[8][9][10] it is a water-clear glassy solid when cold, which becomes viscous and sticky if warmed. A pharmaceutical formulation of (−)-trans-Δ9 -tetrahydrocannabinol, known by its INN dronabinol, is available by prescription in the U.S. and Canada under the brand name Marinol. An aromatic terpenoid, THC has a very low solubility in water, but good solubility in most organic solvents, specifically lipids and alcohols.[7] Along with CBD, CBN, CBC, CBG and other 80 molecules make up the phytocannabinoid family, found in different quantities in Cannabis Sativa plants.[11]
Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug’s therapeutic window.[18] However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamateinduced excitotoxicity.[19]
Like most pharmacologically-active secondary metabolites of plants, THC in cannabis is assumed to be involved in self-defense, perhaps against herbivores.[12] THC also possesses high UV-B (280–315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.[13][14][15]
182.1.1 Appetite and taste
Tetrahydrocannabinol with double bond isomers and their stereoisomers is one of only three cannabinoids scheduled by Convention on Psychotropic Substances (the other two are dimethylheptylpyran and parahexyl). Cannabis as a plant is scheduled by the Single Convention on Narcotic Drugs (Schedule I and IV).
182.1 Effects See also: Effects of cannabis, Long-term effects of cannabis and Cannabis in pregnancy THC has mild to moderate analgesic effects, and cannabis can be used to treat pain by altering transmitter release on dorsal root ganglion of the spinal cord and in
It has long been known that, in humans, cannabis increases appetite and consumption of food. The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis. CB1 activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger hormone ghrelin increase prior to consuming a meal. After chyme is ed into the duodenum, signaling hormones such as cholecystokinin and leptin are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus. Cannabinoid activity is reduced through the satiety signals induced by leptin release. A study in mice suggested that based on the connection between palatable food and stimulation of dopamine (DA) transmission in the shell of the nucleus accumbens (NAc), cannabis may not only stimulate taste, but possibly the hedonic (pleasure) value of food as well. The study later demonstrates habitual use of THC lessening this heightened pleasure response, indicating a possible similarity in humans.[20] The inconsistency between DA
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CHAPTER 182. TETRAHYDROCANNABINOL
habituation and enduring appetite observed after THC application suggests that cannabis-induced appetite stimulation is not only mediated by enhanced pleasure from palatable food, but through THC stimulation of another appetitive response as well.
182.2 Chemistry 182.2.1
Discovery and structure identification
The discovery of THC by team of researchers from Hebrew University Pharmacy School was first described in “Isolation, structure and partial synthesis of an active constituent of hashish”, published in the Journal of the American Chemical Society in 1964.[8] Research was also published in the academic journal Science, with “Marijuana chemistry” by Raphael Mechoulam in June 3D rendering of the THC molecule 1970,[21] In the latter, the team of researchers from Hebrew University and Tel Aviv University experimented on monkeys to isolate the active compounds in hashish. Their results provided evidence that, except for tetrahydrocannabinol, no other major active compounds were present in hashish.
182.2.2
Isomerism
A hybrid Cannabis strain (White Widow) flower coated with trichomes, which contain more THC than any other part of the plant
Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6Hbenzo[c]chromen-1-ol. • Further reading on cannabanoid isomerism: John C. Leffingwell (May 2003). “Chirality & Bioactivity I.: Pharmacology” 3 (1). pp. 18–20. Retrieved 12 January 2014. Closeup of THC-filled trichomes on a Cannabis sativa leaf
182.3 Medical uses medical marijuana and marijuana-derived products in In April 2014 the American Academy of Neurology pub- certain neurological disorders.[22] The review identified lished a systematic review of the efficacy and safety of 34 studies meeting inclusion criteria, of which 8 were
182.4. ADVERSE EFFECTS
237
rated as Class I quality.[22] The study found evidence sup• Epilepsy. Data was considered insufficient to judge porting the effectiveness of cannabis extracts and THC in the utility of cannabis products in reducing seizure treating certain symptoms of multiple sclerosis, but found frequency or severity.[22] insufficient evidence to determine the effectiveness of cannabis products in treating several other neurological 182.3.4 Other studies in humans diseases.[22]
182.3.1
Multiple sclerosis symptoms
• Spasticity. Based on the results of 3 high quality trials and 5 of lower quality, oral cannabis extract was rated as effective, and THC as probably effective, for improving patient’s subjective experience of spasticity. Oral cannabis extract and THC both were rated as possibly effective for improving objective measures of spasticity.[22] • Centrally mediated pain and painful spasms. Based on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.[22] • Bladder dysfunction. Based on a single high quality study, oral cannabis extract and THC were rated as probably ineffective for controlling bladder complaints in multiple sclerosis[22]
182.3.2
Neurodegenerative disorders
Evidence suggests that THC helps alleviate symptoms suffered both by AIDS patients, and by cancer patients undergoing chemotherapy, by increasing appetite and decreasing nausea.[24][25][26][27] It has also been shown to assist some glaucoma patients by reducing pressure within the eye, and is used in the form of cannabis by a number of multiple sclerosis patients, who use it to alleviate neuropathic pain and spasticity. The National Multiple Sclerosis Society is currently ing further research into these uses.[28] Studies in humans have been limited by federal and state laws criminalizing marijuana. In August 2009 a phase IV clinical trial by the Hadassah Medical Center in Jerusalem, Israel started to investigate the effects of THC on post-traumatic stress disorders.[29] Studies have been conducted with spinal injury patients and THC.[30]
182.4 Adverse effects 182.4.1 Acute toxicity
There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form.[31] However, numerous reports have suggested an association of cannabis smoking with an increased risk of myocardial infarction.[32][33] Information about the toxicity of THC is primarily based on results from animal studies. The toxicity depends on the route • Parkinson disease. Based on a single study, oral of istration and the laboratory animal. cannabis extract was rated probably ineffective in The estimated lethal dose of intravenous dronabinol in treating levodopa-induced dyskinesia in Parkinson humans is 30 mg/kg,[34] meaning lethality is unlikely. disease.[22] The typical medicinal dosage istered is two 2.5 mg capsules daily; for an 80 kg man (~170 lb). A lethal dose • Alzheimer’s disease. A 2011 Cochrane Review for such a person would be 960 of those capsules infused found insufficient evidence to conclude whether intravenously. Non-fatal overdoses have occurred: “Sigcannabis products have any utility in the treatment nificant CNS symptoms in antiemetic studies followed of Alzheimer’s disease.[23] oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules.”[34] • Huntington disease. No reliable conclusions could be drawn regarding the effectiveness of THC or oral cannabis extract in treating the symptoms of Huntington disease as the available trials were too small to reliably detect any difference[22]
182.3.3
Other neurological disorders
• Tourette syndrome. The available data was determined to be insufficient to allow reliable conclusions to be drawn regarding the effectiveness of oral cannabis extract or THC in controlling tics.[22] • Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[22]
A meta analysis of cannabis and THC clinical trials conducted by the American Academy of Neurology found that of 1619 persons treated with cannabis products (including some treated with smoked cannabis and nabiximols), 6.9% discontinued due to side effects, compared to 2.2% of 1,118 treated
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CHAPTER 182. TETRAHYDROCANNABINOL with placebo. Detailed information regarding side effects was not available from all trials, but nausea, increased weakness, behavioral or mood changes, suicidal ideation, hallucinations, dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication were each described as side effects in at least 2 trials. There was a single death rated by the investigator as “possibly related” to treatment. This person had a seizure followed by aspiration pneumonia. The paper does not describe whether this was one of the patients from the epilepsy trials.[22]
182.4.2
Cognitive effects
cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is “neither necessary nor sufficient” to cause psychosis.[41] A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.[42] Some studies have suggested that cannabis s have a greater risk of developing psychosis than non-s. This risk is most pronounced in cases with an existing risk of psychotic disorder.[43][44] A 2005 paper from the Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene.[45] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.[46] A 2008 German review reported that cannabis was a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis.[47]
Its status as an illegal drug in most countries can make research difficult; for instance in the United States where 182.4.4 Other potential long-term effects the National Institute on Drug Abuse was the only legal source of cannabis for researchers until it recently became A 2008 National Institutes of Health study of 19 chronic legalized in Colorado and Washington state.[35] heavy marijuana s with cardiac and cerebral abnorA 2011 systematic review evaluated published studies of malities (averaging 28 g to 272 g (1 to 9+ oz) weekly) the acute and long-term cognitive effects of cannabis. and 24 controls found elevated levels of apolipoprotein [48] An inTHC intoxication is well established to impair cognitive C-III (apoC-III) in the chronic smokers. functioning on an acute basis, including effects on the crease in apoC-III levels induces the development of ability to plan, organize, solve problems, make decisions, hypertriglyceridemia. and control impulses. The extent of this impact may be greater in novice s, and paradoxically, those habituated to high level ingestion may have reduced cognition Detection in body fluids during withdrawal. Studies of long-term effects on cognition have provided conflicting results, with some studies THC, 11-OH-THC and THC-COOH can be detected and finding no difference between long-term abstainers and quantitated in blood, urine, hair, oral fluid or sweat usnever-s and others finding long term deficits. The dis- ing a combination of immunoassay and chromatographic crepancies between studies may reflect greater long term techniques as part of a drug use testing program or in a effects among heavier s relative to occasional s, forensic investigation of a traffic or other criminal offense and greater duration of effect among those with heavy or suspicious death.[49][50][51] use as adolescents compared to later in life.[36] A second systematic review focused on neuroimaging studies found little evidence ing an effect of cannabis use 182.4.5 Interactions on brain structure and function.[37] A 2003 meta analysis concluded that any long term cognitive effects were relatively modest in magnitude and limited to certain aspects The effects of the drug can be reduced by the CB1 receptor inverse agonist rimonabant (SR141716A) as well of learning and memory.[38] as opioid receptor antagonists (opioid blockers) naloxone and naloxonazine.[20][52] The α7 nicotinic receptor antagonist methyllycaconitine can block self-istration of 182.4.3 Impact on psychosis THC in rates comparable to the effects of varenicline on nicotine istration.[53] A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use.[39] A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related.[40] A 2004 literature review on the subject concluded that
Cannabidiol, the second most abundant cannabinoid found in cannabis, is an indirect antagonist against cannabinoid agonists; thus reducing the effects of anandamide and THC agonism on the CB1 and CB2 receptors.
182.7. CHEMICAL SYNTHESIS
239
182.5 Mechanism of action For a review of the mechanisms behind endocannabinoid synaptic transmission, see Endocannabinoid system. The pharmacological actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Kᵢ=10nM[54] ), located mainly in the central nervous system, and the CB2 receptor (Kᵢ=24nM[54] ), mainly expressed in cells of the immune system.[19] The psychoactive effects of THC are primarily mediated by its activation of CB1 G-protein coupled receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyBiosynthesis of THC clase.[16] The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.[18] THC is a lipophilic molecule[55] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[56][57]
is decarboxylated, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops.[62][63]
182.7 Chemical synthesis
Total chemical syntheses largely depend on carefully controlled acid catalyzed condensation of selected monoterpenes with olivetol. If citral is used as start material only the racemic product is formed. The condensation is acid catalyzed, but 0.0005 N hydrogen chloride THC, similarly to cannabidiol, albeit less potently, is an only affords a 12% yield. ∴ 1% boron trifluoride is used allosteric modulator of the μ- and δ-opioid receptors.[58] as the catalyst.
182.5.1
Pharmacokinetics
THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.[59] More than 55% of THC is excreted in the feces and ~20% in the urine. The main metabolite in urine is the ester of glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[60]
Since isomerization of Δ1 THC to virtually inactive Δ6 THC takes place readily in acid or upon heating, the cyclizations must be carefully controlled. Optically active verbenol can be used instead of citral. Please note the attached citations:[64][65][66]
182.8 Marinol
Dronabinol is the INN for a pure isomer of THC, (–)trans-Δ9 -tetrahydrocannabinol,[67] which is the main isomer found in cannabis. It is sold as Marinol (a ed trademark of Solvay Pharmaceuticals). Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies. Synthesized THC may be 182.6 Biosynthesis generally referred to as dronabinol. It is available as a prescription drug (under Marinol[68] ) in several countries In the cannabis plant, THC occurs mainly as including the United States and . In the United tetrahydrocannabinolic acid (THCA, 2-COOH-THC). States, Marinol is a Schedule III drug, available by preGeranyl pyrophosphate and olivetolic acid react, catal- scription, considered to be non-narcotic and to have a ysed by an enzyme to produce cannabigerolic acid,[61] low risk of physical or mental dependence. Efforts to which is cyclized by the enzyme THC acid synthase get cannabis rescheduled as analogous to Marinol have to give THCA. Over time, or when heated, THCA not succeeded thus far, though a 2002 petition has been
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accepted by the DEA. As a result of the rescheduling ics like nabilone.[79] of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol has been approved by the U.S. Food and Drug istration (FDA) in the treatment of anorexia in AIDS patients, as well as for refractory nausea and vomiting of patients undergoing chemotherapy, which has raised much controversy[69] as 182.9 Regulatory to why natural THC is still a schedule I drug.[70]
history
An overdose usually presents with lethargy, decreased motor coordination, slurred speech, and postural hy- For more details on this topic, see Removal of cannabis potension. The FDA estimates the lethal human dose from Schedule I of the Controlled Substances Act. of intravenous dronabinol to be 30 mg/kg (2100 mg/ 70 kg).[71] Since at least 1986, the trend has been for THC in genAn analog of dronabinol, nabilone, is available commer- eral, and especially the Marinol preparation, to be downcially in Canada under the trade name Cesamet, manu- graded to less and less stringently-controlled schedules of factured by Valeant Pharmaceuticals. Cesamet has also controlled substances, in the U.S. and throughout the rest received FDA approval and began marketing in the U.S. of the world. in 2006. Nabilone is a Schedule II drug.[72] On May 13, 1986, the Drug Enforcement istration (DEA) issued a Final Rule and Statement of Pol182.8.1 Comparisons with medical mari- icy authorizing the “Rescheduling of Synthetic Dronabinol in Sesame Oil and Encapsulated in Soft Gelatin juana Capsules From Schedule I to Schedule II” (DEA 51 FR 17476-78). This permitted medical use of Marinol, alFurther information: Medical cannabis beit with the severe restrictions associated with Schedule II status.[80] For instance, refills of Marinol prescripFemale cannabis plants contain more than 60 cannabi- tions were not permitted. At its 1045th meeting, on noids, including cannabidiol (CBD), thought to be April 29, 1991, the Commission on Narcotic Drugs, in the major anticonvulsant that helps multiple sclero- accordance with article 2, paragraphs 5 and 6, of the sis patients;[73] and cannabichromene (CBC), an anti- Convention on Psychotropic Substances, decided that Δ9 inflammatory which may contribute to the pain-killing tetrahydrocannabinol (also referred to as Δ9 -THC) and effect of cannabis.[74] its stereochemical variants should be transferred from It takes over one hour for Marinol to reach full systemic Schedule I to Schedule II of that Convention. This reeffect,[75] compared to seconds or minutes for smoked leased Marinol from the restrictions imposed by Article or vaporized cannabis.[76] Some patients accustomed to 7 of the Convention (See also United Nations Convention inhaling just enough cannabis smoke to manage symp- Against Illicit Traffic in Narcotic Drugs and Psychotropic toms have complained of too-intense intoxication from Substances). Marinol’s predetermined dosages. Many patients have An article published in the April–June 1998 issue of the said that Marinol produces a more acute psychedelic ef- Journal of Psychoactive Drugs found that “Healthcare fect than cannabis, and it has been speculated that this professionals have detected no indication of scrip-chasing disparity can be explained by the moderating effect of or doctor-shopping among the patients for whom they the many non-THC cannabinoids present in cannabis. have prescribed dronabinol”. The authors state that MariFor that reason, alternative THC-containing medications nol has a low potential for abuse.[81] based on botanical extracts of the cannabis plant such as nabiximols are being developed. Mark Kleiman, di- In 1999, Marinol was rescheduled from Schedule II to III rector of the Drug Policy Analysis Program at UCLA’s of the Controlled Substances Act, reflecting a finding that School of Public Affairs said of Marinol, “It wasn't any THC had a potential for abuse less than that of cocaine fun and made the feel bad, so it could be approved and heroin. This rescheduling constituted part of the arwithout any fear that it would penetrate the recreational gument for a 2002 petition for removal of cannabis from market, and then used as a club with which to beat back Schedule I of the Controlled Substances Act, in which pethe advocates of whole cannabis as a medicine.”[77] Mr. titioner Jon Gettman noted, “Cannabis is a natural source Kleiman’s opinion notwithstanding, clinical trials com- of dronabinol (THC), the ingredient of Marinol, a Schedcannabis paring the use of cannabis extracts with Marinol in the ule III drug. There are no grounds to schedule [82] in a more restrictive schedule than Marinol”. treatment of cancer cachexia have demonstrated equal efficacy and well-being among patients in the two treat- At its 33rd meeting, in 2003, the World Health Organiment arms.[78] United States federal law currently regis- zation Expert Committee on Drug Dependence recomters dronabinol as a Schedule III controlled substance, but mended transferring THC to Schedule IV of the Convenall other cannabinoids remain Schedule I, except synthet- tion, citing its medical uses and low abuse potential.[83]
182.11. REFERENCES
182.10 See also • Anandamide • Cannabis (drug) • Psychoactive drug • Cannabinoids • 11-Hydroxy-THC, metabolite of THC • Anandamide, 2-Arachidonoylglycerol, endogenous cannabinoid agonists • Cannabidiol (CBD), an isomer of THC • Cannabinol (CBN), a metabolite of THC • Dimethylheptylpyran • Parahexyl • Tetrahydrocannabinolic acid, the biosynthetic precursor for THC • HU-210, WIN 55,212-2, JWH-133, synthetic cannabinoid agonists • Medical cannabis • War on Drugs • Cannabis rescheduling in the United States • Health issues and the effects of cannabis
182.11 References [1] http://www.fda.gov/ohrms/dockets/dockets/05n0479/ 05N-0479-emc0004-04.pdf
241
[7] Garrett ER, Hunt CA (July 1974). “Physicochemical properties, solubility, and protein binding of Δ9 tetrahydrocannabinol”. J. Pharm. Sci. 63 (7): 1056–64. doi:10.1002/jps.2600630705. PMID 4853640. [8] Gaoni Y, Mechoulam R (1964). “Isolation, structure and partial synthesis of an active constituent of hashish”. Journal of the American Chemical Society 86 (8): 1646–1647. doi:10.1021/ja01062a046. [9] “Interview with the winner of the first ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel”. February 2007. [10] Geller, Tom (2007). “Cannabinoids: A Secret History”. Chemical Heritage Newsmagazine 25 (2). Archived from the original on 19 June 2008. [11] Alchimiaweb Blog, Cannabinoids and their medicinal properties [12] Pate, David W. (1994). “Chemical ecology of Cannabis”. Journal of the International Hemp Association 1 (29): 32– 37. [13] Pate, David W. (1983). “Possible role of ultraviolet radiation in evolution of Cannabis chemotypes”. Economic Botany 37 (4): 396–405. doi:10.1007/BF02904200. [14] Lydon, John; Teramura, Alan H. (1987). “Photochemical decomposition of cannabidiol in its resin base”. Phytochemistry 26 (4): 1216–1217. doi:10.1016/S00319422(00)82388-2. [15] Lydon J, Teramura AH, Coffman CB (1987). “UVB radiation effects on photosynthesis, growth and cannabinoid production of two Cannabis sativa chemotypes”. Photochemistry and Photobiology 46 (2): 201– 206. doi:10.1111/j.1751-1097.1987.tb04757.x. PMID 3628508.
[2] Marlowe, Douglas B. (December 2010). “The Facts On Marijuana”. NAD. “Based upon several nationwide epidemiological studies, marijuana’s dependence liability has been reliably determined to be 8 to 10 percent.”
[16] Elphick MR, Egertová M (2001). “The neurobiology and evolution of cannabinoid signalling”. Philosophical Transactions of the Royal Society B: Biological Sciences 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486.
[3] Grotenhermen, F (2003). “Pharmacokinetics and pharmacodynamics of cannabinoids”. Clin Pharmacokinet 42 (4): 327–60. doi:10.2165/00003088-200342040-00003. PMID 12648025. (subscription required (help)).
[17] Hoaken PN, Stewart SH (2003). “Drugs of abuse and the elicitation of human aggressive behavior”. Addictive Behaviors 28 (9): 1533–1554. doi:10.1016/j.addbeh.2003.08.033. PMID 14656544.
[4] The Royal Pharmaceutical Society of Great Britain (30 November 2006). “Cannabis”. In Sean C. Sweetman. Martindale: The Complete Drug Reference: Single (35th ed.). Pharmaceutical Press. ISBN 978-0-85369703-9.
[18] Pertwee RG (2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin”. British Journal of Pharmacology 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291.
[5] “Tetrahydrocannabinol – Compound Summary”. National Center for Biotechnology Information. PubChem. Retrieved 12 January 2014. “Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%.” [6] “Marijuana Water Pipe and Vaporizer Study”. Multidisciplinary Association for Psychedelic Studies. Retrieved 15 May 2014.
[19] Pertwee RG (2006). “The pharmacology of cannabinoid receptors and their ligands: An overview”. International Journal of Obesity 30: S13–S18. doi:10.1038/sj.ijo.0803272. PMID 16570099. [20] De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G (2011). “Cannabinoid facilitation of behavioral and biochemical hedonic taste reNeuropharmacology 63 (1): 161–168. sponses”.
242
CHAPTER 182. TETRAHYDROCANNABINOL
doi:10.1016/j.neuropharm.2011.10.018. PMC 3705914. PMID 22063718. [21] Mechoulam R (1970). “Marihuana chemistry”. Science 168 (3936): 1159–66. Bibcode:1970Sci...168.1159M. doi:10.1126/science.168.3936.1159. PMID 4910003. [22] Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D (April 2014). “Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology”. Neurology 82 (17): 1556– 63. doi:10.1212/WNL.0000000000000363. PMID 24778283. [23] Krishnan S, Cairns R, Howard R (2009). “Cannabinoids for the treatment of dementia”. In Krishnan, Sarada. “Cochrane Database of Systematic Reviews”. Cochrane database of systematic reviews (Online) (2): CD007204. doi:10.1002/14651858.CD007204.pub2. PMID 19370677. [24] “Cannabis and Cannabinoids”. National Cancer Institute. Retrieved 12 January 2014. [25] Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, Foltin RW (2007). “Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep”. Journal of Acquired Immune Deficiency Syndromes 45 (5): 545– 54. doi:10.1097/QAI.0b013e31811ed205. PMID 17589370. [26] Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M (2003). “Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial”. Annals of Internal Medicine 139 (4): 258–66. doi:10.7326/0003-4819-1394-200308190-00008. PMID 12965981. [27] Grotenhermen, Franjo; Russo, Ethan, eds. (2002). “Review of Therapeutic Effects”. Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. New York City: Psychology Press. p. 124. ISBN 978-0-7890-1508-2. “The only approved preparations to date, Marinol (dronabinol, Δ9 -THC) and Cesamet (nabilone), are approved for the indication of nausea and vomiting associated with cancer chemotherapy. Marinol is also approved for anorexia and cachexia in HIV/AIDS.” [28] “Marijuana (Cannabis)". National Multiple Sclerosis Society. Retrieved 5 September 2009.
[31] Walker JM, Huang SM (August 2002). “Cannabinoid analgesia”. Pharmacol. Ther. 95 (2): 127–35. doi:10.1016/S0163-7258(02)00252-8. PMID 12182960. "...to date, there are no deaths known to have resulted from overdose of cannabis. (p. 128)" [32] Thomas G, Kloner RA, Rezkalla S (January 2014). “Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know”. Am. J. Cardiol. 113 (1): 187–90. doi:10.1016/j.amjcard.2013.09.042. PMID 24176069. [33] Aryana A, Williams MA (May 2007). “Marijuana as a trigger of cardiovascular events: speculation or scientific certainty?". Int. J. Cardiol. 118 (2): 141–4. doi:10.1016/j.ijcard.2006.08.001. PMID 17005273. [34] “DRONABINOL capsule [American Health Packaging]". National Library of Medicine. Daily Med. July 2012. Retrieved 12 January 2014. “The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules.” [35] “Medical Marijuana”. Multidisciplinary Association for Psychoactive Substances. Retrieved 12 January 2014. [36] Crean RD, Crane NA, Mason BJ (March 2011). “An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions”. J Addict Med 5 (1): 1–8. doi:10.1097/.0b013e31820c23fa. PMC 3037578. PMID 21321675. [37] Martín-Santos R, Fagundo AB, Crippa JA, Atakan Z, Bhattacharyya S, Allen P, Fusar-Poli P, Borgwardt S, Seal M, Busatto GF, McGuire P (March 2010). “Neuroimaging in cannabis use: a systematic review of the literature”. Psychol Med 40 (3): 383–98. doi:10.1017/S0033291709990729. PMID 19627647. [38] Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T (2003). “Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study”. Journal of the International Neuropsychological Society 9 (5). doi:10.1017/S1355617703950016. PMID 12901774. Lay summary – WebMD (1 July 2003). [39] Large M, Sharma S, Compton MT, Slade T, Nielssen O (June 2011). “Cannabis use and earlier onset of psychosis: a systematic meta-analysis”. Arch. Gen. Psychiatry 68 (6): 555–61. doi:10.1001/archgenpsychiatry.2011.5. PMID 21300939.
[29] ClinicalTrials.gov NCT00965809 Add on Study on Δ9THC Treatment for Posttraumatic Stress Disorders (PTSD) (THC_PTSD)
[40] Semple DM, McIntosh AM, Lawrie SM (March 2005). “Cannabis as a risk factor for psychosis: systematic review”. J. Psychopharmacol. (Oxford) 19 (2): 187–94. doi:10.1177/0269881105049040. PMID 15871146.
[30] Hannigan WC, Destree R, Truong XT (1986). “The effect of delta-9-THC on human spasticity”. American Society for Clinical Pharmacology and Therapeutics, Eightyseventh Annual Meeting, March 20–22, 1986 39: 198, abstract B45.
[41] Arseneault L, Cannon M, Witton J, Murray RM (2004). “Causal association between cannabis and psychosis: examination of the evidence”. The British Journal of Psychiatry 184 (2): 110–117. doi:10.1192/bjp.184.2.110. PMID 14754822.
182.11. REFERENCES
243
[42] Laqueille X (2009). “Le cannabis est-il un facteur de vulnérabilité des troubles schizophrènes?" [Is cannabis is a vulnerability factor of schizophrenic disorders?]. Archives de Pédiatrie 16 (9): 1302–5. doi:10.1016/j.ared.2009.03.016. PMID 19640690. (registration required (help)).
[51] Baselt, R. (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 1644–8.
[43] Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G (2007). “Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review”. The Lancet 370 (9584): 319–28. doi:10.1016/S0140-6736(07)61162-3. PMID 17662880.
[52] Lupica CR, Riegel AC, Hoffman AF (2004). “Marijuana and cannabinoid regulation of brain reward circuits”. British Journal of Pharmacology 143 (2): 227–34. doi:10.1038/sj.bjp.0705931. PMC 1575338. PMID 15313883.
[44] Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J (2005). “Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people”. BMJ 330 (7481): 11– 0. doi:10.1136/bmj.38267.664086.63. PMC 539839. PMID 15574485.
[53] Solinas M, Scherma M, Fattore L, Stroik J, Wertheim C, Tanda G, Fratta W, Goldberg SR (2007). “Nicotinic 7 Receptors as a New Target for Treatment of Cannabis Abuse”. Journal of Neuroscience 27 (21): 5615– 20. doi:10.1523/JNEUROSCI.0027-07.2007. PMID 17522306. Lay summary – New Scientist (22 May 2007).
[45] Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW (2005). “Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the CatecholO-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction”. Biological Psychiatry 57 (10): 1117–27. doi:10.1016/j.biopsych.2005.01.026. PMID 15866551.
[54] “PDSP Database – UNC”. NIMH Psychoactive Drug Screening Program. Retrieved 11 June 2013.
[46] Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ; Spurlock (2007). “Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use”. The British Journal of Psychiatry 191 (5): 402–7. doi:10.1192/bjp.bp.107.036129. PMID 17978319. Lay summary – MedWireNews. [47] Kawohl W, Rössler W (2008). “Cannabis and Schizophrenia: new findings in an old debate”. Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater 22 (4): 223–9. PMID 19080993. [48] Jayanthi S, Buie S, Moore S, Herning RI, Better W, Wilson NM, Contoreggi C, Cadet JL (2008). “Heavy marijuana s show increased serum apolipoprotein C-III levels: evidence from proteomic analyses”. Molecular Psychiatry 15 (1): 101–112. doi:10.1038/mp.2008.50. PMC 2797551. PMID 18475272. Lay summary – Reuters (May 13, 2008). [49] Schwilke EW, Schwope DM, Karschner EL, Lowe RH, Darwin WD, Kelly DL, Goodwin RS, Gorelick DA, Huestis MA (2009). "Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous HighDose Oral THC”. Clinical Chemistry 55 (12): 2180–2189. doi:10.1373/clinchem.2008.122119. PMC 3196989. PMID 19833841. [50] Röhrich J, Schimmel I, Zörntlein S, Becker J, Drobnik S, Kaufmann T, Kuntz V, Urban R (2010). “Concentrations of Δ9 -Tetrahydrocannabinol and 11-Nor-9Carboxytetrahydrocannabinol in Blood and Urine After ive Exposure to Cannabis Smoke in a Coffee
Shop”. Journal of Analytical Toxicology 34 (4): 196–203. doi:10.1093/jat/34.4.196. PMID 20465865.
[55] Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R, Duetz WA (November 2009). “Hydroxylation and Further Oxidation of Δ9-Tetrahydrocannabinol by AlkaneDegrading Bacteria” (PDF). Appl Environ Microbiol 75 (22): 7135–7141. doi:10.1128/AEM.01277-09. PMC 2786519. PMID 19767471. "Δ9-THC and many of its derivatives are highly lipophilic and poorly water soluble. Calculations of the n-octanol/water partition coefficient (Ko/w) of Δ9-THC at neutral pH vary between 6,000, using the shake flask method, and 9.44 × 106, by reversephase high-performance liquid chromatography estimation.” [56] Ashton CH (February 2001). “Pharmacology and effects of cannabis: a brief review”. Br J Psychiatry 178: 101– 106. doi:10.1192/bjp.178.2.101. PMID 11157422. “Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4–5 days. They are then slowly released back into other body compartments, including the brain. ... Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas.” [57] Huestis MA (August 2007). “Human cannabinoid pharmacokinetics”. Chem Biodivers 4 (8): 1770–804. doi:10.1002/cbdv.200790152. PMC 2689518. PMID 17712819. “THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver.” [58] Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (February 2006). “Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors”. Naunyn Schmiedebergs Arch. Pharmacol. 372 (5): 354–61. doi:10.1007/s00210-006-0033-x. PMID 16489449. [59] Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I (March 2007). “Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes”. Life Science 80 (15): 1415–9. doi:10.1016/j.lfs.2006.12.032. PMID 17303175.
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[60] Huestis MA (2005). “Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ9 -Tetrahydrocannabinol, Cannabidiol and Cannabinol”. Cannabinoids. Handbook of Experimental Pharmacology 168 (168): 657–90. doi:10.1007/3-540-26573-2_23. ISBN 3-540-22565-X. PMID 16596792. [61] Fellermeier M, Zenk MH (1998). “Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol”. FEBS Letters 427 (2): 283–5. doi:10.1016/S0014-5793(98)00450-5. PMID 9607329. [62] Marks MD, Tian L, Wenger JP, Omburo SN, SotoFuentes W, He J, Gang DR, Weiblen GD, Dixon RA (2009). “Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa”. Journal of Experimental Botany 60 (13): 3715– 26. doi:10.1093/jxb/erp21. PMC 2736886. PMID 19581347. [63] Baker PB, Taylor BJ, Gough TA (June 1981). “The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products”. J Pharm Pharmacol. 33 (6): 369–72. doi:10.1111/j.2042-7158.1981.tb13806.x. PMID 6115009. [64] Razdan RK (1970). “Hashish. V. A stereospecific synthesis of (-)−.DELTA.1-and (-).DELTA.1(6)tetrahydrocannabinols”. Journal of the American Chemical Society 92 (20): 6061–6062. doi:10.1021/ja00723a044. [65] Petrzilka T (1969). “Synthese von HaschischInhaltsstoffen. 4. Mitteilung”. Helvetica Chimica Acta 52 (4): 1102–1134. doi:10.1002/hlca.19690520427. [66] Jen T (1967). “Total synthesis of (.DELTA.1(6)-tetrahydrocannabinol, a active constituent of hashish (marijuana)". the American Chemical Society 89 (17): doi:10.1021/ja00993a071.
.DELTA.8biologically Journal of 4551–4552.
[67] “List of psychotropic substances under international control” (PDF). International Narcotics Control Board. p. 5. Archived from the original on 7 September 2005. Retrieved 20 April 2011. “This international non-proprietary name refers to only one of the stereochemical variants of delta-9-tetrahydrocannabinol, namely (-)-trans-delta-9tetrahydrocannabinol” [68] “Marinol – the Legal Medical Use for the Marijuana Plant”. Drug Enforcement istration. Archived from the original on 21 October 2002. Retrieved 20 April 2011. [69] Downs, David (21 October 2014). “War on marijuana unconstitutional, doctors testify in federal court Monday”. sfgate.com. Retrieved 21 October 2014. [70] Eustice, Carol (12 August 1997). “Medicinal Marijuana: A Continuing Controversy”. About.com. Retrieved 20 April 2011. [71] “Marinol”. FDA.gov. Retrieved 14 March 2014.
[72] “Title 21 of the Code of Federal Regulations – PART 1308 — SCHEDULES OF CONTROLLED SUBSTANCES”. US Department of Justice. DEA Office of Diversion Control. Retrieved 12 January 2014. With changes through 77 F.R. 4235 (January 27, 2012). [73] Pickens JT (1981). “Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content”. British Journal of Pharmacology 72 (4): 649–56. doi:10.1111/j.1476-5381.1981.tb09145.x. PMC 2071638. PMID 6269680. [74] Burns TL, Ineck JR (2006). “Cannabinoid Analgesia as a Potential New Therapeutic Option in the Treatment of Chronic Pain”. Annals of Pharmacotherapy 40 (2): 251– 260. doi:10.1345/aph.1G217. PMID 16449552. [75] MARINOL (dronabinol) capsule drug label/data at Daily Med from U.S. National Library of Medicine, National Institutes of Health. [76] McKim, William A (2002). Drugs and Behavior: An Introduction to Behavioral Pharmacology (5th ed.). Prentice Hall. p. 400. ISBN 0-13-048118-1. [77] Greenberg, Gary (1 November 2005). “Respectable Reefer”. Mother Jones. Retrieved 8 April 2010. [78] “Cannabis and Cannabinoids (PDQ®)". Cancer Topics. National Cancer Institute, U.S. Department of Health and Human Services. [79] “Government eases restrictions on pot derivative”. Online Athens. Retrieved 12 January 2014. [80] 51 Fed. Reg. 17476 (1986), Tuesday, May 13, 1986, pages 17476-17478 [81] Calhoun SR, Galloway GP, Smith DE (1998). “Abuse potential of dronabinol (Marinol)". Journal of Psychoactive Drugs 30 (2): 187–96. doi:10.1080/02791072.1998.10399689. PMID 9692381. [82] “Petition to Reschedule Cannabis (Marijuana)". Coalition for Rescheduling Cannabis. 9 October 2002. [83] “WHO Expert Committee on Drug Dependence”. World Health Organization. Retrieved 12 January 2014.
182.12 Further reading • Calhoun SR, Galloway GP, Smith DE (1998). “Abuse potential of dronabinol (Marinol)". J Psychoactive Drugs 30 (2): 187–96. doi:10.1080/02791072.1998.10399689. PMID 9692381. • DEA Moves Marinol To Schedule Three, But Leaves Marijuana in Schedule One. The Magic of Sesame Oil, Richard Cowan, MarijuanaNews.com.
182.13. EXTERNAL LINKS • Petition to Reschedule Cannabis (Marijuana) per 21 CFR § 1308.44(b) at the Wayback Machine (archived December 6, 2002), Filed October 9, 2002 with the DEA by the Coalition for Rescheduling Cannabis.
182.13 External links • U.S. National Library of Medicine: Drug Information Portal – Tetrahydrocannabinol
245
Chapter 183
Tetrahydrocannabinol-C4 Tetrahydrocannabinol-C4, also known as THC-C4 and butyl-THC, is a homologue of tetrahydrocannabinol (THC), the active component of cannabis. They are only different by the pentyl side chain being replaced by a butyl side chain. It is unknown whether THCC4 is an agonist, partial agonist, or antagonist at the cannabinoid receptors. The propyl analog, THCV, is a cannabinoid receptor type 1 and cannabinoid receptor type 2 antagonist,[1] while THC is a CB1 agonist. THCC4 has rarely been isolated from cannabis samples,[2] but appears to be less commonly present than THC or THCV. It is metabolised in a similar manner to THC.[3] Similarly to THC, it has 7 double bond isomers and 30 stereoisomers. It is not scheduled by Convention on Psychotropic Substances.
183.1 See also • Cannabinoids • Cannabis • Parahexyl
183.2 References [1] Thomas, Adèle; Stevenson, Lesley A; Wease, Kerrie N; Price, Martin R; Baillie, Gemma; Ross, Ruth A; Pertwee, Roger G (December 2005). “Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist”. British Journal of Pharmacology 146 (7): 917–926. doi:10.1038/sj.bjp.0706414. PMID 16205722. [2] Harvey DJ. Characterization of the butyl homologues of delta1-tetrahydrocannabinol, cannabinol and cannabidiol in samples of cannabis by combined gas chromatography and mass spectrometry. Journal of Pharmacy and Pharmacology. 1976 Apr;28(4):280-5. PMID 6715 [3] Brown NK, Harvey DJ. In vivo metabolism of the n-butylhomologues of delta 9-tetrahydrocannabinol and delta 8tetrahydrocannabinol by the mouse. Xenobiotica. 1988 Apr;18(4):417-27. PMID 2840781
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Chapter 184
Tetrahydrocannabinolic acid Not to be confused with 11-nor-9-Carboxy-THC.
39767–74, 15190053
Tetrahydrocannabinolic acid (THCA, 2COOH-THC), is a biosynthetic precursor of tetrahydrocannabinol (THC), the active component of Cannabis.[1][2][3][4] THCA is found in variable quantities in fresh, undried cannabis, but is progressively decarboxylated to THC with drying, and especially under intense heating such as when cannabis is smoked.[5] While THCA does not have psychoactive effects in its own right, it does have antiinflammatory and neuroprotective effects.[6][7] Despite the ready decarboxylation by drying or heating ex vivo, conversion of THCA to THC in vivo appears to be very limited, giving it only very slight efficacy as a prodrug for THC.[8] Consequently it is believed to be important in less-psychoactive preparations of cannabis used for medical use, such as cannabis tea.[9] It is also commonly used as a biomarker in drug testing along with THCV, to distinguish between prescribed synthetic Delta-9tetrahydrocannabinol, such as Marinol, and cannabis plant material which may also be used by patients.[10]
184.1 See also
doi:10.1074/jbc.M403693200,
PMID
[3] Moore C, Rana S, Coulter C. (2007-06-01), Simultaneous identification of 2-carboxy-tetrahydrocannabinol, tetrahydrocannabinol, cannabinol and cannabidiol in oral fluid, J Chromatogr B Analyt Technol Biomed Life Sci. 852 (12): 459–64, doi:10.1016/j.jchromb.2007.02.016, PMID 17321807 [4] Taura F. (Jun 2009), Studies on tetrahydrocannabinolic acid synthase that produces the acidic precursor of tetrahydrocannabinol, the pharmacologically active cannabinoid in marijuana, Drug Discoveries and Therapeutics 3 (3): 83–7, PMID 22495534 [5] Dussy FE, Hamberg C, Luginbühl M, Schwerzmann T, Briellmann TA. (2005-04-20), Isolation of Delta9THCA-A from hemp and analytical aspects concerning the determination of Delta9-THC in cannabis products, Forensic Science International 149 (1): 3–10, doi:10.1016/j.forsciint.2004.05.015, PMID 15734104 [6] Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. (2011), Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa, Biological and Pharmaceutical Bulletin 34 (5): 774–8, doi:10.1248/bpb.34.774, PMID 21532172 [7] Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, Rausch WD. (2012-05-07), Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)tetrahydrocannabinolic acid and cannabidiol in MPP(+) affected murine mesencephalic cultures, Phytomedicine 19 (8-9): 819–24, doi:10.1016/j.phymed.2012.04.002, PMID 22571976
• Cannabinoids • Cannabidiol
184.2 References [1] Baker PB, Taylor BJ, Gough TA. (Jun 1981), The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products, Journal of Pharmacy and Pharmacology 33 (6): 369–72, doi:10.1111/j.20427158.1981.tb13806.x, PMID 6115009 [2] Sirikantaramas S, Morimoto S, Shoyama Y, Ishikawa Y, Wada Y, Shoyama Y, Taura F. (2004-09-17), The gene controlling marijuana psychoactivity: molecular cloning and heterologous expression of Delta1tetrahydrocannabinolic acid synthase from Cannabis sativa L., Journal of Biological Chemistry 279 (38):
247
[8] Jung J, Meyer MR, Maurer HH, Neusüss C, Weinmann W, Auwärter V. (Oct 2009), Studies on the metabolism of the Delta-9-tetrahydrocannabinol precursor delta-9-tetrahydrocannabinolic acid A (Delta9-THCA-A) in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniques, Journal of Mass Spectrometry 44 (10): 1423–33, doi:10.1002/jms.1624, PMID 19728318 [9] Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte R. (2007-07-15), Cannabis tea revisited: a systematic evaluation of the cannabinoid composition of cannabis tea, Journal of Ethnopharmacology 113 (1): 85–90, doi:10.1016/j.jep.2007.05.019, PMID 17604926
248
[10] Radünz L, Westphal F, Maser E, Rochholz G. (201202-10), THCVA-A - a new additional marker for illegal cannabis consumption, Forensic Science International 215 (1-3): 171–4, doi:10.1016/j.forsciint.2011.03.001, PMID 21454026
CHAPTER 184. TETRAHYDROCANNABINOLIC ACID
Chapter 185
Tetrahydrocannabivarin Tetrahydrocannabivarin (THCV, THV) is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain. This terpeno-phenolic compound is found naturally in Cannabis, sometimes in significant amounts. The psychoactive effects of THCV in Cannabis preparations are not well characterized.
185.3 See also • Cannabinoids • Cannabis • Medical marijuana
Similarly to THC, it has 7 double bond isomers and 30 stereoisomers (see: Tetrahydrocannabinol#Isomerism). It is not scheduled by Convention on Psychotropic Substances.
• Rimonabant (synthetic CB1 antagonist) • Tetrahydrocannabinol-C4 • Parahexyl
185.1 Description
185.4 References [1] Turner, C.E., Hadley, K.W., and Fetterman, P. 1973. Constituents of Cannabis Sativa L., VI: Propyl Homologues in Samples of Known Geographical Origin. J. Pharm. Sci. 62(10):1739-1741
Plants with elevated levels of propyl cannabinoids (including THCV) have been found in populations of Cannabis sativa L. ssp. indica (= Cannabis indica Lam.) from China, India, Nepal, Thailand, Afghanistan, and Pakistan, as well as southern and western Africa. THCV levels up to 53.7% of total cannabinoids have been reported. [1] [2]
[2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). American Journal of Botany 91(6): 966975.
THCV is a cannabinoid receptor type 1 antagonist and cannabinoid receptor type 2 partial agonist.[3] Δ8-THCV has also been shown to be a CB1 antagonist.[4] Both papers describing the antagonistic properties of THCV were demonstrated in murine models.
[3] Pertwee, Roger G (September 2007). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9tetrahydrocannabivarin”. British Journal of Pharmacology 153 (2): 199–215. doi:10.1038/sj.bjp.0707617. [4] Pertwee RG, Thomas A, Stevenson LA, et al. 2007. The psychoactive plant cannabinoid, Δ9tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo. Br. J. Pharmacol. 150(5): 586–94.
185.2 Biosynthesis Unlike THC, cannabidiol (CBD), and cannabichromene (CBC), THCV doesn’t begin as cannabigerolic acid (CBGA). Instead of combining with olivetolic acid to create CBGA, geranyl pyrophosphate s with divarinolic acid, which has 2 less carbon molecules. The result is cannabigerovarin acid (CBGVA). Once CBGVA is created, the process continues exactly same as it would for THC. CBGVA is broken down to tetrahydrocannabivarin carboxylic acid (THCVA) by the enzyme THCV synthase. At that point, THCVA can be decarboxylated with heat or UV light to create THCV.[5]
[5] MedicalJane. “What is Tetrahydrocannabivarin?".
185.5 External links
249
• Erowid Compounds found in Cannabis sativa • www.tetrahydrocannabivarin.com THCV
Article
on
Chapter 186
THC-O-acetate THC acetate ester is a derivative of THC which has been found by the DEA as an apparent controlled substance analogue of THC. It was apparently made by extracting and purifying THC from cannabis plant material using a soxhlet extractor, followed by reaction with acetic anhydride in an analogous manner to how heroin is made from morphine.[1] A similar case was reported in June 1995 in the UK and THC-O-acetate was ruled to be a Class A drug.[2] THC acetate was also reported to have been found by New Zealand police in 1995, again made by acetylation of purified cannabis extracts with acetic anhydride.[3] The acetylation of THC does not change the properties of the compound to the same extent as with other acetate esters (e.g. morphine vs heroin), as the parent compound is already highly lipophilic, but potency is nonetheless increased to some extent. This derivative of THC is interesting as one of the few analogues of THC to have been encountered as a recreational drug sold and used in a highly pure smokable form. THC acetate ester was also investigated as a possible nonlethal incapacitating agent, as part of the Edgewood Arsenal experiments.[4]
186.1 References [1] Donald A. Cooper. Future Synthetic Drugs of Abuse. Drug Enforcement istration, McLean, Virginia [2] David T. Brown. Cannabis: The Genus Cannabis. p82 ISBN 90-5702-291-5 [3] Valentine MD. Δ9-THC acetate from acetylation of cannabis oil. Science and Justice 1995; 36(3):195–197. [4] Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants (1984) Commission on Life Sciences. The National Academies Press. pp79-99.
250
Chapter 187
THC-O-phosphate THC-O-phosphate is a water-soluble phosphate ester derivative of THC, invented in 1978 in an attempt to get around the poor water solubility of THC and make it easier to inject for the purposes of animal research into its pharmacology and mechanism of action. The main disadvantage of THC phosphate ester is the slow rate of hydrolysis of the ester link, resulting in delayed onset of action and lower potency than the parent drug. THC phosphate ester is made by reacting THC with phosphoryl chloride using pyridine as a solvent, following by quenching with water to produce THC phosphate ester. In the original research the less active but more stable isomer Δ8THC was used, but the same reaction scheme could be used to make the phosphate ester of the more active isomer Δ9THC. [1]
187.1 References [1] Yoshimura H, Watanabe K, Oguri K, Fujiwara M, Ueki S. Synthesis and pharmacological activity of a phosphate ester of delta8-tetrahydrocannabinol. Journal of Medicinal Chemistry. 1978 Oct;21(10):1079-81.
251
Chapter 188
Tinabinol Tinabinol (INN; SP-119) is a synthetic cannabinoid drug and analogue of dronabinol which was patented as an antihypertensive but was never marketed.[1][2]
188.1 See also • Dronabinol • Nabitan
188.2 References [1] David T. Brown (19 November 1998). Cannabis: The Genus Cannabis. CRC Press. p. 80. ISBN 978-90-5702291-3. Retrieved 27 April 2012. [2] Martin Negwer (1994). Organic-chemical drugs and their synonyms: an international survey. Indices. Akad.-Verl. p. 2242. ISBN 978-3-05-501629-5. Retrieved 27 April 2012.
252
Chapter 189
URB602 URB602 ([1,1'-biphenyl]−3-yl-carbamic acid, cyclohexyl ester) is a compound that has been found to inhibit hydrolysis of monoacyl glycerol compounds, such as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG). It was first described in 2003.[1] A study performed in 2005 found that the compound had specificity for metabolizing 2-AG over anandamide (another cannabinoid ligand) in rat brain presumably by inhibiting the enzyme monoacylglycerol lipase (MAGL), which is the primary metabolic enzyme of 2-AG.[2] However, subsequent studies have shown that URB602 lacks specificity for MAGL inhibition in vitro.[3]
189.1 References [1] Tarzia, G; Duranti, A; Tontini, A; Piersanti, G; Mor, M; Rivara, S; Plazzi, PV; Park, C et al. (2003). “Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors”. Journal of Medical Chemistry 46 (12): 2352–60. doi:10.1021/jm021119g. PMID 12773040. [2] Hohmann, Andrea G.; Suplita, Richard L.; Bolton, Nathan M.; Neely, Mark H.; Fegley, Darren; Mangieri, Regina; Krey, Jocelyn F.; Michael Walker, J. et al. (2005). “An endocannabinoid mechanism for stress-induced analgesia”. Nature 435 (7045): 1108–12. Bibcode:2005Natur.435.1108H. doi:10.1038/nature03658. PMID 15973410. [3] Vandevoorde, S; Jonsson, K-O; Labar, G; Persson, E; Lambert, D M; Fowler, C J (2007). “Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysisin vitro”. British Journal of Pharmacology 150 (2): 186–91. doi:10.1038/sj.bjp.0706971. PMC 2042901. PMID 17143303.
253
Chapter 190
URB754 URB754 was originally reported by Piomelli et al. to be a potent, noncompetitive inhibitor of monoacylglycerol lipase.[1] However, recent studies have shown that URB754 failed to inhibit recombinant MGL, and brain FAAH activity was also resistant to URB754.[2] In a later study by Piomelli et al. showed that the MGL-inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane.[3]
190.1 References [1] Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D (2005). “Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus”. Nat. Neurosci. 8 (9): 1139–41. doi:10.1038/nn1521. PMID 16116451. [2] Saario SM, Palomäki V, Lehtonen M, Nevalainen T, Järvinen T, Laitinen JT (2006). “URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain”. Chem. Biol. 13 (8): 811–4. doi:10.1016/j.chembiol.2006.07.008. PMID 16931330. [3] Tarzia, G; et al. (2007). “Identification of a bioactive impurity in a commercial sample of 6-methyl-2-ptolylaminobenzo[d][1,3]oxazin-4-one (URB754.”. Ann Chim. 97 (9): 887–94.
254
Chapter 191
VCHSR VCHSR is a drug used in scientific research which acts as a selective antagonist of the cannabinoid receptor CB1 . It is derived from the widely used CB1 antagonist rimonabant, and has similar potency and selectivity for the CB1 receptor, but has been modified to remove the hydrogen bonding capability in the C-3 substituent region, which removes the inverse agonist effect that rimonabant produces at high doses, so that VCHSR instead acts as a neutral antagonist, blocking the receptor but producing no physiological effect of its own.[1][2]
191.1 References [1] Hurst, DP; Lynch, DL; Barnett-Norris, J; Hyatt, SM; Seltzman, HH; Zhong, M; Song, ZH; Nie, J et al. (2002). “N-(piperidin-1-yl)−5-(4-chlorophenyl)−1-(2,4dichlorophenyl)−4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor”. Molecular Pharmacology 62 (6): 1274–87. doi:10.1124/mol.62.6.1274. PMID 12435794. [2] Hurst, D; Umejiego, U; Lynch, D; Seltzman, H; Hyatt, S; Roche, M; McAllister, S; Fleischer, D et al. (2006). “Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction”. Journal of Medical Chemistry 49 (20): 5969–87. doi:10.1021/jm060446b. PMID 17004712.
255
Chapter 192
VDM-11 VDM-11 is a potent cannabinoid reuptake inhibitor. It is light-sensitive and therefore must be stored within an inert gas such as argon, in a dark place and at an ideal temperature of −20°C.[1] This gold-colored substance is rarely found outside research laboratories.
192.1 See also • AM-404
192.2 References [1] VDM 11 at Sigma-Aldrich
256
Chapter 193
WIN 54,461 WIN 54,461 (6-Bromopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2 .[1]
193.1 See also • AM-630 (6-Iodopravadoline) • WIN 48,098 (Pravadoline) • WIN 55,212-2
193.2 References [1] Howlett AC, Berglund B, Melvin LS (October 1995). “Cannabinoid Receptor Agonists and Antagonists”. Current Pharmaceutical Design 1 (3): 343–352.
257
Chapter 194
WIN 55,212-2 WIN 55,212-2, along with HU-210 and JWH-133, may prevent the inflammation caused by amyloid beta proteins involved in Alzheimer’s disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through agonist action at cannabinoid receptors, which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglial activation in rat models. WIN 55,212-2 is a full agonist at the CB1 cannabinoid receptor (Kᵢ = 1.9 nM) and has much higher affinity than THC (Kᵢ = 41 nM) for this receptor.[10] WIN 55,212-2 reduces voluntary wheel running in laboratory mice, but with effects that depend on both genetic background and sex.[11]
194.1 See also • WIN 48,098 • WIN 54,461 • WIN 55,225 • WIN 56,098
Pancreatic stellate cells. The cells in the lower frame are under the action of WIN 55,212-2. They are thought to assume a more "quiescent" phenotype. From Michalski et al., 2008.[1]
194.2 References
WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.[2][3][4] WIN 55,212-2 is a potent cannabinoid receptor agonist[5] that has been found to be a potent analgesic[6] in a rat model of neuropathic pain.[7] It activates p42 and p44 MAP kinase via receptor-mediated signaling.[8] At 5 µM WIN 55,212-2 inhibit ATP production in sperm in a CB1 receptor-dependent fashion.[9] 258
[1] Michalski, C., et al. (2008). Gluud, Christian, ed. “Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells”. PLoS ONE 3 (2): e1701. Bibcode:2008PLoSO...3.1701M. doi:10.1371/journal.pone.0001701. PMC 2253501. PMID 18301776. [2] Compton DR, et al. Aminoalkylindole Analogs: Cannabimimetic Activity of a Class of Compounds Structurally Distinct from Δ9 -Tetrahydrocannabinol. Journal of Pharmacology and Experimental Therapeutics. 1992; 263(3):1118-1126. [3] Ferraro, L.; Tomasini, M. C.; Gessa, G. L.; Bebe, B. W.; Tanganelli, S.; Antonelli, T. (2001). “The Cannabinoid Receptor Agonist WIN 55,212-2 Regulates Glutamate Transmission in Rat Cerebral Cortex: An in Vivo
194.3. EXTERNAL LINKS
and in Vitro Study”. Cerebral Cortex 11 (8): 728–733. doi:10.1093/cercor/11.8.728. PMID 11459762. [4] Zhang, Q., et al. (2002). “In vitro metabolism of R(+)−2,3-dihydro-5-methyl-3(morpholinyl)methylpyrrolo 1,2,3-de1,4-benzoxazinyl(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist”. Drug metabolism and disposition: the biological fate of chemicals 30 (10): 1077–1086. doi:10.1124/dmd.30.10.1077. PMID 12228183. [5] Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; MacKie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R. L. (1995). “Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors”. Molecular pharmacology 48 (3): 443–450. PMID 7565624. [6] Meng, I. D.; Manning, B. H.; Martin, W. J.; Fields, H. L. (1998). “An analgesia circuit activated by cannabinoids”. Nature 395 (6700): 381–383. doi:10.1038/26481. PMID 9759727. [7] Herzberg, U.; Eliav, E.; Bennett, G. J.; Kopin, I. J. (1997). “The analgesic effects of R(+)-WIN 55,212–2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain”. Neuroscience Letters 221 (2–3): 157–160. doi:10.1016/S0304-3940(96)13308-5. PMID 9121688. [8] Bouaboula, M.; Poinot-Chazel, C.; Bourrié, B.; Canat, X.; Calandra, B.; Rinaldi-Carmona, M.; Le Fur, G.; Casellas, P. (1995). “Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1”. The Biochemical journal. 312 ( Pt 2) (Pt 2): 637– 641. PMC 1136308. PMID 8526880. [9] Morgan, D. J.; Muller, C. H.; Murataeva, N. A.; Davis, B. J.; MacKie, K. (2012). "Δ9-Tetrahydrocannabinol (Δ9THC) attenuates mouse sperm motility and male fecundity”. British Journal of Pharmacology 165 (8): 2575– 2583. doi:10.1111/j.1476-5381.2011.01506.x. PMC 3423255. PMID 21615727. [10] Kuster, J. E., et al. (1993). “Aminoalkylindole binding in rat cerebellum: selective displacement by natural and synthetic cannabinoids”. The Journal of Pharmacology and Experimental Therapeutics 264 (3): 1352–1363. PMID 8450470. [11] Keeney BK, et al. (2012). “Sex differences in cannabinoid receptor-1 (CB1) pharmacology in mice selectively bred for high voluntary wheel-running behavior”. Pharmacology, Biochemistry and Behavior 101: 528–537. doi:10.1016/j.pbb.2012.02.017.
194.3 External links • Enzo Life Sciences Win 55,212-2 Data Sheet • The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. 2006 Jul 18; PubMed 16849427
259 • JNeurosci.org Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation • New Scientist: Hope for cannabis-based drug for Alzheimer’s
Chapter 195
WIN 56,098 WIN 56,098 is a chemical that is considered to be an aminoalkylindole derivative. It is a tricyclic aryl derivative that acts as a competitive antagonist at the CB2 cannabinoid receptor. Its activity at CB1 was significantly less effective. WIN 56,098 failed to antagonize any of the in vivo effects of THC.[1]
195.1 See also • WIN 55,212-2 • WIN 55,225
195.2 References [1] Howlett AC, Berglund B, Melvin LS (October 1995). “Cannabinoid Receptor Agonists and Antagonists”. Current Pharmaceutical Design 1 (3): 343–352.
260
Chapter 196
XLR-11 (drug) 196.4 See also
Not to be confused with Reaction Motors XLR11. XLR-11 (5"-fluoro-UR-144) is a drug that acts as a potent agonist for the cannabinoid receptors CB1 and CB2 with a Kᵢ of 24.2nM and a EC50 of 359nM at CB1 . It is a 3-(tetramethylcyclopropylmethanoyl)indole derivative related to compounds such as UR-144, A-796,260 and A-834,735, but it is not specifically listed in the patent or scientific literature alongside these other similar compounds,[2][3] and appears to have not previously been made by Abbott Laboratories, despite falling within the claims of patent WO 2006/069196.
• JWH-018 • STS-135 • UR-144
196.5 References [1] SD HB1024 [2] WO application 2006069196, Pace JM, Tietje K, Dart MJ, Meyer MD, “3-Cycloalkylcarbonyl indoles as cannabinoid receptor ligands”, published 2006-06-29, assigned to Abbott Laboratories
196.1 Detection A forensic standard for this compound is available, and a representative mass spectrum has been posted on Forendex.[4] An ELISA immunoassay technique for detecting XLR-11 and UR-144 in blood and urine as part of general drug screens has been developed by Randox Laboratories and Tulip Biolabs, Inc.[5]
[3] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (January 2010). “Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity”. J. Med. Chem. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781. [4] “XLR-11”. Structural, chemical, and analytical data on controlled substances. Southern Association of Forensic Scientists (SAFS).
196.2 Recreational use XLR-11 was instead first identified by laboratories in 2012 as an ingredient in synthetic cannabis smoking blends, and appears to be a novel compound invented specifically for grey-market recreational use. It was banned in New Zealand by being added to the temporary class drug schedule, effective from 13 July 2012.[6] It has also been banned in Florida as of 11 December 2012.[7] Arizona banned XLR-11 on April 3, 2013.[8]
[5] “Randox Toxicology launches ELISA for the detection of new generation Synthetic Cannabinoids (Spice) drugs UR144 and XLR-11”. Press Release. Randox Laboratories Ltd. 2013-04-29. [6] “CB-13, MAM-2201, AKB48, and XLR11 are classified as temporary class drugs”. Temporary Class Drug Notice. The Department of Internal Affairs: New Zealand Gazette. 2012-07-05. [7] “News Release - Attorney General Pam Bondi Outlaws Additional Synthetic Drugs”. News Release. State of Florida. 2012-12-11.
196.3 Toxicity XLR-11 has been linked to acute kidney injury in some s,[9] along with AM-2201.[10][11] 261
[8] State of Arizona, Office of the Governor. azgovernor.gov http://azgovernor.gov/dms//PR_040313_ SyntheticDrugs.pdf |url= missing title (help). Retrieved 2014-08-27.
262
[9] “Alphabet Soup, or the newer synthetic cannabinoids...”. The Dose Makes The Poison Blog. 11 December 2013. Retrieved 18 September 2014. [10] Bhanushali GK, Jain G, Fatima H, Leisch LJ, ThornleyBrown D (April 2013). “AKI associated with synthetic cannabinoids: a case series”. Clin J Am Soc Nephrol 8 (4): 523–6. doi:10.2215/CJN.05690612. PMID 23243266. [11] “Acute Kidney Injury Associated with Synthetic Cannabinoid Use — Multiple States, 2012”. Morbidity and Mortality Weekly Report. U.S. Centers for Disease Control and Prevention (CDC). 2013-92-13. Retrieved 2013-02-15. Check date values in: |date= (help)
CHAPTER 196. XLR-11 (DRUG)
Chapter 197
AM251 AM-251 is an inverse agonist at the CB1 cannabinoid receptor. AM-251 is structurally very close to SR141716A (rimonabant); both are biarylpyrazole cannabinoid receptor antagonists. In AM-251 the p-chloro group attached to the phenyl substituent at C-5 of the pyrazole ring is replaced with a p-iodo group. The resulting compound exhibits slightly better binding affinity for the CB1 receptor (with a Kᵢ value of 7.5nM) than SR141716A, which has a Kᵢ value of 11.5nM, AM-251 is, however, about twofold more selective for the CB1 receptor when compared to SR141716A.[1]
197.1 See also • Discovery and development of Cannabinoid Receptor 1 Antagonists
197.2 References [1] Lan, R., Liu, Q., Fan, P., et al. Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42 769-776 (1999). PubMed 10052983
263
Chapter 198
Aminoalkylindole Aminoalkylindoles (AAIs) are a family of cannabinergic compound that act as a cannabinoid receptor agonist. They were invented by pharmaceutical company Sterling-Winthrop in the early 1990s as potential non-steroidal anti-inflammatory agents.[1]
198.1 Legality Aminoalkylindole are now commonly found in synthetic cannabis designer drugs.[2] In the United States, the DEA added the aminoalkylindole JWH-200 to Schedule I of the Controlled Substances Act on 1 March 2011 for 12 months.[2][3]
198.2 References [1] Emmanuel S. Onaivi (2006). Marijuana and Cannabinoid Research: Methods and Protocols. Springer. pp. 128–. ISBN 978-1-59259-999-8. [2] “Synthetic Cannabinoids”. American Association for Clinical Chemistry. 2013-02-01. Retrieved 2013-11-17. [3] “Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I”. Federal . 2011-03-01. Retrieved 2013-11-17.
198.3 External links • Aminoalkylindoles, ChEBI
264
Chapter 199
Cannabipiperidiethanone Cannabipiperidiethanone, (E, or 1(N-methylpiperidin-2-ylmethyl)−3-(2methoxyphenylacetyl)indole), is a synthetic cannabinoid that has been found as an ingredient of “herbal” synthetic cannabis blends sold in Japan, alongside JWH122 and JWH-081. Its binding affinity was measured at the CB1 and CB2 receptors and it was found to have an IC50 of 591nM at CB1 and 968nM at CB2 , making it 2.3x and 9.4x weaker than JWH-250 at these two targets respectively.[1]
199.1 See also • AM-1220 • AM-1248 • AM-2233 • JWH-203 • RCS-8
199.2 References [1] Uchiyama N, Kikura-Hanajiri R, Goda Y (2011). “Identification of a novel cannabimimetic phenylacetylindole, cannabipiperidiethanone, as a designer drug in a herbal product and its affinity for cannabinoid CB₁ and CB₂ receptors”. Chemical & Pharmaceutical Bulletin 59 (9): 1203–5. doi:10.1248/b.59.1203. PMID 21881274.
265
Chapter 200
JWH-193 JWH-193 is a drug from the aminoalkylindole family which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sanofi-Winthrop in the early 1990s. JWH-193 has a binding affinity at the CB1 receptor of 6nM, binding around seven times more tightly than the parent compound JWH-200,[1] though with closer to twice the potency of JWH-200 in activity tests. A structural isomer of JWH-193 with the methyl group on the indole ring instead of the naphthoyl ring, was also found to be of similarly increased potency over JWH-200.[2][3]
• JWH-198
200.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. [2] Eissenstat MA, et al. (August 1995). “Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics”. Journal of Medicinal Chemistry 38 (16): 3094–105. doi:10.1021/jm00016a013. PMID 7636873. [3] Shim JY, et al. (November 1998). “Three-dimensional quantitative structure-activity relationship study of the cannabimimetic (aminoalkyl)indoles using comparative molecular field analysis”. Journal of Medicinal Chemistry 41 (23): 4521–32. doi:10.1021/jm980305c. PMID 9804691.
6-Methyl-JWH-200
200.1 See also • JWH-122 266
Chapter 201
JWH-198 JWH-198 is a drug from the aminoalkylindole family which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sanofi-Winthrop in the early 1990s. JWH-198 has a binding affinity at the CB1 receptor of 10nM, binding around four times more tightly than the parent compound JWH-200, which has no substitution on the naphthoyl ring.[1] It has been used mainly in molecular modelling of the cannabinoid receptors.[2][3]
201.1 See also • JWH-081 • JWH-193
201.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. [2] Eissenstat MA, et al. (August 1995). “Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics”. Journal of Medicinal Chemistry 38 (16): 3094–105. doi:10.1021/jm00016a013. PMID 7636873. [3] Shim JY, et al. (November 1998). “Three-dimensional quantitative structure-activity relationship study of the cannabimimetic (aminoalkyl)indoles using comparative molecular field analysis”. Journal of Medicinal Chemistry 41 (23): 4521–32. doi:10.1021/jm980305c. PMID 9804691.
267
Chapter 202
JWH-200 JWH-200 (WIN 55,225)[1] is an analgesic chemical from the aminoalkylindole family that acts as a cannabinoid receptor agonist. Its binding affinity at the CB1 receptor is 42nM, around the same as that of THC,[2] but its analgesic potency in vivo was higher than that of other analogues with stronger CB1 binding affinity in vitro,[3] around 3 times that of THC but with less sedative effect,[4] most likely reflecting favourable pharmacokinetic characteristics. It was discovered by, and named after, Dr. John W. Huffman. The US DEA temporarily declared JWH-200 a schedule I controlled substance on 1 March 2011 through 76 FR 11075, and permanently instated the same schedule on 9 July 2012 in the Section 1152 of the Food and Drug istration Safety and Innovation Act.[5] As of 26 June 2011, the drug is legal in Canada.[6]
202.1 See also • JWH-018 • JWH-073 • -47,497 • HU-210 • A-796,260 • WIN 55,212-2
202.2 References [1] Dutta, A. K. , E. A. ; Ryan, W.; Thomas, B. F.; Singer, M.; Compton, D. R.; Martin, B. R.; Razdan, R. K. (1997). “Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs)". Bioorganic & Medicinal Chemistry 5 (8): 1591–1600. doi:10.1016/S0968-0896(97)00111-9. PMID 9313864. [2] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411.
268
[3] Bell, MR, et al.. “Antinociceptive (aminoalkyl)indoles”. Journal of Medicinal Chemistry 34 (3): 1099–1110. doi:10.1021/jm00107a034. PMID 1900533. [4] Compton, DR, et al. (1992). “Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol”. Journal of Pharmacology and Experimental Therapeutics 263 (3): 1118–26. PMID 1335057. [5] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [6] http://laws.justice.gc.ca/en/C-38.8/
Chapter 203
Pravadoline Pravadoline (WIN 48,098) is an antiinflammatory and analgesic drug with an IC50 of 4.9 µM and a Kᵢ of 2511nM at CB1 , related in structure to non-steroidal antinflammtory drugs (NSAIDs) such as indometacin. It was developed in the 1980s as a new antiinflammatory and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase (COX). However, pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as a COX inhibitor. These effects were not blocked by opioid antagonists such as naloxone,[1] and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonists, the aminoalkylindoles.[2] Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself),[3] however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drug WIN 55,212-2, which is now widely used in scientific research.[4][5]
The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadolineinduced antinociception was not antagonized by naloxone (1 mg/kg, s.c.) and pravadoline did not bind to the opioid receptors at concentrations up to 10μM.[1]
203.2 See also • AM-630 (6-iodopravadoline) • WIN 54,461 (6-bromopravadoline) • WIN 55,212-2 • RCS-4 (1-pentyl-3-(4-methoxybenzoyl)indole)
203.3 References [1] Haubrich DR, et al. (1990). “Pharmacology of pravadoline: a new analgesic agent”. J. Pharmacol. Exp. Ther. 255 (2): 511–22. PMID 2243340. [2] Bell MR, et al. (1991). “Antinociceptive (aminoalkyl)indoles”. J. Med. Chem. 34 (3): 1099–110. doi:10.1021/jm00107a034. PMID 1900533. [3] Everett RM, et al. (1993). “Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: evidence of maleic acid-induced acute tubular necrosis”. Fundam Appl Toxicol 21 (1): 59–65. doi:10.1006/faat.1993.1072. PMID 8365586.
203.1 Animal studies istration of pravadoline on rats showed:[1] • Prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees Celsius (minimum effective dose, 100 mg/kg s.c.) • Prevented hyperalgesia in rats with Brewer’s Yeast injections during (Randall-Selitto test) (minimum effective dose, 1 mg/kg, p.o.) • Prevented the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50,41 mg/kg, p.o.) • Prevented the nociceptive response of bradykinininduced head and forepaw flexion (ED50, 78 mg/kg, p.o.) 269
[4] D'Ambra TE, et al. (1992). “Conformationally restrained analogues of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor”. J. Med. Chem. 35 (1): 124–35. doi:10.1021/jm00079a016. PMID 1732519. [5] Compton DR, et al. (1992). “Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol”. J. Pharmacol. Exp. Ther. 263 (3): 1118–26. PMID 1335057.
Chapter 204
RCS-4 RCS-4, or 1-pentyl-3-(4-methoxybenzoyl)indole, is a synthetic cannabinoid drug sold under the names SR-19, BTM-4, or Eric-4 (later shortened to E-4), but originally, OBT-199.
204.2 See also • AM-630 • AM-679 • RCS-8 • Pravadoline (WIN 48,098)
204.1 Legality RCS-4 was banned in Sweden on 1 October 2010 as a hazardous good harmful to health, after being identified as an ingredient in “herbal” synthetic cannabis products.[2][3] It was outlawed in Denmark on 11 March 2011.[4] In August 2011, New Zealand added not only RCS-4 but also its 1-butyl homologue, and the 2methoxybenzoyl isomers of both these compounds, to a temporary class drug schedule (i.e. equivalent to Class C but reviewed after 12 months, and with personal possession and use of small amounts decriminalised), which was newly created under the Misuse of Drugs Amendment Act 2011 ed a week earlier.[5][6][7]
204.3 References [1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 12 June 2011. [2] Swedish Code of Statutes Regulation (2010:1086). [3] Swedish Code of Statutes Regulation (2010:1086). (pdf) [4] http://laegemiddelstyrelsen.dk/~{}/media/ AC4F04EB48F74523A76BA84DAB9B6067.ashx [5] “Kronic ban ed by Parliament”. The New Zealand Herald. NZPA. 4 August 2011. Retrieved 4 November 2011. [6] “Synthetic cannabis off shelves by Wednesday”. The New Zealand Herald. NZPA. 9 August 2011. Retrieved 4 November 2011. [7] New Zealand Gazette. Tuesday 9 August 2011. Issue No 122, pp 3365-3366. Departmental Notices. Health. Misuse of Drugs Act 1975. Temporary Class Drug Notice.
RCS-4 and related analogues detected in synthetic cannabis blends
270
Chapter 205
Anandamide Anandamide, also known as Narachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word (and Hinduistic religious term) ananda, which means “joy, bliss, delight", and amide.[1][2] It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.[3] It is degraded primarily by the fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.[4][5]
205.1 History It was isolated and its structure first described in 1992 by W. A. Devane, Lumír Hanuš et al. who were working in a team led by Raphael Mechoulam at the Hebrew University of Jerusalem.[6]
205.2 Physiological functions Anandamide’s effects can be either central, in the brain, or peripheral, in other parts of the body. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[7] The latter are mainly involved in functions of the immune system. Cannabinoid receptors were originally discovered as being sensitive to Δ9 -tetrahydrocannabinol (Δ9 -THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors.
uterus. Therefore cannabinoids such as Δ9 -THC might influence processes during the earliest stages of human pregnancy.[9] Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and gonadotrophin levels, suggesting that these may be involved in the regulation of AEA (anandamide) levels.[10] Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.[11] Anandamide plays a role in the regulation of feeding behavior, and the neural generation of motivation and pleasure. In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[7][12] A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.[13] Some studies have linked anandamide release as a mechanism of analgesic effects induced by exercise, particularly by running.[14] In 1996, researchers discovered anandamide in chocolate. They also detected the presence of two substances that might mimic the effects of anandamide, Noleoylethanolamine and N-linoleoylethanolamine.[15]
205.3 Synthesis and degradation The human body synthesizes anandamide from Narachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.[16][17] Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD.[3]
Anandamide has been shown to impair working memory in rats.[8] Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief.
Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free arachidonic acid and ethanolamine. StudAnandamide is also important for implantation of the ies of piglets show that dietary levels of arachidonic acid early stage embryo in its blastocyst form into the and other essential fatty acids affect the levels of anan271
272 damide and other endocannabinoids in the brain.[18] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[19] This suggests that anandamide may play a role in the development of obesity, at least in rodents. Paracetamol (or acetaminophen in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form AM404.[20] This metabolite of paracetamol is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. As a result, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the analgesic effects of paracetamol.[21][22] There have been identified transport proteins for anandamide and its sister molecule 2-arachidonoylglycerol. These include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs).[23][24]
205.4 Medical benefits The Royal Society of Chemistry have stated that research indicates that AM1172 could potentially be developed into a drug that would increase the brain’s anandamide levels to help treat anxiety and depression.[25]
205.5 See also • Cannabinoids • Virodhamine • Tetrahydrocannabinol (THC) • 2-Arachidonoylglycerol • Fatty acid amide hydrolase • Endocannabinoid transporters • Raphael Mechoulam
205.6 References [1] Devane WA et al. (December 1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science 258 (5090): 1946–9. doi:10.1126/science.1470919. PMID 1470919. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help); |first8= missing |last8= in Authors list (help); |first9= missing |last9= in Authors list (help); |first10= missing |last10= in Authors list (help)
CHAPTER 205. ANANDAMIDE
[2] Mechoulam R, Fride E (1995). “The unpaved road to the endogenous brain cannabinoid ligands, the anandamides”. In Pertwee RG. Cannabinoid receptors. Boston: Academic Press. pp. 233–258. ISBN 0-12-551460-3. [3] Wang, J.; Ueda, N. (2009). “Biology of endocannabinoid synthesis system”. Prostaglandins & Other Lipid Mediators 89 (3–4): 112–119. doi:10.1016/j.prostaglandins.2008.12.002. PMID 19126434. [4] Gaetani, S.; Dipasquale, P.; Romano, A.; Righetti, L.; Cassano, T.; Piomelli, D.; Cuomo, V. (2009). “Chapter 5 The Endocannabinoid System as A Target for Novel Anxiolytic and Antidepressant Drugs”. “International Review of Neurobiology - 85”. International Review of Neurobiology 85. pp. 57–13. doi:10.1016/S00747742(09)85005-8. ISBN 9780123748935. [5] Hwang, J.; Adamson, C.; Butler, D.; Janero, D. R.; Makriyannis, A.; Bahr, B. A. (2009). “Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: A neuroprotective therapeutic Life Sciences 86 (15–16): 615–623. modality”. doi:10.1016/j.lfs.2009.06.003. PMC 2848893. PMID 19527737. [6] Mechoulam, WA; Hanus L; Breuer A; Pertwee RG; Stevenson LA; Griffin G; Gibson D; Mandelbaum A; Etinger A; Mechoulam R (December 1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science 258 (5090): 1946–9. Bibcode:1992Sci...258.1946D. doi:10.1126/science.1470919. PMID 1470919. [7] Pacher P, Batkai S, Kunos G; Bátkai; Kunos (2006). “The Endocannabinoid System as an Emerging Target of Pharmacotherapy”. Pharmacol Rev. 58 (3): 389– 462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947. [8] allet PE, Beninger RJ; Beninger (1996). “The endogenous cannabinoid receptor agonist anandamide impairs memory in rats”. Behavioural Pharmacology 7 (3): 276–284. doi:10.1097/00008877-199605000-00008. [9] Piomelli D (January 2004). “THC: moderation during implantation”. Nat. Med. 10 (1): 19–20. doi:10.1038/nm0104-19. PMID 14702623. [10] El-Talatini MR, Taylor AH, Konje JC; Taylor; Konje (April 2010). “The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle”. Fertil. Steril. 93 (6): 1989–96. doi:10.1016/j.fertnstert.2008.12.033. PMID 19200965. [11] Rapino, C.; Battista, N.; Bari, M.; Maccarrone, M. (2014). “Endocannabinoids as biomarkers of human reproduction”. Human Reproduction Update 20 (4): 501– 516. doi:10.1093/humupd/dmu004. ISSN 1355-4786. PMID 24516083. [12] Mahler SV, Smith KS, Berridge KC; Smith; Berridge (November 2007). “Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances 'liking' of a sweet
205.7. EXTERNAL LINKS
reward”. Neuropsychopharmacology 32 (11): 2267–78. doi:10.1038/sj.npp.1301376. PMID 17406653. [13] De Petrocellis L et al. (July 1998). “The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation”. Proc. Natl. Acad. Sci. U.S.A. 95 (14): 8375–80. doi:10.1073/pnas.95.14.8375. PMC 20983. PMID 9653194. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help) [14] http://www.harford.de/arne/articles/NeuroReport.pdf [15] di Tomaso E, Beltramo M, Piomelli D.; Beltramo; Piomelli (Aug 1996). “Brain cannabinoids in chocolate”. Nature 382 (6593): 677–8. doi:10.1038/382677a0. PMID 8751435. [16] Natarajan V, Reddy PV, Schmid PC, Schmid HH; Reddy; Schmid; Schmid (August 1982). “NAcylation of ethanolamine phospholipids in canine myocardium”. Biochim. Biophys. Acta 712 (2): 342–55. doi:10.1016/0005-2760(82)90352-6. PMID 7126608. [17] Cadas H, di Tomaso E, Piomelli D; Di Tomaso; Piomelli (February 1997). “Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain”. J. Neurosci. 17 (4): 1226–42. PMID 9006968. [18] Berger A et al. (May 2001). “Anandamide and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding Nacylethanolamines in piglets”. Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6402–6. doi:10.1073/pnas.101119098. PMC 33480. PMID 11353819. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help) [19] Osei-Hyiaman D et al. (May 2005). “Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity”. J. Clin. Invest. 115 (5): 1298–305. doi:10.1172/JCI23057. PMC 1087161. PMID 15864349. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help); |first8= missing |last8= in Authors list (help); |first9= missing |last9= in Authors list (help); |first10= missing |last10= in Authors list (help); |first11= missing |last11= in Authors list (help) [20] Högestätt, E. D.; Jönsson, B. A.; Ermund, A.; Andersson, D. A.; Björk, H.; Alexander, J. P.; Cravatt, B. F.; Basbaum, A. I.; Zygmunt, P. M. (2005). “Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System” (pdf). Journal of Biological Chemistry 280 (36): 31405–31412. doi:10.1074/jbc.M501489200. PMID 15987694.
273
[21] Bertolini A et al. (2006). “Paracetamol: new vistas of an old drug”. CNS Drug Rev 12 (3–4): 250– 75. doi:10.1111/j.1527-3458.2006.00250.x. PMID 17227290. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help) [22] Sinning C et al. (December 2008). “New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra5,8,11,14-enamide”. J. Med. Chem. 51 (24): 7800–5. doi:10.1021/jm800807k. PMID 19053765. |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help); |first5= missing |last5= in Authors list (help); |first6= missing |last6= in Authors list (help); |first7= missing |last7= in Authors list (help); |first8= missing |last8= in Authors list (help) [23] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). “Identification of intracellular carriers for the endocannabinoid anandamide”. Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565. [24] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgro, A.; Maccarrone, M. (2009). “Molecular identification of albumin and Hsp70 as cytosolic anandamidebinding proteins”. Chemistry & Biology 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. [25] http://www.rsc.org/chemistryworld/Issues/2004/July/ anandamide.asp
205.7 External links • Could anandamide be the missing link to “runner’s high"? Accessed 2008-10-18
Chapter 206
N-Arachidonoyl dopamine N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor[1] and the transient receptor potential V1 (TRPV1) ion channel. Its discovery was described in 2002 by an academic research group from Italy and the USA. It was found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50nM. The high potency makes it the putative endogenous TRPV1 agonist.[2]
206.1 See also • Endocannabinoid
206.2 References [1] Ralevic V (July 2003). “Cannabinoid modulation of peripheral autonomic and sensory neurotransmission”. European Journal of Pharmacology 472 (1–2): 1–21. doi:10.1016/S0014-2999(03)01813-2. PMID 12860468. [2] Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V (June 2002). “An endogenous capsaicinlike substance with high potency at recombinant and native vanilloid VR1 receptors”. Proceedings of the National Academy of Sciences of the United States of America 99 (12): 8400–5. doi:10.1073/pnas.122196999. PMC 123079. PMID 12060783.
206.3 External links • General information about NADA.
274
Chapter 207
2-Arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor.[1][2] It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994-1995, although had been discovered some time before that. The activities of Phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).
207.3 Pharmacology
Unlike anandamide, formation of 2-AG is calciumdependent and is mediated by the activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL).[2] 2-AG acts as a full agonist at the CB1 receptor.[10] At a concentration of 0.3nM, 2-AG induces a rapid, transient increase in intracellular free calcium in NG108-15 neuroblastoma X glioma cells through a CB1 receptor-dependent mechanism.[2] 2-AG is hydrolyzed in vitro by monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and the uncharacterized serine hydrolase enzymes ABHD6 and ABHD12.[11] The exact contribution of each of these enzymes to the termination of 2-AG signaling in vivo is unknown, 207.1 Occurrence though it is estimated that MAGL is responsible for ~85% of this activity in the brain.[12] There have been 2-AG, unlike anandamide (another endocannabinoid), is identified transport proteins for 2-arachidonoylglycerol present at relatively high levels in the central nervous sys- and anandamide. These include the heat shock proteins tem; it is the most abundant molecular species of monoa- (Hsp70s) and fatty acid binding proteins (FABPs).[13][14] cylglycerol found in mouse and rat brain (~5-10 nmol/g tissue).[2][3] Detection of 2-AG in brain tissue is complicated by the relative ease of its isomerization to 1-AG 207.4 Biosynthesis during standard lipid extraction conditions. It has been found in maternal bovine and human milk.[4] 2-Arachidonoylglycerol is synthesized from arachidonic acid-containing diacylglycerol (DAG), which is derived from the increase of inositol phospholipid metabolism by the action of diacylglycerol lipase. The molecule 207.2 Discovery can also be formed from pathways like the hydrolysis Shimon Ben-Shabat, of Ben-Gurion University, discov- derived (by diglyceride) from both phosphatidylcholine ered the chemical.[5] 2-AG was a known chemical com- (PC) and phosphatidic acid (PAs) by the action of DAG pound but its occurrence in mammals and its affinity for lipase and the hydrolysis of arachidonic acid-containing [15] the cannabinoid receptors were first described in 1994- lysophosphatidic acid by the action of a phosphatase. 1995. A research group at Teikyo University reported the affinity of 2-AG for the cannabinoid receptors in 1994-1995,[6][7] but the isolation of 2-AG in the canine gut was first reported in 1995 by the research group of Raphael Mechoulam at the Hebrew University of Jerusalem, which additionally characterized its pharmacological properties in vivo.[8] 2-Arachidonoylglycerol, next with Anandamide, was the second endocannabinoid discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system.[9]
207.5 See also • 2-Arachidonoyl glyceryl ether • Endocannabinoid transporters
207.6 References
275
276
207.6.1
CHAPTER 207. 2-ARACHIDONOYLGLYCEROL
Notes
[1] Stella N, Schweitzer P, Piomelli D (August 1997). “A second endogenous cannabinoid that modulates longterm potentiation”. Nature 388 (6644): 773–8. doi:10.1038/42015. PMID 9285589. [2] Sugiura T, Kodaka T, Nakane S, et al. (January 1999). “Evidence that the cannabinoid CB1 receptor is a 2arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds”. The Journal of Biological Chemistry 274 (5): 2794–801. doi:10.1074/jbc.274.5.2794. PMID 9915812. [3] Kondo S, Kondo H, Nakane S, et al. (June 1998). “2Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and independent mechanisms”. FEBS Letters 429 (2): 152–6. doi:10.1016/S0014-5793(98)00581-X. PMID 9650580. [4] Fride E, Bregman T, Kirkham TC. (April 2005). “Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood”. Experimental Biology and Medicine 230 (4): 225–234. PMID 15792943. [5] Pizzorno, Lara; MDiv; MA; LMT. “New Developments in Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam”. Longevity Medicine Review. Retrieved 2011-05-26. [6] Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Proceedings of Japanese conference on the Biochemistry of Lipids, 36, 71-74 (in Japanese) [7] Sugiura T, Kondo S, Sukagawa A, et al. (October 1995). “2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain”. Biochem. Biophys. Res. Commun. 215 (1): 89–97. doi:10.1006/bbrc.1995.2437. PMID 7575630. Retrieved 2009-01-27. [8] Mechoulam R, Ben-Shabat S, Hanuš L, et al. (June 1995). “Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors”. Biochemical pharmacology 50 (1): 83–90. doi:10.1016/0006-2952(95)00109-D. PMID 7605349. [9] Marzo, Vincenzo Di (2004). Cannabinoids (Neuroscience Intelligence Unit) (1st ed.). Georgetown, Texas: Springer. pp. 99, 181. ISBN 978-0-306-48228-1. [10] Savinainen JR, Järvinen T, Laine K, Laitinen JT (October 2001). “Despite substantial degradation, 2arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes”. British Journal of Pharmacology 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC 1572991. PMID 11588122. [11] Blankman JL, Simon GM, Cravatt BF (Decem“A comprehensive profile of brain ber 2007). enzymes that hydrolyze the endocannabinoid 2arachidonoylglycerol”. Chemistry & biology 14 (12): 1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC 2692834. PMID 18096503.
[12] Savinainen, JR; Saario, SM; Laitinen, JT (2012). “The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors”. Acta physiologica (Oxford, England) 204 (2): 267–76. doi:10.1111/j.17481716.2011.02280.x. PMC 3320662. PMID 21418147. [13] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). “Identification of intracellular carriers for the endocannabinoid anandamide”. Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565. [14] Oddi, S.; Fezza, F.; Pasquariello, N.; d'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgrò, A.; MacCarrone, M. (2009). “Molecular identification of albumin and Hsp70 as cytosolic anandamidebinding proteins”. Chemistry & Biology 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. [15] Köfalvi, Attila (2008). Cannabinoids and the Brain. New York City: Axel Springer AG. p. 15. ISBN 978-0-38774348-6. “2-Arachidonoylglycerol can be synthesized from arachidonic acid-containing diacylglycerol derived from increaded inositol phospholid metabolism by the action of a diacylglycerol lipase. 2-Arachidonoylglycerol can also be formed via other pathways such as the hydrolysis of the diaclygly derived from PC and phosphatidic acid by the action of a diacyglycerol lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic acid by the action of a phosphatase. The relative importance of these pathways may depend on the types of cells and stimuli.”
207.6.2 General references • Dinh TP, Carpenter D, Leslie FM, et al. (August 2002). “Brain monoglyceride lipase participating in endocannabinoid inactivation”. Proceedings of the National Academy of Sciences of the United States of America 99 (16): 10819– 24. doi:10.1073/pnas.152334899. PMC 125056. PMID 12136125.
Chapter 208
2-Arachidonyl glyceryl ether 2-Arachidonyl glyceryl ether (2-AGE, Noladin ether) is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem, Israel. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001.[1]
208.1 Discovery
receptors.[2] The presence of 2-AGE in body tissue is disputed. Although a research group from Teikyo University, Kanagawa, Japan could not detect it in the brains of mice, hamsters, guinea-pigs or pigs,[3] two other research groups successfully detected it in animal tissues.[4][5]
208.3 Pharmacology
Lumír Hanuš, Saleh Abu-Lafi, Ester Fride, Aviva Breuer, Zvi Vogel, Deborah E. Shalev, Irina Kustanovich, and Raphael Mechoulam found the endogenous agonist of the cannabinoid receptor type 1 (CB1) in 2000. The discovery was 100 gram of porcine brain, (approximately a single brain) was added to a mixture of 200 mL of chloroform and 200 mL of methanol and mixed in a laboratory blender for 2 minutes. 100 mL of Water was then added, and the mixing process continued for another minute. After this, the mixture was filtered. Two layers then formed and the layer of water-methanol was separated and evaporated when pressure was reduced. Synaptosomal membranes were prepared from 250g of the brains of Sabra male rats. A Hewlett Packard G 1800B GCD system that has a HP-5971 GC with electron ionization detector was used.[1]
2-AGE binds with a Kᵢ of 21 nM to the CB1 receptor[1] and 480 nM to the CB2 receptor.[6] It shows agonistic behaviour on both receptors and is a partial agonist for the TRPV1 channel.[7] After binding to CB2 receptors it inhibits adenylate cyclase and stimulates ERK-MAPK and regulates calcium transients.[8] In comparison to 2arachidonoyl glycerol, noladin is metabolically more stable resulting in a longer half-life.[9] It lowers Intraocular pressure,[9] increases the uptake of GABA in the globus pallidus of rats[10] and is neuroprotective by binding to and activation of PPARα.[11]
208.4 See also • 2-Arachidonoylglycerol
208.2 Production 208.5 References The production of the endocannabinoid is enhanced in normal, but not in endothelium-denuded rat aorta on reacting with carbachol, an parasympathomimetic drug. It potently reduces blood pressure in rats and may represent an endothelium-derived hypotension factor.[1] 2-Arachidonyl glyceryl ether’s structure can be determined by mass spectrometry and Rutherford backscattering spectrometry. It was confirmed by comparison with a synthetic sample of the endocannabinoid. It binds to the Cannabinoid receptor type 1 (Ki = 21.2 ± 0.5 nM), which causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice.[1] The endocannabinoid exhibits Ki values of 21.2 nM and >3 µM at the Cannabinoid receptor type 1 and the peripheral cannabinoid 277
[1] Hanus, L.; Abu-Lafi, S.; Fride, E.; Breuer, A.; Vogel, Z.; Shalev, D.; Kustanovich, I.; Mechoulam, R. (2001). “2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor”. Proceedings of the National Academy of Sciences 98 (7): 3662–3665. doi:10.1073/pnas.061029898. PMC 31108. PMID 11259648. [2] “2-Arachidonyl Glycerol ether · Noladin; 2-AG ether (CAS 222723-55-9) || Cayman Chemical”. Cayman Chemical. Retrieved 2011-05-29. [3] Oka S, Tsuchie A, Tokumura A et al. (2003). “Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various
278
CHAPTER 208. 2-ARACHIDONYL GLYCERYL ETHER
mammalian species”. J. Neurochem. 85 (6): 1374– 81. doi:10.1046/j.1471-4159.2003.01804.x. PMID 12787057. [4] Fezza F, Bisogno T, Minassi A, Appendino G, Mechoulam R, Di Marzo V (2002). “Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues”. FEBS Lett. 513 (2–3): 294–8. doi:10.1016/S00145793(02)02341-4. PMID 11904167. [5] Richardson D, Ortori CA, Chapman V, Kendall DA, Barrett DA (2007). “Quantitative profiling of endocannabinoids and related compounds in rat brain using liquid chromatography-tandem electrospray ionization mass spectrometry”. Anal. Biochem. 360 (2): 216–26. doi:10.1016/j.ab.2006.10.039. PMID 17141174. [6] Shoemaker JL, Joseph BK, Ruckle MB, Mayeux PR, Prather PL (2005). “The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors”. J. Pharmacol. Exp. Ther. 314 (2): 868–75. doi:10.1124/jpet.105.085282. PMID 15901805. [7] Duncan M, Millns P, Smart D, Wright JE, Kendall DA, Ralevic V (2004). “Noladin ether, a putative endocannabinoid, attenuates sensory neurotransmission in the rat isolated mesenteric arterial bed via a non-CB1/CB2 Gi/o linked receptor”. Br. J. Pharmacol. 142 (3): 509– 18. doi:10.1038/sj.bjp.0705789. PMC 1574960. PMID 15148262. [8] Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL (2005). “Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors”. J. Pharmacol. Exp. Ther. 315 (2): 828–38. doi:10.1124/jpet.105.089474. PMID 16081674. [9] Laine K, Järvinen K, Mechoulam R, Breuer A, Järvinen T (2002). “Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid”. Invest. Ophthalmol. Vis. Sci. 43 (10): 3216–22. PMID 12356827. [10] Venderova K, Brown TM, Brotchie JM (2005). “Differential effects of endocannabinoids on [(3)H]-GABA uptake in the rat globus pallidus”. Exp. Neurol. 194 (1): 284–7. doi:10.1016/j.expneurol.2005.02.012. PMID 15899265. [11] Sun Y, Alexander SP, Garle MJ et al. (2007). “Cannabinoid activation of PPARα; a novel neuroprotective mechanism”. Br. J. Pharmacol. 152 (5): 734– 43. doi:10.1038/sj.bjp.0707478. PMC 2190030. PMID 17906680.
208.6 External links • Commercial supplier of Noladin ether
Chapter 209
Oleamide Oleamide is an amide of the fatty acid oleic acid. It is an endogenous substance: it occurs naturally in the body of animals. It accumulates in the cerebrospinal fluid during sleep deprivation and induces sleep in animals.[4] It is being studied as a potential medical treatment for mood and sleep disorders, and cannabinoidregulated depression.[5][6]
[2] http://www.chemicalbook.com/ ProductChemicalPropertiesCB3238286_EN.htm [3] http://www.chemspider.com/Chemical-Structure. 4446508.html [4] Salvador Huitron-Resendiz, Lhys Gombart, Benjamin F. Cravatt, and Steven J. Henriksen (2001). “Effect of Oleamide on Sleep and Its Relationship to Blood Pressure, Body Temperature, and Locomotor Activity in Rats”. Experimental Neurology 172 (1): 235–243. doi:10.1006/exnr.2001.7792. PMID 11681856.
The mechanism of action of oleamide’s sleep inducing effects is an area of current research. It is likely that oleamide interacts with multiple neurotransmitter systems.[7] Oleamide is structurally related to the endogenous cannabinoid anandamide, and has the ability to bind to the CB1 receptor as a full agonist.
[5] Methods of treating anxiety and mood disorders with oleamide - US Patent 6359010 [6] Raphael Mechoulam, Ester Fride, Lumír Ondřej Hanuš, Tzviel Sheskin, Tiziana Bisogno, Vincenzo Di Marzo, Michael Bayewitch and Zvi Vogel (1997). “Anandamide may mediate sleep induction”. Nature 389 (6646): 25–26. doi:10.1038/37891. PMID 9288961.
Synthetically produced oleamide has a variety of industrial uses including as a slip agent, a lubricant, and a corrosion inhibitor.[8] Oleamide was originally characterized as an endogenous bioactive substance, isolated from the cerebrospinal fluid of sleep deprived cats. It was characterised in 1995 by Benjamin Cravatt III and Richard Lerner at The Scripps Research Institute in La Jolla, CA.[9]
[7] Fedorova I, Hashimoto A, Fecik RA et al. (2001). “Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems”. J. Pharmacol. Exp. Ther. 299 (1): 332–42. PMID 11561096.
Oleamide was found by researchers to be leaking out of polypropylene plastics used in laboratory experiments, affecting experimental results.[10] Since polypropylene is used in a wide number of food containers such as those for yogurt, the problem is being studied.[11]
[8] Surfactants : Westco Oleamide a Slip Agent In Polyethylene Films [9] Cravatt BF, et al. (June 1995). “Chemical characterization of a family of brain lipids that induce sleep”. Science 268 (5216): 1506–9. doi:10.1126/science.7770779. PMID 7770779.
A chemical analysis of 44 products containing synthetic cannabinoid drugs marketed as “herbal incense” revealed oleamide in 7 of the products tested.[12] [10] McDonald, RG. et al. (2008). “Bioactive Contaminants
Leach from Disposable Laboratory Plasticware”. Science 322 (5903): 917. doi:10.1126/science.1162395. PMID 18988846.
209.1 See also • Anandamide • Fatty acid amide hydrolase • Virodhamine
209.2 References
[11] Mittelstaedt, Martin (6 November 2008). “Researchers Raise Alarm After Chemical Leak Found In Common Plastic”. Globe and Mail. Retrieved 10 June 2013. [12] Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Ogata, Jun; Goda, Yukihiro (2010). “Chemical analysis of synthetic cannabinoids as designer drugs in herbal products”. Forensic Science International 198 (1–3): 31–8. doi:10.1016/j.forsciint.2010.01.004. PMID 20117892.
[1] Oleamide at chemicalland21.com
279
Chapter 210
RVD-Hpα RVD-Hpα is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-ValAsn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist.[1] All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide.[2] Recently it was shown that RVD-Hpα (also called Pepcan-12) is an potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans) [3]
210.1 References [1] Heimann, A.; Gomes, I.; Dale, C.; Pagano, R.; Gupta, A.; De Souza, L.; Luchessi, A.; Castro, L.; Giorgi, R.; Rioli, V.; Ferro, E. S.; Devi, L. A. (2007). “Hemopressin is an inverse agonist of CB1 cannabinoid receptors”. Proceedings of the National Academy of Sciences of the United States of America 104 (51): 20588–20593. Bibcode:2007PNAS..10420588H. doi:10.1073/pnas.0706980105. PMC 2154475. PMID 18077343. [2] Gomes, I.; Grushko, J.; Golebiewska, U.; Hoogendoorn, S.; Gupta, A.; Heimann, A.; Ferro, E.; Scarlata, S.; Fricker, L.; Devi, L. A. (2009). “Novel endogenous peptide agonists of cannabinoid receptors”. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 (9): 3020– 3029. doi:10.1096/fj.09-132142. PMC 2735371. PMID 19380512. [3] Bauer, M.; Chicca, A.; Tamborrini, M.; Eisen, D.; Lerner, R.; Lutz, B.; Poetz, O.; Pluschke, G.; Gertsch, J. (2012). “Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors”.
280
Journal of Biological Chemistry 287 (44): 36944–36967. doi:10.1074/jbc.M112.382481. PMC 3481297. PMID 22952224.
Chapter 211
Virodhamine Virodhamine (O-arachidonoyl ethanolamine) is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. O-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine ed by an ester linkage, the opposite of the amide linkage found in anandamide. Based on this opposite orientation, the molecule was named virodhamine from the Sanskrit word virodha, which means opposition. It acts as an antagonist of the CB1 receptor and agonist of the CB2 receptor. Concentrations of virodhamine in the human hippocampus are similar to those of anandamide, but they are 2to 9-fold higher in peripheral tissues that express CB2 . Virodhamine lowers body temperature in mice, demonstrating cannabinoid activity in vivo.[1]
211.1 See also • Anandamide • Oleamide
211.2 References [1] Porter AC, Sauer JM, Knierman MD et al. (2002). “Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor”. J. Pharmacol. Exp. Ther. 301 (3): 1020– 4. doi:10.1124/jpet.301.3.1020. PMID 12023533. Retrieved 2007-10-31.
281
Chapter 212
HU-320 HU-320 is a drug related to cannabidiol, which has strong antiinflammatory and immunosuppressive properties while demonstrating no psychoactive effects.[1]
212.1 See also • HU-210 • HU-308 • HU-331
212.2 References [1] Sumariwalla PF, et al. (2004). “A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis”. Arthritis Rheum. 50 (3): 985–998. doi:10.1002/art.20050. PMID 15022343.
282
Chapter 213
HU-336 HU-336 is a strongly antiangiogenic compound, significantly inhibiting angiogenesis at concentrations as low as 300nM. It inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro- and antiangiogenic cytokines and their receptors. HU-336 is highly effective against tumor xenografts in nude mice.[1]
213.1 See also • HU-210 • HU-331 • HU-345
213.2 References [1] Natalya M. Kogan, et al. (2006). “A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells”. Molecular Pharmacology 70 (1): 51–59. doi:10.1124/mol.105.021089. PMID 16571653.
283
Chapter 214
HU-345 HU-345 (cannabinol quinone) is a drug that is able to inhibit aortic ring angiogenesis more potently than its parent compound cannabinol.[1][2]
214.1 See also • HU-210 • HU-336
214.2 References [1] Natalya M. Kogan, et al. (2006). “A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells”. Molecular Pharmacology 70 (1): 51–59. doi:10.1124/mol.105.021089. PMID 16571653. [2] US patent 0092584, Mechoulam R, Kogan NM, Rabinowitz R, Schlesinger M, “Therapeutic Use of Quinonoid Derivatives of Cannabinoids”, granted 2011-04-21
284
Chapter 215
Raphael Mechoulam Raphael Mechoulam (Hebrew: ( )רפאל משולםborn 1930) is an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of Jerusalem in Israel. Mechoulam is best known for his work (together with Y. Gaoni) in the isolation, structure elucidation and total synthesis of Δ9 -tetrahydrocannabinol, the main active principle of cannabis and for the isolation and the identification of the endogenous cannabinoids anandamide from the brain and 2-arachidonoyl glycerol (2-AG) from peripheral organs together with his students, postdocs and collaborators.
215.2 Research Raphael Mechoulam’s major scientific interest is the chemistry and pharmacology of cannabinoids. He and his research group succeeded in the total synthesis of the major plant cannabinoids Δ9 -tetrahydrocannabinol, cannabidiol, cannabigerol and various others. Another research project initiated by him led to the isolation of the first described endocannabinoid anandamide which was isolated and characterized by two of his postdoctoral researchers, Lumír Ondřej Hanuš and William Devane. Another endogenous cannabinoid, 2-AG, was soon discovered by Shimon Ben-Shabat, one of his PhD students. He published more than 350 scientific articles.
215.1 Biography 215.3 References Raphael Mechoulam was born in Sofia, Bulgaria on November 5, 1930. His father was a physician and head of a local hospital, while his mother “who had studied in Berlin, enjoyed the life of a well-to-do Jewish family”. He attended an “American Grade School” until his parents were forced to leave their hometown because of antisemitic laws and his father was subsequently sent to a concentration camp, from which he survived. After the communist takeover of hitherto pro-German Bulgaria in 1944 he studied chemical engineering, which he “disliked.” In 1949 his family immigrated to Israel where he later studied chemistry. He gained his first research experience in the Israeli Army working on insecticides.[2]
[1] http://www.nndb.com/people/699/000210069/ [2] Conversation with Raphael Mechoulam, Addiction (Wiley) 102 (6), 2007: 887–893, doi:10.1111/j.13600443.2007.01795.x, PMID 17523982 [3] Michael Denman (2007), “MECHOULAM, RAPHAEL”, Encyclopaedia Judaica 13 (2nd ed.), Thomson Gale, pp. 711–712
215.4 Podcasts
He received his M.Sc. in biochemistry from the Hebrew University of Jerusalem (1952), and his Ph.D. at the Weizmann Institute, Reḥovot (1958), with a thesis on the chemistry of steroids. After postdoctoral studies at the Rockefeller Institute, New York (1959–60), he was on the scientific staff of the Weizmann Institute (1960–65), before moving to the Hebrew University of Jerusalem, where he became professor (1972) and Lionel Jacobson Professor of Medicinal Chemistry from 1975. He was rector (1979–82) and pro-rector (1983–85). In 1994 he was elected a member of the Israel Academy of Sciences. His honors include the Kolthof Prize in chemistry from the Haifa Technion (1994) and the Israel Prize in chemistry (2000).[3] 285
• A podcast (open access) of an interview with Raphael Mechoulam, recorded by Steve Alexander for the British Journal of Pharmacology on the occasion of his 80th Birthday in November 2010.
Chapter 216
John W. Huffman John William Huffman (born 1932) is a professor emeritus of organic chemistry at Clemson University who first synthesised many novel cannabinoids.[1] His research, funded by the National Institute on Drug Abuse, was focused on making a drug to target endocannabinoid receptors in the body.[2]
216.2 See also • List of JWH cannabinoids
216.3 References
Beginning in 1984, Huffman and his team of researchers began developing cannabinoid compounds to aid in research of multiple sclerosis, HIV/AIDS, and chemotherapy. Over the course of twenty years, Huffman and his team developed 450 synthetic cannabinoid compounds which were used to test the effect of cannabinoid receptors in the brain and other organs. Ultimately, the cannabinoid research provided understanding of diseases and information for medication development. In the late 2000s, two of Huffman’s cannabinoid compounds began being sold in as marijuana alternatives known as K2 and Spice. “I figured once it got started in it was going to spread. I'm concerned that it could hurt people,” Huffman said. “I think this was something that was more or less inevitable. It bothers me that people are so stupid as to use this stuff”. Huffman may have developed these compounds for scientific research, but now he gets blamed for its abuse. As JWH-018 is more potent and easy to make, Huffman believes it is a more widely used synthetic cannabinoid of the JWH series.[3]
216.1 Law enforcement More than half a dozen countries have banned herbal blends containing synthetic cannabinoids since 2008. Many countries also consider banning these mixtures. In the US, the states of Kansas, Georgia, Alabama, Tennessee, Missouri, Louisiana, Mississippi, Arkansas, and New York banned K2, herbal incense. JWH-018 is currently banned by controlled substances act. [3] Law enforcement officials in Canada asked Huffman to serve as a consultant and expert witness. He received numerous media queries and requests for analytical help from law enforcement officials.[3] 286
[1] “Clemson University :: Department of Chemistry”. Clemson.edu. Retrieved 2010-08-24. [2] Brownstein, Joseph (March 17, 2010), K2 Giving People Another Dangerous Way to Get High, ABC News [3] Wang, Linda (June 28, 2010). “C&EN Talks With John W. Huffman”. Chemical & Engineering News 88 (26): 43. Retrieved October 8, 2011.
Chapter 217
JWH-007 JWH-007 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It was the most active of the first group of N-alkyl naphoylindoles discovered by the team led by John W Huffman, several years after the family was initially described with the discovery of the N-morpholinylethyl compounds pravadoline (WIN 48,098), WIN 55,225 (JWH-200) and WIN 55,212-2 by the Sterling Winthrop group.[1] Several other N-alkyl substituents were found to be active by Huffman’s team including the n-butyl, n-hexyl, 2-heptyl and cyclohexylethyl groups,[2] but it was subsequently determined that the 2-methyl group on the indole ring is not required for CB1 binding, and tends to increase affinity for CB2 instead.[3][4] Consequently the 2-desmethyl derivative of JWH-007, JWH-018 has slightly higher binding affinity for CB1 , with an optimum binding of 9.00nM at CB1 and 2.94nM at CB2 , and JWH-007 displayed optimum binding of 9.50nM at CB1 and 2.94nM at CB2 .[5]
217.3 References
217.1 Law Sweden: JWH-007 was banned in Sweden on 1 October 2010 as a hazardous good harmful to health, after being identified as an ingredient in “herbal” synthetic cannabis products.[6][7] Poland: JWH-007 is illegal in Poland since 08.06.2010 on the basis of 'Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii' published in Dz.U. 2011 nr 105 poz. 614[8]
217.2 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073 287
[1] Compton, D. R., et al. (1992). “Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol”. The Journal of Pharmacology and Experimental Therapeutics 263 (3): 1118–1126. PMID 1335057. [2] Huffman JW, Dong D. Design, Synthesis and Pharmacology of Cannabimimetic Indoles. Bioorganic and Medicinal Chemistry Letters. 1994;4(4):563-566. [3] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455. [4] Huffman, J. W.; Padgett, L. W. (2005). “Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes”. Current medicinal chemistry 12 (12): 1395–1411. doi:10.2174/0929867054020864. PMID 15974991. [5] Aung, M. M., et al. (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding”. Drug and alcohol dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [6] Swedish Code of Statutes Regulation (2010:1086). [7] Swedish Code of Statutes Regulation (2010:1086). (pdf) [8] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". ISAP. Retrieved 12 June 2011.
Chapter 218
Naphthoylindole JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM678[1] is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2 . It produces effects in animals similar to those of THC, a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products such as “legal cannabis herbal incense blends” which in some countries are sold legally as “incense”, labeled “not for human consumption”.[2][3][4][5][6]
218.2.1 Pharmacokinetics JWH-018 istered to rats resulted in the excretion of an indole-N-desalkyl metabolite as well as several hydroxylated metabolites in urine. The highest signals were observed for the hydroxylated N-desalkyl metabolites. Hydroxylation took place on the side chain and in both aromatic systems, the naphthalene and the indole rings, as could be shown by mass shift of the corresponding fragments and by MS3 experiments.[13] Human metabolites were similar although most metabolism took place on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with glucuronide.[14]
218.1 History John W. Huffman, an organic chemist at Clemson University, synthesized analogues and metabolites of Δ9 tetrahydrocannabinol (THC), the principal active component of cannabis. JWH-018 is one of these analogues, with studies showing an affinity for the cannabinoid (CB1 ) receptor five times greater than that of THC. Cannabinoid receptors are found in mammalian brain and spleen tissue; however, the structural details of the active sites are currently unknown.[7][8] On December 15, 2008, it was reported by the German pharmaceutical company THC Pharm that JWH-018 was found as one of the active components in at least three versions of the herbal blend Spice, which has been sold as an incense in a number of countries around the world since 2002.[9][10][11] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[12]
218.3 Usage At least one case of JWH-018 dependence has been reported by the media.[2] The consumed JWH-018 daily for eight months. Withdrawal symptoms were similar to those experienced as a result of cannabis dependence. JWH-018 has been shown to cause profound changes in CB1 receptor density following istration, causing desensitization to its effects more rapidly than related cannabinoids.[6] On October 15, 2011, Anderson County coroner Greg Shore attributed the death of a South Carolina college basketball player to “drug toxicity and organ failure” caused by JWH-018.[15] An email dated Nov 4, 2011 concerning the case was finally released by the city of Anderson S.C. on Dec 16, 2011 under the Freedom of Information Act after multiple requests by media to see the information had been denied.[16]
Compared to THC, which is a partial agonist at CB1 receptors, JWH-018 (and many of its analogues) are full agonists. THC has been shown to inhibit GABA receptor neurotransmission in the brain via several pathways.[17][18] JWH-018 may cause intense anxiety, ag218.2 Pharmacology itation, and, in rare cases (generally with non-regular JWH s), has been assumed to have been the cause of JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotranscannabinoid receptors, with a reported binding affinity of mission more effectively than THC. Cannabinoid recep9.00 ± 5.00 nM at CB1 and 2.94 ± 2.65 nM at CB2 .[3] tor full agonists may present serious dangers to the 288
218.6. SYNTHESIS
289
when used to excess.[19] Various physical and psychological adverse effects have been reported from JWH-018 use. One study reported psychotic relapses and anxiety symptoms in welltreated patients with mental illness following JWH-018 inhalation.[20] Due to concerns about the potential of JWH-018 and other synthetic cannabinoids to cause psychosis in vulnerable individuals, it has been recommended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51] nesses (like a past or family history of psychosis) not use these substances.[21]
218.6 Synthesis 218.7 See also
218.4 Detection in biological fluids JWH-018 usage is readily detected in urine using “spice” screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and carboxyl metabolites.[22] JWH-018 will not be detected by older methods employed for detecting THC and other cannabis terpenoids. Determination of the parent drug in serum or its metabolites in urine has been accomplished by GC-MS or LC-MS. Serum JWH-018 concentrations are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolite is a compound that is monohydroxylated on the omega minus one carbon atom of the alkyl side chain. A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of 6 s of the drug at concentrations of 6–50 μg/L, primarily as a glucuronide conjugate.[23][24][25][26][27][28][29][30][31]
218.5 Legal status
• AM-2201 • BB-22 (drug) • JWH-073 • JWH-250 • JWH-200 • PB-22 • SDB-001
218.8 References [1] “Department of Justice :: Drug Enforcement istration”. 2011-03-01. Retrieved 2011-03-02. [2] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal Phenomena and Dependence Syndrome After the Consumption of “Spice Gold"". Dtsch Arztebl Int 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [3] Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [4] US patent 6900236, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200505-31 [5] US patent 7241799, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200707-10
JWH-018 powder as it was commonly sold online
[6] Atwood, B.K., et al., “JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB1 receptor agonist.” British Journal of Pharmacology, Vol. 160, No. 3. 585-593. 2010.
290
CHAPTER 218. NAPHTHOYLINDOLE
[7] “Clemson University :: Department of Chemistry”. Clemson.edu. Retrieved 2010-08-23. [8] “Drugs Forum”. Drugs Forum. Retrieved 2010-08-23. [9] Gefährlicher Kick mit Spice (German) [10] Erstmals Bestandteile nachgewiesen (German)
der
Modedroge
“Spice”
[11] Spice enthält chemischen Wirkstoff (German) [12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L, Beuerle T (30 October 2009). “Spice: A never ending story?". Forensic Science International (Forensic Science International) 191 (1): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [13] T. Kraemer, et al. Studies on the metabolism of JWH018 and of a homologue of 47,497, pharmacologically active ingredients of different misused incense (“Spice”) using GC-MS and LC-MSn techniques (Institute of Legal Medicine, Saarland University, 66421 Homburg, http://www.gtfch.org/cms/images/ stories/media/tk/tk76_2/abstractsvortraege.pdf [14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010). “Detection of JWH-018 metabolites in smoking mixture post-istration urine”. Forensic Science International 200 (1–3): 141–7. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [15] wyff4.com, Coroner: Synthetic Pot Killed College Athlete, posted 10/14/11, accessed 12/22/11, http://www. wyff4.com/news/29497549/detail.html, [16] Mayo, Nikie, “City Releases Email in Lamar Jacks Case”, independentmail.com, posted Dec 16, 2011, accessed 12/22/11, http://www.independentmail.com/news/2011/ dec/16/city-releases-email-lamar-jack-case/ [17] Laaris N, Good CH, Lupica CR (July–August 2010). "Δ9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus”. Neuropharmacology 59 (1–2): 121–127. doi:10.1016/j.neuropharm.2010.04.013. PMC 2882293. PMID 20417220. [18] Hoffman AF, Lupica CR (2000-04-01). “Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus”. The Journal of Neuroscience 20 (7): 2470–2479. ISSN 0270-6474. PMID 10729327. Retrieved 2011-07-26. [19] European Monitoring Centre for Drugs and Drug Addiction. “Understanding the Spice Phenomenon.” 2009. ISBN 978-92-9168-411-3. [20] Every-Palmer, S. Synthetic cannabinoid use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011. [Epub ahead of print]. [21] Every-Palmer S (2010). “WARNING: LEGAL SYNTHETIC CANNABINOID-RECEPTOR AGONISTS SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS IN VULNERABLE INDIVIDUALS”. Addiction 105: doi:10.1111/j.1360-0443.2010.03119.x. 1859–1860. PMID 20840203.
[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/ content/37/5/284.abstract, https://www.caymanchem. com/app/template/Product.vm/catalog/580210; http://www.randoxtoxicology.com/Products/Elisa-p-50, http://tulipbiolabs.com/our-product-areas/ synthetic-cannabinoids and others. [23] Möller I, et al. Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls. Drug Test. Anal. Sep 24, 2010. [Epub ahead of print] [24] Teske J, et al. Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatography-tandem mass spectrometry. J Chrom. B 878: 2659-2663, 2010. [25] Auwärter V, Dresen S, Weinmann W, Müller M, Pütz M, Ferreirós N (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. Free version [26] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal phenomena and dependence syndrome after the consumption of “spice gold"". Deutsches Arzteblatt international 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). “Detection of JWH-018 metabolites in smoking mixture postistration urine”. Forensic Science International 200 (1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [28] Beuck S, Möller I, Thomas A, Klose A, Schlörer N, Schänzer W, Thevis M (August 2011). “Structure characterisation of urinary metabolites of the cannabimimetic JWH-018 using chemically synthesised reference material for the of LC-MS/MS-based drug testing”. Anal Bioanal Chem 401 (2): 493–505. doi:10.1007/s00216-011-4931-5. PMID 21455647. [29] Moran CL, Le VH, Chimalakonda KC, Smedley AL, Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski PJ, Wessinger WD, Fantegrossi WE, Prather PL, James LP, Radominska-Pandya A, Moran JH (June 2011). “Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine”. Anal. Chem. 83 (11): 4228–36. doi:10.1021/ac2005636. PMID 21506519. [30] Logan BK, et al. Identification of primary JWH018 and JWH-073 metabolites in human urine. NMS Labs Technical Bulletin, May 25, 2011. http://toxwiki.wikispaces.com/file/view/JWH_ metabolites_Technical_Bulletin_Final_v1.1.pdf [31] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 10th edition, Biomedical Publications, Seal Beach, CA, 2014, p. 1863. [32]
218.9. EXTERNAL LINKS
291
[33] “Controlled Drugs and Substances Act”. Laws.justice.gc.ca. 2010-08-16. Retrieved 201008-23. [34] *** Tiedote/Valtioneuvoston viestintäyksikkö: VALTIONEUVOSTON YLEISISTUNTO 1.3.2012 *** (Finnish) [35] “EMCDDA | Drug profile: Synthetic cannabinoids and 'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved 2010-08-23. [36] http://www.afssaps.fr/var/afssaps_site/storage/original/ application/d23d05edc58479d91c803b496017f073.pdf [37] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19. Januar 2009, S. 49–50. [38] Many head shop products banned - Irish Times. [39] http://www.politicheantidroga.it/ comunicazione/comunicati/2010/luglio/spice, -n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian) [40] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are [41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465. html [42]
(2 July 2009). “1 ‘5- - ’ . Retrieved 18 February 2010.
".
[43] http://www.regeringen.se/sb/d/12102/a/130038 (Swedish) [44] “Illicit Drug Report of Turkey 2010”. Department of Anti-smuggling and Organised Crime. Retrieved 201205-03.(Turkish) [45] “Decision of the Council of Ministers, Enactment 2011/1310”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [46] “Attachment to Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [47] “Decision of the Council of Ministers, Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [48] Ford, Richard (2009-12-23). “Three legal highs banned after deaths linked to the drugs”. The Times (London). Retrieved 2010-05-07. [49] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [50]
218.9 External links • JWH-018 Report Psychonaut Web Mapping Research Project • of legal high
Chapter 219
JWH-019 JWH-019 is an analgesic chemical from the naphthoylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is the N1-hexyl homologue of the more common synthetic cannabinoid compound JWH-018. Unlike the butyl homologue JWH-073, which is several times weaker than JWH-018, the hexyl homologue is only slightly less potent, although extending the chain one carbon longer to the heptyl homologue JWH-020 results in dramatic loss of activity. These results show that the optimum side chain length for CB1 binding in the naphthoylindole series is the five-carbon pentyl chain, shorter than in the classical cannabinoids where a seven-carbon heptyl chain produces the most potent compounds. This difference is thought to reflect a slightly different binding conformation adopted by the naphthoylindole compounds as compared to the classical cannabinoids, and may be useful in characterising the active site of the CB1 and CB2 receptors.[2][3][4]
219.2 See also • JWH-007 • JWH-018 • JWH-073 • JWH-200
219.3 References
219.1 Legal Status 219.1.1
Poland
[4] Ashton JC, Wright JL, Martland JM, Tyndall JD (2008). “Cannabinoid CB1 and CB2 receptor ligand specificity and the development of CB2-selective agonists”. Current Medicinal Chemistry 15 (14): 1428–43. doi:10.2174/092986708784567716. PMID 18537620.
Sweden
JWH-019 is illegal in Sweden
219.1.3
UK
[5] http://crimlaw.blogspot.com/2011/04/ no-more-synthetic-cannabinoid.html
JWH-019 is Class B in the United Kingdom.
219.1.4
[2] Aung MM, et al. (August 2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding”. Drug and Alcohol Dependence 60 (2): 133–40. doi:10.1016/S03768716(99)00152-0. PMID 10940540. [3] Poso A, Huffman JW (January 2008). “Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands”. British Journal of Pharmacology 153 (2): 335–46. doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID 17982473.
In Poland, JWH-019 is I-N (Poland)[1]
219.1.2
[1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 12 June 2011.
USA
JWH-019 is not controlled federally in the United States, however if intended for human consumption, possession or sales could possibly be prosecuted under the Federal Analog Act. JWH-019 is illegal in Virginia.[5] 292
Chapter 220
JWH-030 JWH-030 is a research chemical which is a cannabinoid receptor agonist.[1] It has analgesic effects and is used in scientific research.[2] It is a partial agonist at CB1 receptors, with a Ki of 87nM, making it roughly half the potency of THC.[3] It was discovered and named after Dr. John W. Huffman.
220.1 See also • JWH-147
220.2 References [1] Lainton JAH, Huffman JW, Martin BR, Compton DR. Tetrahedron Letters. 1995; 36:1401. [2] Pertwee RG, Griffin, G, Lainton JAH, Huffman JW. European Journal of Pharmacology. 1995; 284:241. [3] Griffin, G.; Atkinson, P. J.; Showalter, V. M.; Martin, B. R.; Abood, M. E. (1998). “Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5'O-(3-35Sthio)-triphosphate binding assay in rat cerebellar membranes”. The Journal of Pharmacology and Experimental Therapeutics 285 (2): 553–560. PMID 9580597.
293
Chapter 221
JWH-047 JWH-047 is a selective cannabinoid ligand, with a bindining affinity of Kᵢ = 0.9 nM for the CB2 subtype, and more than 65 times selectivity over the CB1 .[1]
221.1 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073
221.2 References [1] Aung MM, Griffin G, Huffman JW, Wu M-J, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
294
Chapter 222
JWH-048 JWH-048 is a selective cannabinoid ligand, with a bindining affinity of Kᵢ = 0.5 ± 0.1 nM for the CB2 subtype, and more than 22 times selectivity over the CB1 .[1]
222.1 See also • JWH-015 • JWH-018 • JWH-019 • JWH-073
222.2 References [1] Aung MM, Griffin G, Huffman JW, Wu M-J, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
295
Chapter 223
JWH-073 JWH-073 is an analgesic chemical from the synthetic cannabis smoking blends. naphthoylindole family that acts as a partial agonist at both the CB1 and CB2 cannabinoid receptors. It is somewhat selective for the CB1 subtype, with affinity at this subtype approximately 5x the affinity at CB2 .[2] The abbreviation JWH stands for John W. Huffman, one of the inventors of the compound. On 20 April 2009, JWH-073 was claimed by researchers at the University of Freiburg to have been found in a “fertiliser” product called “Forest Humus”, along with another synthetic cannabinoid (C8)- 47,497.[3] These claims were confirmed in July 2009 when tests of Spice product, seized after the legal ban on JWH-018 had gone into effect in , were shown to contain the unregulated compound JWH-073 instead.[4]
223.1 Pharmacology JWH-073 has been shown to produce behavioral effects very similar to THC in animals.[5] Its effects are produced by binding and acting as an ago4'-Methyl-JWH-073 nist to the CB1 and CB2 cannabinoid receptors. The CB1 receptor is found in the brain. JWH-073 bind to CB1 with a higher affinity than THC, suggesting that taking more too soon after the initial dose could lead to diminished 223.3 Legal status effects. CB2 is found outside the brain, mostly in the immune system. The binding with CB2 receptors has been 223.3.1 United States shown to be similar between JWH-073 and THC.[5] A search in the literature yielded no published studies of See also: JWH-018 the effects of JWH-073 in humans, but these studies in The US DEA temporarily declared JWH-073 a schedule animals suggest with high probability that JWH-073 pro- I controlled substance on 1 March 2011 through 76 FR duces effects very similar to those of THC in humans.[5] 11075, and permanently instated the same schedule on 9 July 2012 in the Section 1152 of the Food and Drug istration Safety and Innovation Act.[7]
223.2 Derivatives
The 4'-methyl derivative of JWH-073 has been encountered as an ingredient of synthetic cannabis blends in and several other European countries since 2010.[6] The 4'-methoxy derivative JWH-080 is also known to be a potent cannabinoid agonist and has been banned in some countries, though it is unclear if it has also been used in
223.3.2 Australia See also: JWH-018 On 8 July 2011 the AUS government banned the sale of JWH-073.[8]
296
223.5. REFERENCES
297
[9] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are
1 g of JWH-073
223.3.3
New Zealand
On 8 May 2014 the New Zealand government banned the sale of JWH-073. [9]
223.4 See also • JWH-081 • JWH-018 • JWH-019 • HU-210
223.5 References [1] http://www.likumi.lv/doc.php?id=201101&from=off [2] Aung MM, et al. (August 2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding”. Drug Alcohol Depend 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [3] Forest Humus - Enthält synthetische Cannabinoide (in German) [4] Lindigkeit R, et al. (July 2009). “Spice: A never ending story?". Forensic Science International 191 (1–3): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [5] http://www.deadiversion.usdoj.gov/drugs_concern/ spice/spice_jwh073.html [6] EMCDDA Annual Report 2010 [7] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [8] http://www.tga.gov.au/pdf/scheduling/ scheduling-decisions-1107-final.pdf
Chapter 224
JWH-081 JWH-081 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors.[2] With a Kᵢ of 1.2nM it is fairly selective for the CB1 subtype, its affinity at this subtype approximately 10x the affinity at CB2 .[3] It was discovered by and named after Dr. John W. Huffman.
224.1 See also • JWH-018 • JWH-098 • JWH-164 • JWH-198 • JWH-210
224.2 References [1] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii (Dz.U. 2011 nr 105 poz. 614)". Internetowy System Aktów Prawnych. Retrieved 12 June 2011. [2] Aung MM, et al. Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding. Drug and Alcohol Dependence 2000; 60:133140. [3] Huffman JW, et al. Structure–activity relationships for 1alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists. Bioorganic and Medicinal Chemistry. 2005; 13:89-112.
298
Chapter 225
JWH-098 JWH-098 is a synthetic cannabinoid receptor agonist from the naphthoylindole family. It is the indole 2-methyl derivative of a closely related compound JWH-081, but has markedly different affinity for the CB1 and CB2 receptors. While JWH-081 is around 10x selective for CB1 over CB2 , in JWH-098 this is reversed, and it is around 4 times weaker than JWH-081 at CB1 while being six times more potent at CB2 , giving it a slight selectivity for CB2 overall. This makes JWH-098 a good example of how methylation of the indole 2-position in the naphthoylindole series tends to increase CB2 affinity, but often at the expense of CB1 binding.[1] JWH-098 is illegal in Russia,[2] Sweden,[3] and the UK,[4] although it is unclear whether it has any history of human use.
225.1 See also • JWH-007 • JWH-081
225.2 References [1] Huffman JW, et al. Structure–activity relationships for 1alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists. Bioorganic and Medicinal Chemistry. 2005; 13:89-112. PMID 15582455 [2] "Постановление от 31 декабря 2009 г. № 1186 О внесении изменений в некоторые постановления Правительства Российской Федерации по вопросам, связанным с оборотом наркотических средств". Government.ru. Retrieved 2010-09-09. [3] Svensk författningssamling [4] The Misuse of Drugs Act 1971 (Amendment) Order 2009
299
Chapter 226
JWH-116 JWH-116 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the indole 2-ethyl derivative of related compound JWH-018. The binding affinity of JWH-116 for the CB1 receptor is reported as Kᵢ = 52 ± 5 nM.[1]
226.1 See also • JWH-018 • JWH-081
226.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
300
Chapter 227
JWH-147 JWH-147 is an analgesic drug used in scientific research, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Ki of 11.0nM at CB1 vs 7.1nM at CB2 .[1] It was discovered and named after Dr. John W. Huffman. JWH-147 was banned in Sweden on 1 October 2010 as a hazardous good harmful to health, after being identified as an ingredient in “herbal” synthetic cannabis products.[2][3]
227.1 See also • JWH-030 • JWH-307
227.2 References [1] Huffman JW, Padgett LW, Isherwood ML, Wiley JL, Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New high affinity ligands for the cannabinoid CB1 and CB2 receptors. Bioorganic & Medicinal Chemistry Letters 2006; 16:5432-5435. [2] Swedish Code of Statutes Regulation (2010:1086). [3] Swedish Code of Statutes Regulation (2010:1086). (pdf)
301
Chapter 228
JWH-164 JWH-164 is a synthetic cannabinoid receptor agonist from the naphthoylindole family. It has approximately equal affinity for the CB1 and CB2 receptors, with a Kᵢ of 6.6nM at CB1 and 6.9nM at CB2 . JWH-164 is a positional isomer of the related compound JWH-081, but with a methoxy group at the 7-position of the naphthyl ring, rather than the 4-position as in JWH-081. Its potency is intermediate between that of JWH-081 and its ring unsubstituted derivative JWH-018, demonstrating that substitution of the naphthyl 7-position can also result in increased cannabinoid receptor binding affinity.[1][2]
228.1 References [1] Huffman JW, et al. Structure–activity relationships for 1alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB2 receptor agonists. Bioorganic and Medicinal Chemistry. 2005; 13:89-112. PMID 15582455 [2] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411. PMID 15974991
302
Chapter 229
Phenylacetylindole JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 1.75x selectivity for CB1 with a Kᵢ of 90nM ± 17 and 159nM ± 14 at CB2 . Similar to the related 2'-methoxy compound JWH-250, and the 2'-chloro compound JWH-203, JWH-167 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds.[1][2]
229.1 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
303
Chapter 230
JWH-175 JWH-175 is a drug from the naphthylmethylindole family which acts as a cannabinoid receptor agonist. It was invented by the scientist John W. Huffman and colleagues at Clemson University. JWH-175 is closely related to the widely used cannabinoid designer drug JWH-018, but with the ketone bridge replaced by a simpler methylene bridge. It is several times weaker than JWH-018, having a binding affinity at the CB1 receptor of 22nM, though some derivatives substituted at the 4-position of the naphthyl ring have potency more closely approaching that of the equivalent naphthoylindoles.[1] This makes JWH-175 considerably less potent than most synthetic cannabinoid drugs used in synthetic cannabis blends, and it is unclear if JWH-175 has ever been used for this purpose. However it has still been explicitly banned in several jurisdictions including Russia and some Australian states, in order to stop its potential use as an ingredient in such products.
230.1 See also • JWH-176 • JWH-184 • JWH-185
230.2 References [1] Huffman JW, Padgett LW. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Current Medicinal Chemistry, 2005; 12: 1395-1411.
304
Chapter 231
JWH-184 JWH-184 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the carbonyl-reduced derivative of related compound JWH-122. The binding affinity of JWH-184 for the CB1 receptor is reported as Kᵢ = 23 ± 6 nM.[1]
231.1 See also • JWH-018 • JWH-122 • JWH-185
231.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
305
Chapter 232
JWH-185 JWH-185 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the carbonyl-reduced derivative of related compound JWH-081. The binding affinity of JWH-185 for the CB1 receptor is reported as Kᵢ = 17 ± 3 nM.[1]
232.1 See also • JWH-081 • JWH-184
232.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
306
Chapter 233
JWH-196 JWH-196 is a synthetic cannabinoid receptor ligand from the naphthoylindole family. It is the indole 2-methyl derivative of related compound JWH-175, and the carbonyl reduced analog of JWH-007. The binding affinity of JWH-196 for the CB1 receptor is reported as Kᵢ = 151 ± 18 nM.[1]
233.1 See also • JWH-007 • JWH-175
233.2 References [1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539– 549. doi:10.1016/s0968-0896(02)00451-0.
307
Chapter 234
JWH-203 JWH-203 (1-pentyl-3-(2-chlorophenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family that acts as a cannabinoid agonist with approximately equal affinity at both the CB1 and CB2 receptors, having a Kᵢ of 8.0nM at CB1 and 7.0nM at CB2 . It was originally discovered by, and named after, Dr. John W. Huffman, but has subsequently been sold without his permission as an ingredient of synthetic cannabis smoking blends.[2] Similar to the related 2'-methoxy compound JWH-250, the 2'-bromo compound JWH-249, and the 2'-methyl compound JWH-251, JWH-203 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds, and has the strongest in vitro binding affinity for the cannabinoid receptors of any compound in the phenylacetyl group.[3][4][5] Unexpectedly despite its weaker CB1 Kᵢ in vitro, the 2methylindole derivative JWH-204 is actually more potent than JWH-203 in animal tests for cannabinoid activity, though it is still weaker than JWH-249.[6]
234.1 See also JWH-204
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7methoxyindole-3-carboxamide
[4] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
234.2 References [1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 17 June 2011.
[5] Bononi M, Belgi P, Tateo F (2011). “Analytical data for identification of the Cannabimimetic Phenylacetylindole JWH-203”. Journal of Analytical Toxicology 35 (6): 360– 3. doi:10.1093/anatox/35.6.360. PMID 21740693.
[2] “Analytical data for identification of the Cannabimimetic Phenylacetylindole JWH-203”. J Anal Toxicol 35 (6): 360–3. July 2011. doi:10.1093/anatox/35.6.360. PMID 21740693.
[6] “1-Pentyl-3-phenylacetylindoles and JWH-018 share in vivo cannabinoid profiles in mice”. Drug Alcohol Depend. November 2011. doi:10.1016/j.drugalcdep.2011.11.001. PMID 22127210.
[3] Huffman, JW, et al. (2005). “1-Pentyl-3phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
308
Chapter 235
JWH-210 JWH-210 is an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both the CB1 and CB2 receptors, with Kᵢ values of 0.46nM at CB1 and 0.69nM at CB2 . It is one of the most potent 4-substituted naphthoyl derivatives in the naphthoylindole series, having a higher binding affinity (i.e. lower Kᵢ) at CB1 than both its 4-methyl and 4-n-propyl homologues JWH-122 (CB1 Kᵢ 0.69nM) and JWH-182 (CB1 Kᵢ 0.65nM) respectively, and than the 4-methoxy compound JWH-081 (CB1 Kᵢ 1.2nM).[2] It was discovered by and named after Dr. John W. Huffman. JWH-210 and JWH-122 were banned in Sweden on 1 October 2010 as hazardous goods harmful to health, after being identified as ingredients in “herbal” synthetic cannabis products.[3][4] The substances JWH-210, JWH-122 and JWH-203 were classified as illegal drugs by the Swedish government as of 1 September 2011.[5]
235.1 See also • JWH-081 • JWH-193 • JWH-398
235.2 References [1] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 12 June 2011. [2] Huffman, J., et al. (2005). “Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.”. Bioorganic & Medicinal Chemistry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050. PMID 15582455. [3] Swedish Code of Statutes Regulation (2010:1086). [4] Swedish Code of Statutes Regulation (2010:1086). (pdf)
309
[5] LVFS 2011:8
Chapter 236
JWH-249 JWH-249 (1-pentyl-3-(2-bromophenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 2.4x selectivity for CB1 with a Kᵢ of 8.4nM ± 1.8 and 20nM ± 2 at CB2 . Similar to the related 2'-methoxy compound JWH-250, the 2'-chloro compound JWH-203, and the 2'-methyl compound JWH-251, JWH-249 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds. [1][2]
236.1 See also • AM-679
236.2 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
310
Chapter 237
JWH-250 JWH-250 or (1-pentyl-3-(2methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors, with a Kᵢ of 11nM at CB1 and 33nM at CB2 . Unlike many of the older JWH series compounds, this compound does not have a naphthalene ring, instead occupying this position with a 2'-methoxy-phenylacetyl group, making JWH-250 a representative member of a new class of cannabinoid ligands.[2] Other 2'substituted analogues such as the methyl, chloro and bromo compounds are also active and somewhat more potent.[3][4]
237.1 History JWH-250 was discovered by, and named after the researcher Dr. John W. Huffman. He created JWH250 and a number of other compounds to research the structure and function of the endocannabinoid system of mammals. Samples of JWH-250 were first identified in May 2009 by the German Federal Criminal Police, as an ingredient in new generation "herbal smoking blends" that had been released since the banning of the original ingredients (C8)- 47,497 and JWH-018.[5] An ELISA immunoassay technique for detecting JWH-250 in urine has been reported.[6]
237.2 References [1] Legal article in Latvian (www.likumi.lv) [2] Huffman, JW, et al. (2005). “1-Pentyl-3phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [3] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928. [4] The Cannabinoid Receptors. Edited by Patricia H Reggio. Humana Press 2009. ISBN 978-1-58829-712-9
311
[5] Understanding the ‘Spice’ phenomenon. EMCDDA, Lisbon, November 2009 [6] Arntson et al (2013) http://jat.oxfordjournals.org/ content/37/5/284.abstract
Chapter 238
JWH-251 JWH-251 (1-pentyl-3-(2-methylphenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 5x selectivity for CB1 with a Kᵢ of 29nM and 146nM at CB2 . Similar to the related 2'-methoxy compound JWH-250, the 2'-chloro compound JWH-203, and the 2'-bromo compound JWH-249, JWH-251 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds. [1][2]
238.1 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
312
Chapter 239
JWH-302 JWH-302 or (1-pentyl-3-(3methoxyphenylacetyl)indole) is an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist with moderate affinity at both the CB1 and CB2 receptors. It is a positional isomer of the more common drug JWH-250, though it is slightly less potent with a Kᵢ of 17nM at CB1 , compared to 11nM for JWH-250.[1][2] Because of their identical molecular weight and similar fragmentation patterns, JWH-302 and JWH-250 can be very difficult to distinguish by GC-MS testing.[3]
239.1 References [1] Huffman, JW. et al. (2005). “1-Pentyl-3phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C; Tuccinardi, T; Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928. [3] 'Herbal High' synthetic Cannabinoid composition, released by ESR July 2011
313
Chapter 240
JWH-307 JWH-307 is an analgesic drug used in scientific research, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a Ki of 7.7nM at CB1 vs 3.3nM at CB2 .[1] It was discovered by, and named after, Dr. John W. Huffman. JWH-307 was detected as an ingredient in synthetic cannabis smoking blends in 2012, initially in .[2][3]
240.1 See also • JWH-147
240.2 References [1] Huffman JW, Padgett LW, Isherwood ML, Wiley JL, Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New high affinity ligands for the cannabinoid CB1 and CB2 receptors. Bioorganic & Medicinal Chemistry Letters 2006; 16:5432-5435. [2] Ernst, L.; Krüger, K.; Lindigkeit, R.; Schiebel, H. M.; Beuerle, T. (2012). “Synthetic cannabinoids in “spice-like” herbal blends: First appearance of JWH307 and recurrence of JWH-018 on the German market”. Forensic Science International 222 (1–3): 216–22. doi:10.1016/j.forsciint.2012.05.027. PMID 22748479. [3] Kneisel, S.; Auwärter, V. (2012). “Analysis of 30 synthetic cannabinoids in serum by liquid chromatographyelectrospray ionization tandem mass spectrometry after liquid-liquid extraction”. Journal of Mass Spectrometry 47 (7): 825–835. doi:10.1002/jms.3020. PMID 22791249.
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JWH-398 JWH-398 is an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It has mild selectivity for CB1 with a Kᵢ of 2.3nM and 2.8nM at CB2 .[2] It was identified by the EMCDDA as an ingredient in three separate "herbal incense" products purchased from online shops between February to June 2009.[3] It was discovered by, and named after, Dr. John W. Huffman.[4]
241.1 See also • JWH-122 • JWH-424
241.2 References [1] [2] Huffman JW (2009) Cannabimimetic indoles, pyrroles, and indenes: structure-activity relationships and receptor interactions. Cited in: The cannabinoid receptors, Reggio PH (Ed), Humana Press. ISBN 978-1-58829-712-9 doi:10.1007/978-1-59745-503-9 [3] Understanding the ‘Spice’ phenomenon. EMCDDA, Lisbon, November 2009 [4] John W. Huffman, et al. STRUCTURE-ACTIVITY RELATIONSHIPS AT THE CB1 AND CB2 RECEPTORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8HALOGEN SUBSTITUTED) INDOLES (2009) 19th Annual Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, Page 2.
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JWH-424 JWH-424 is a drug from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors, but with moderate selectivity for CB2 , having a Kᵢ of 5.44nM at CB2 vs 20.9nM at CB1 . The heavier 8-iodo analogue is even more CB2 selective, with its 2-methyl derivative having 40x selectivity for CB2 . However the 1-propyl homologues in this series showed much lower affinity at both receptors, reflecting a generally reduced affinity for the 8-substituted naphthoylindoles overall.[1][2]
242.1 See also • JWH-018 • JWH-398
242.2 References [1] Valerie Smith, John Huffman, Jenny Wiley and Billy Martin. EFFECTS OF HALOGEN SUBSTITUENTS UPON CB1 AND CB2 RECEPTOR AFFINITIES IN THE SERIES OF N-ALKYL-3-(8HALO-1-NAPTHOYL)INDOLES. (2007) 17th Annual Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, Page 72. [2] John W. Huffman, et al. STRUCTURE-ACTIVITY RELATIONSHIPS AT THE CB1 AND CB2 RECEPTORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8HALOGEN SUBSTITUTED) INDOLES (2009) 19th Annual Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, Page 2.
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Naphthoylindole JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM678[1] is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1 and CB2 cannabinoid receptors, with some selectivity for CB2 . It produces effects in animals similar to those of THC, a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products such as “legal cannabis herbal incense blends” which in some countries are sold legally as “incense”, labeled “not for human consumption”.[2][3][4][5][6]
243.2.1 Pharmacokinetics JWH-018 istered to rats resulted in the excretion of an indole-N-desalkyl metabolite as well as several hydroxylated metabolites in urine. The highest signals were observed for the hydroxylated N-desalkyl metabolites. Hydroxylation took place on the side chain and in both aromatic systems, the naphthalene and the indole rings, as could be shown by mass shift of the corresponding fragments and by MS3 experiments.[13] Human metabolites were similar although most metabolism took place on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with glucuronide.[14]
243.1 History John W. Huffman, an organic chemist at Clemson University, synthesized analogues and metabolites of Δ9 tetrahydrocannabinol (THC), the principal active component of cannabis. JWH-018 is one of these analogues, with studies showing an affinity for the cannabinoid (CB1 ) receptor five times greater than that of THC. Cannabinoid receptors are found in mammalian brain and spleen tissue; however, the structural details of the active sites are currently unknown.[7][8] On December 15, 2008, it was reported by the German pharmaceutical company THC Pharm that JWH-018 was found as one of the active components in at least three versions of the herbal blend Spice, which has been sold as an incense in a number of countries around the world since 2002.[9][10][11] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[12]
243.3 Usage At least one case of JWH-018 dependence has been reported by the media.[2] The consumed JWH-018 daily for eight months. Withdrawal symptoms were similar to those experienced as a result of cannabis dependence. JWH-018 has been shown to cause profound changes in CB1 receptor density following istration, causing desensitization to its effects more rapidly than related cannabinoids.[6] On October 15, 2011, Anderson County coroner Greg Shore attributed the death of a South Carolina college basketball player to “drug toxicity and organ failure” caused by JWH-018.[15] An email dated Nov 4, 2011 concerning the case was finally released by the city of Anderson S.C. on Dec 16, 2011 under the Freedom of Information Act after multiple requests by media to see the information had been denied.[16]
Compared to THC, which is a partial agonist at CB1 receptors, JWH-018 (and many of its analogues) are full agonists. THC has been shown to inhibit GABA receptor neurotransmission in the brain via several pathways.[17][18] JWH-018 may cause intense anxiety, ag243.2 Pharmacology itation, and, in rare cases (generally with non-regular JWH s), has been assumed to have been the cause of JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotranscannabinoid receptors, with a reported binding affinity of mission more effectively than THC. Cannabinoid recep9.00 ± 5.00 nM at CB1 and 2.94 ± 2.65 nM at CB2 .[3] tor full agonists may present serious dangers to the 317
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when used to excess.[19] Various physical and psychological adverse effects have been reported from JWH-018 use. One study reported psychotic relapses and anxiety symptoms in welltreated patients with mental illness following JWH-018 inhalation.[20] Due to concerns about the potential of JWH-018 and other synthetic cannabinoids to cause psychosis in vulnerable individuals, it has been recommended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51] nesses (like a past or family history of psychosis) not use these substances.[21]
243.6 Synthesis 243.7 See also
243.4 Detection in biological fluids JWH-018 usage is readily detected in urine using “spice” screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and carboxyl metabolites.[22] JWH-018 will not be detected by older methods employed for detecting THC and other cannabis terpenoids. Determination of the parent drug in serum or its metabolites in urine has been accomplished by GC-MS or LC-MS. Serum JWH-018 concentrations are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolite is a compound that is monohydroxylated on the omega minus one carbon atom of the alkyl side chain. A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of 6 s of the drug at concentrations of 6–50 μg/L, primarily as a glucuronide conjugate.[23][24][25][26][27][28][29][30][31]
243.5 Legal status
• AM-2201 • BB-22 (drug) • JWH-073 • JWH-250 • JWH-200 • PB-22 • SDB-001
243.8 References [1] “Department of Justice :: Drug Enforcement istration”. 2011-03-01. Retrieved 2011-03-02. [2] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal Phenomena and Dependence Syndrome After the Consumption of “Spice Gold"". Dtsch Arztebl Int 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [3] Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000). “Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug and Alcohol Dependence 60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. [4] US patent 6900236, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200505-31 [5] US patent 7241799, Alexandros Makriyannis, Hongfeng Deng, “Cannabimimetic indole derivatives”, issued 200707-10
JWH-018 powder as it was commonly sold online
[6] Atwood, B.K., et al., “JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB1 receptor agonist.” British Journal of Pharmacology, Vol. 160, No. 3. 585-593. 2010.
243.8. REFERENCES
319
[7] “Clemson University :: Department of Chemistry”. Clemson.edu. Retrieved 2010-08-23. [8] “Drugs Forum”. Drugs Forum. Retrieved 2010-08-23. [9] Gefährlicher Kick mit Spice (German) [10] Erstmals Bestandteile nachgewiesen (German)
der
Modedroge
“Spice”
[11] Spice enthält chemischen Wirkstoff (German) [12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L, Beuerle T (30 October 2009). “Spice: A never ending story?". Forensic Science International (Forensic Science International) 191 (1): 58–63. doi:10.1016/j.forsciint.2009.06.008. PMID 19589652. [13] T. Kraemer, et al. Studies on the metabolism of JWH018 and of a homologue of 47,497, pharmacologically active ingredients of different misused incense (“Spice”) using GC-MS and LC-MSn techniques (Institute of Legal Medicine, Saarland University, 66421 Homburg, http://www.gtfch.org/cms/images/ stories/media/tk/tk76_2/abstractsvortraege.pdf [14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010). “Detection of JWH-018 metabolites in smoking mixture post-istration urine”. Forensic Science International 200 (1–3): 141–7. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [15] wyff4.com, Coroner: Synthetic Pot Killed College Athlete, posted 10/14/11, accessed 12/22/11, http://www. wyff4.com/news/29497549/detail.html, [16] Mayo, Nikie, “City Releases Email in Lamar Jacks Case”, independentmail.com, posted Dec 16, 2011, accessed 12/22/11, http://www.independentmail.com/news/2011/ dec/16/city-releases-email-lamar-jack-case/ [17] Laaris N, Good CH, Lupica CR (July–August 2010). "Δ9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus”. Neuropharmacology 59 (1–2): 121–127. doi:10.1016/j.neuropharm.2010.04.013. PMC 2882293. PMID 20417220. [18] Hoffman AF, Lupica CR (2000-04-01). “Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus”. The Journal of Neuroscience 20 (7): 2470–2479. ISSN 0270-6474. PMID 10729327. Retrieved 2011-07-26. [19] European Monitoring Centre for Drugs and Drug Addiction. “Understanding the Spice Phenomenon.” 2009. ISBN 978-92-9168-411-3. [20] Every-Palmer, S. Synthetic cannabinoid use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011. [Epub ahead of print]. [21] Every-Palmer S (2010). “WARNING: LEGAL SYNTHETIC CANNABINOID-RECEPTOR AGONISTS SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS IN VULNERABLE INDIVIDUALS”. Addiction 105: doi:10.1111/j.1360-0443.2010.03119.x. 1859–1860. PMID 20840203.
[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/ content/37/5/284.abstract, https://www.caymanchem. com/app/template/Product.vm/catalog/580210; http://www.randoxtoxicology.com/Products/Elisa-p-50, http://tulipbiolabs.com/our-product-areas/ synthetic-cannabinoids and others. [23] Möller I, et al. Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls. Drug Test. Anal. Sep 24, 2010. [Epub ahead of print] [24] Teske J, et al. Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatography-tandem mass spectrometry. J Chrom. B 878: 2659-2663, 2010. [25] Auwärter V, Dresen S, Weinmann W, Müller M, Pütz M, Ferreirós N (2009). "'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832–837. doi:10.1002/jms.1558. PMID 19189348. Free version [26] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K (2009). “Withdrawal phenomena and dependence syndrome after the consumption of “spice gold"". Deutsches Arzteblatt international 106 (27): 464–467. doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID 19652769. [27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). “Detection of JWH-018 metabolites in smoking mixture postistration urine”. Forensic Science International 200 (1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003. PMID 20430547. [28] Beuck S, Möller I, Thomas A, Klose A, Schlörer N, Schänzer W, Thevis M (August 2011). “Structure characterisation of urinary metabolites of the cannabimimetic JWH-018 using chemically synthesised reference material for the of LC-MS/MS-based drug testing”. Anal Bioanal Chem 401 (2): 493–505. doi:10.1007/s00216-011-4931-5. PMID 21455647. [29] Moran CL, Le VH, Chimalakonda KC, Smedley AL, Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski PJ, Wessinger WD, Fantegrossi WE, Prather PL, James LP, Radominska-Pandya A, Moran JH (June 2011). “Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine”. Anal. Chem. 83 (11): 4228–36. doi:10.1021/ac2005636. PMID 21506519. [30] Logan BK, et al. Identification of primary JWH018 and JWH-073 metabolites in human urine. NMS Labs Technical Bulletin, May 25, 2011. http://toxwiki.wikispaces.com/file/view/JWH_ metabolites_Technical_Bulletin_Final_v1.1.pdf [31] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 10th edition, Biomedical Publications, Seal Beach, CA, 2014, p. 1863. [32]
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[33] “Controlled Drugs and Substances Act”. Laws.justice.gc.ca. 2010-08-16. Retrieved 201008-23. [34] *** Tiedote/Valtioneuvoston viestintäyksikkö: VALTIONEUVOSTON YLEISISTUNTO 1.3.2012 *** (Finnish) [35] “EMCDDA | Drug profile: Synthetic cannabinoids and 'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved 2010-08-23. [36] http://www.afssaps.fr/var/afssaps_site/storage/original/ application/d23d05edc58479d91c803b496017f073.pdf [37] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19. Januar 2009, S. 49–50. [38] Many head shop products banned - Irish Times. [39] http://www.politicheantidroga.it/ comunicazione/comunicati/2010/luglio/spice, -n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian) [40] https://www.drugfoundation.org.nz/ synthetic-cannabinoids/what-they-are [41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465. html [42]
(2 July 2009). “1 ‘5- - ’ . Retrieved 18 February 2010.
".
[43] http://www.regeringen.se/sb/d/12102/a/130038 (Swedish) [44] “Illicit Drug Report of Turkey 2010”. Department of Anti-smuggling and Organised Crime. Retrieved 201205-03.(Turkish) [45] “Decision of the Council of Ministers, Enactment 2011/1310”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [46] “Attachment to Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [47] “Decision of the Council of Ministers, Enactment 2012/2861”. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish) [48] Ford, Richard (2009-12-23). “Three legal highs banned after deaths linked to the drugs”. The Times (London). Retrieved 2010-05-07. [49] “Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I”. DEA Office of Diversion Control. Retrieved 11 March 2014. [50]
243.9 External links • JWH-018 Report Psychonaut Web Mapping Research Project • of legal high
Chapter 244
Phenylacetylindole JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a synthetic cannabinoid from the phenylacetylindole family, which acts as a cannabinoid agonist with about 1.75x selectivity for CB1 with a Kᵢ of 90nM ± 17 and 159nM ± 14 at CB2 . Similar to the related 2'-methoxy compound JWH-250, and the 2'-chloro compound JWH-203, JWH-167 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds.[1][2]
244.1 References [1] Huffman, JW, Szklennik, PV, Almond, A, Bushell, K, Selley, DE, He, H, Cassidy, MP, Wiley, JL, Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles”. Bioorganic & Medicinal Chemistry Letters 15 (18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID 16005223. [2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “Indoles and related compounds as cannabinoid ligands”. Mini reviews in medicinal chemistry 8 (4): 370–87. doi:10.2174/138955708783955935. PMID 18473928.
321
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RCS-8 RCS-8, or 1-(2-cyclohexylethyl)−3-(2methoxyphenylacetyl)indole, is a synthetic cannabinoid also known as SR-18 or BTM-8 that has been found as an ingredient of “herbal” synthetic cannabis blends. It can be described as an analogue of JWH-250 with the 1-pentyl group replaced by 1-(2-cyclohexylethyl), and can be expected to be less potent than JWH-250 (cf. JWH-007 and its cyclohexylethyl analogue).[1] Despite not having been reported in the scientific or patent literature as yet, reputed recreational use of RCS-8 in the United States has led to it being specifically listed in a proposed 2011 amendment to the Controlled Substances Act, aiming to add a number of synthetic drugs into Schedule I.[2]
245.1 See also • Cannabipiperidiethanone • JWH-250 • RCS-4
245.2 References [1] Huffman, J. W.; Dai, D.; Martin, B. R.; Compton, D. R. (1994). “Design, Synthesis and Pharmacology of Cannabimimetic Indoles”. Bioorganic & Medicinal Chemistry Letters 4 (4): 563. doi:10.1016/S0960894X(01)80155-4. [2] Synthetic Drug Control Act of 2011
322
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Intravenous Marijuana Syndrome Intravenous Marijuana Syndrome is a distinct shortterm clinical syndrome related to the intravenous injection of boiled cannabis broth, which had been filtered through a cotton cloth. The syndrome has at least 25 known cases in the English language literature, but all of them prior to 1983.[1] It is postulated that contamination, perhaps from the cotton used to strain the liquid of the broth or from particulate plant matter getting through the straining method, could be cause for the cases of illnesses.[1]
246.1 References [1] Daniel Brandenburg; Richard Wernick (July 1986). “Intravenous Marijuana Syndrome”. wjm 145 (1): 94–96. PMC 1306836. PMID 3489321. Retrieved 2008-06-21.
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Chapter 247
Mellow Yellow coffeeshop Mellow Yellow is the oldest cannabis coffee shop in Amsterdam. The coffee shop was founded in 1972 by Wernard Bruinin in Weesperzijde, Amsterdam, on the premises of a former bakery. The shop is named after "Mellow Yellow", a song by Donovan which describes the singer trying to become intoxicated through smoking the peel of banana.[1]
247.3 External links
The intent of the shop is to sell cannabis, despite this being illegal at the time of its creation.[1] Sales were originally disguised by drug dealers seated at the bar posing as customers. Mellow Yellow was unsuccessfully raided by police several times. Unpackaged cannabis, bought from wholesalers including drug lord Klaas Bruinsma, was hidden behind secret doors and shutters. In 1975, the concept was adopted by a shop named Russia situated on the same street as Mellow Yellow and was followed by another coffee shop called The Bulldog. Now there are 223[2] such coffee shops in Amsterdam. Bruining also runs Stichting Mediwiet (Medi Cannabis Foundation), a group that s the legalization of growing marijuana for medicinal uses.
247.1 Citations [1] “De eerste coffeeshop ter wereld” (in Dutch). November 2008. Retrieved December 2012. [2] “FAQ Coffeeshops in Amsterdam”. I Amsterdam. Retrieved 2013-03-24.
247.2 References • “Hasj” (in Dutch). Geschiedenis 24. • Schoof, Rob (1 May 2008). “De achterdeur van de coffeeshop” (in Dutch). NRC Handelsblad. • van Schaik, Nol (7 October 2009). “Dutch Cannabis Coffeeshop History”. 324
• Mellow Yellow Lounge • Stichting Mediwiet
Chapter 248
The Night Train Seizure The Night Train Drug Seizure was a 1978 seizure of 54 tons of marijuana by the United States Coast Guard off the southeastern coast of Florida which marked the beginning of Operation Stopgap, a United States federal law enforcement inter-agency drug interdiction operation focusing on interdicting drugs from Colombian cartels and other illicit Central and South American drug sources.[1] The Night Train seizure was the largest single drug seizure in history at the time it occurred, and it remains one of the largest marijuana seizures made in the territorial waters of the United States.[2]
• List of United States Coast Guard cutters
Operation Stopgap was one of the first inter-agency law enforcement efforts focused on the interdiction of illegal drugs from Central and South America, and it featured personnel of the Coast Guard, DEA and US Federal Marshals Service working together,[3] as well as the resources of the Intelligence Section of the Drug Enforcement istration and Coast Guard Intelligence (CGI).[4]
• United States Coast Guard Legal Division
The Night Train was a 189 foot coastal cargo vessel that had become legendary in the law enforcement community and smuggling circles due to its repeated ability to elude US law enforcement for almost two years before they were finally captured off of West Palm Beach as the first seizure of Stopgap. Operation Stopgap was but the first of a number of highly successful inter-agency intelligence and interdiction operations[5] that led to a large number of successful seizures and prosecutions in the late 1970s and early 1980s, garnering the U.S. Coast Guard considerable press coverage during this period as seizure records continued to be broken.[6] Stopgap was also one of the earliest interdiction operations to effectively use satellite technology in the pursuit and interdiction of drug smugglers.[7]
• List of United States Coast Guard stations • Maritime Law Enforcement Academy • MARSEC • National Data Buoy Center • National Ice Center • Patrol Forces Southwest Asia
• United States Coast Guard officer rank insignia • United States Coast Guard Research & Development Center
248.2 References [1] Name Of Pot-Laden Ship Sounded Familiar To Coast Guard Miami News, December 11, 1977 [2] Marijuana Seizure Was Largest Haul On Record Lakeland (Florida) Ledger, April 20, 1978 [3] “The Battle Against Drugs Takes to the Seas: High Seas Drama When the Night Train was Seized by the Coast Guard.” U.S. News and World Report LXXXIV (Mar 27, 1978), pp. 69–71. [4] DEA and Coast Guard Could Almost Track Drug Ship By The Smell St. Petersburg Times, July 11, 1978 [5] Operation Stopgap The Spokesman Review, September 16, 1978 [6] Operation Stopgap Nails The Legendary Night Train, St. Petersburg Times, July 11, 1978
248.1 See also
[7] Satellites Aiding In Pot Seizures Sarasota Herald-Tribune, July 11, 1978
• Coast Guard Investigative Service • Go-fast boat • t Maritime Training Center • List of active United States military aircraft 325
Chapter 249
PSN-375,963 PSN-375,963 is a selective ligand for the suggested novel cannabinoid receptor GPR119.[1]
249.1 See also • AR-231,453 • PSN-632,408
249.2 References [1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C. (2006). “Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.”. Cell Metab. 3 (3): 167–175. doi:10.1016/j.cmet.2006.02.004. PMID 16517404.
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PSN-632,408 PSN-632,408 is a selective ligand for the suggested novel cannabinoid receptor GPR119.[1]
250.1 See also • AR-231,453 • PSN-375,963
250.2 References [1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C. (2006). “Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.”. Cell Metab. 3 (3): 167–175. doi:10.1016/j.cmet.2006.02.004. PMID 16517404.
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Chapter 251
Soma Seeds Soma Seeds (also known as Soma’s Sacred Seeds) is an Amsterdam based medical cannabis seed company owned by Soma. The company became internationally famous after winning the 1999 High Times Cannabis Cup with Soma’s 'Reclining Buddha' strain in the Indica category;[1] in 2001, 2002, 2003 and 2004 with 'NYC Diesel' strain in the Sativa category,[2] in 2002 with 'Buddha’s Sister' strain in the Indica category [3] in 2004 with 'Amnesia Haze' in the best strain category [4] and in 2005 with 'Lavender' strain in the Indica category.[5]
251.1 References [1] Cannabis Cup winners 1999. [2] Cannabis Cup winners 2001. [3] Cannabis Cup winners 2002. [4] Cannabis Cup winners 2004. [5] Cannabis Cup winners 2005.
251.2 External links • http://www.somaseeds.nl/
328
Chapter 252
TM-38837 TM38837 is a new small molecule inverse agonist/antagonist of the CB1 cannabinoid receptor. It is being developed for the treatment of obesity and metabolic disorders by 7TM Pharma.[1] The company has announced phase I clinical trials. TM38837 is among the first of a new generation of cannabinoid receptor antagonist designed to avoid the central nervous system liabilities of the first generation CB1 receptor antagonists, for example rimonabant.[2]
252.1 See also • AM-6545
252.2 References [1] http://www.7tm.com [2] Hung, M. S.; Chang, C. P.; Li, T. C.; Yeh, T. K.; Song, J. S.; Lin, Y.; Wu, C. H.; Kuo, P. C.; Amancha, P. K.; Wong, Y. C.; Hsiao, W. C.; Chao, Y. S.; Shia, K. S. (2010). “Discovery of 1-(2,4-Dichlorophenyl)−4-ethyl5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen2-yl)-N-(piperidin-1-yl)−1H-pyrazole-3-carboxamide as a Potential Peripheral Cannabinoid-1 Receptor Inverse Agonist”. ChemMedChem 5 (9): 1439–1443. doi:10.1002/cmdc.201000246. PMID 20652930.
252.3 External links • www.7tm.com • Experimental obesity drug avoids brain effects that troubled predecessors
329
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252.4 Text and image sources, contributors, and licenses 252.4.1
Text
• Cannabinoid Source: http://en.wikipedia.org/wiki/Cannabinoid?oldid=630426170 Contributors: Bryan Derksen, Edward, Kwertii, JWSchmidt, Nnh, AnthonyQBachler, Hadal, Fuelbottle, Centrx, Karn, Bens, Jfdwolff, St3vo, Eequor, Christopherlin, OldakQuill, Ferre, Mearlon, Lazypplunite, Freakofnurture, Rich Farmbrough, Cacycle, Kwamikagami, Tgeller, Renice, Arcadian, Kaf, Alansohn, Eric Kvaalen, Howrealisreal, Axl, Mrholybrain, Ombudsman, Gene Nygaard, Natalya, Bobrayner, Qnonsense, Mpj17, WadeSimMiser, Mandarax, SqueakBox, BD2412, Mendaliv, Zachjones4, Rjwilmsi, HappyCamper, Fred Bradstadt, X1987x, Avocado, FlaBot, Margosbot, Jrtayloriv, Nosforit, Fborgnia, YurikBot, Mushin, Chris Capoccia, Gaius Cornelius, Zwobot, S. Neuman, Jeh, Ochiwar, Smaines, Saric, Itub, SmackBot, Unyoyega, Jrockley, Antrophica, Timotheus Canens, Jpvinall, Edgar181, David.Throop, Chris the speller, Bluebot, Droll, Deli nk, Ioscius, Roadnottaken, Radagast83, Drphilharmonic, J306, Provider uk, Ilyse Kazar, Rhetth, CmdrObot, Scoticus, ShelfSkewed, Meodipt, Kupirijo, Dougweller, Thijs!bot, Barticus88, RobArmstrong, Bendroz, Luke poa, Gharmon, Subvertc, Headbomb, Java13690, E. Ripley, Big Bird, Smartse, Astavats, Dougher, Ph.eyes, MudPhud, Probios, PhilKnight, Iownutopia, Cannabis, Hiplibrarianship, CliffC, Leyo, Lumir, J.delanoy, Pharaoh of the Wizards, Extransit, Nonantum, Jeepday, Mikael Häggström, Tanevala, Enix150, Funandtrvl, MenasimBot, Benrr101, LeaveSleaves, GeorgeLTirebiter, Glaman7, Carinabean1, Sapphic, Doc James, Ohiostandard, Nonsomniac, Scarian, Bradgon, Delighted eyes, ClueBot, Andrew Nutter, Drmies, Niceguyedc, Anon lynx, Phil Ian Manning, Vivio Testarossa, Panoramix303, Werson, Tonytross, RexxS, Akofalvi, Jytdog, Chemgirl131, Ost316, Vojtěch Dostál, WikiDao, Addbot, DOI bot, Jncraton, Wormantson, Jameskirby, Tide rolls, OlEnglish, Teles, Jarble, Gaberdine2, Luckas-bot, Yobot, Themfromspace, Clarechenoweth, Dmarquard, AnomieBOT, Götz, Rjanag, JackieBot, Materialscientist, Flaminhaz, Citation bot, Xqbot, Dagrun, GrouchoBot, Slowart, Ajax151, Shadowjams, Custoo, FrescoBot, Lothar von Richthofen, Maria mdv, Biker Biker, Pinethicket, CCIC, Abductive, Tea with toast, Trainwreckwebb, David Hedlund, Minimac, Algarcia85, RjwilmsiBot, Mungox, Alph Bot, EmausBot, Eekerz, SalviaFan, Nuujinn, Beeshoney, Zane Russell,, Tommy2010, Dcirovic, Doddy Wuid, Subtropical-man, MajorVariola, WickedSpice, Wayne Slam, Duncan169, DASHBotAV, Frozen Wind, ClueBot NG, Horoporo, Osterluzei, Mesoderm, HenryScow, Helpful Pixie Bot, BG19bot, Lewisly, Petrarchan47, Nikos 1993, Verified72, Drpainless, Viridis Veritas, Seannyboy219, Papier K, Kingofoviedo, Shisha-Tom, TheBaur, Stark1987, 32cllou, Mogism, Makecat-bot, Cerabot, Aachaos, Eyesnore, Wicked licks, Dymethylated, Meteor sandwich yum, Farmkid1958, Monkbot, Bosch1ltd rc development, Crazykatchic, Medgirl131, Jameshelsing, JuggaloI, SP1977 and Anonymous: 218 • Entourage effect Source: http://en.wikipedia.org/wiki/Entourage_effect?oldid=630508268 Contributors: Bearcat, Afterwriting, ZuluPapa5, Yobot, BG19bot and BattyBot • Synthetic cannabis Source: http://en.wikipedia.org/wiki/Synthetic_cannabis?oldid=629537150 Contributors: Frecklefoot, Deisenbe, Katana0182, Furrykef, Dale Arnett, Alan Liefting, DocWatson42, Everyking, St3vo, Neilc, Chowbok, Gadfium, Beland, Jokestress, Oknazevad, Cacycle, Cyclopia, Mr2001, Alansohn, Eleland, Ynhockey, Sciurinæ, BDD, KevinOKeeffe, SqueakBox, Rjwilmsi, XLerate, Krzysiu, Wgfcrafty, Diza, Therefore, Wavelength, Jimp, RadioFan, Grafen, Alpha 4615, BorgQueen, Fram, JDspeeder1, Paul Erik, SmackBot, KAtremer, Kintetsubuffalo, Edgar181, Ohnoitsjamie, Hmains, Cs-wolves, Chris the speller, Myxsoma, Thumperward, Cybercobra, Derek R Bullamore, Drphilharmonic, Salamurai, Curly Turkey, Ohconfucius, AThing, John, Minna Sora no Shita, IronGargoyle, SandyGeorgia, Skinsmoke, G patkar, MrDolomite, Valoem, Winston Spencer, J Milburn, JForget, Edward Vielmetti, CBM, Nczempin, Meodipt, Funnyfarmofdoom, Doctormatt, Crossmr, Kotiwalo, DumbBOT, FG Fox, Qwyrxian, N5iln, Turkeyphant, Matthew Proctor, Pfranson, Ssr, Shirt58, Smartse, DuncanHill, Adjwilley, Jheiv, Zendu, Umeboshi, Hiplibrarianship, BatteryIncluded, Esteroth12, Andytuba, Leyo, Edgeweyes, 2012Olympian, Malkuth1, Carolfrog, Danwoodard, AngryEoin, DadaNeem, Themoodyblue, Pdcook, 360aerial, Speciate, VolkovBot, Dave Andrew, Trex21, Philip Trueman, TXiKiBoT, Philaweb, Fxhomie, Clarince63, Ownthink, Smb1138, Anarchangel, Falcon8765, Living under a rock, Caltas, Psilonautika, Sokari, Soporaeternus, Sfan00 IMG, Tmtung, ClueBot, The Thing That Should Not Be, Drmies, PixelBot, John Nevard, Coinmanj, Lnelsonmd, Buckethed, XLinkBot, Psych0-007, Richard-of-Earth, WikiDao, MystBot, Addbot, Alex.mccarthy, MartinezMD, Debresser, Favonian, Exor674, 5 albert square, Tide rolls, Teles, MuZemike, Hartz, Hxck, Luckas-bot, Yobot, Preppysob99, Guy1890, AnomieBOT, Metalhead94, Götz, MovieImage, Csigabi, GB fan, ArthurBot, LilHelpa, Ryanjca, NFD9001, Tyrol5, Mlpearc, Ragityman, 931, GrouchoBot, Clark candace, Jezhotwells, A45b22chp, Antitak, Epiftw, Shadowjams, FrescoBot, Wikicool11, Mu Mind, Moloch09, Ttg53, Louperibot, Nirmos, SpacemanSpiff, Pinethicket, Elockid, HRoestBot, Calmer Waters, MastiBot, Theodore.Miller3, Tim1357, PiRSquared17, Tolvic, Benbullen, David Hedlund, Reaper Eternal, Seahorseruler, Diannaa, Phunlee, Fastilysock, Tbhotch, Tzores, RjwilmsiBot, Bento00, Surentity, DASHBot, WikitanvirBot, Nuujinn, Asred, Psychonaut2010, Minimac’s Clone, Renamed01302013, Tisane, Tommy2010, White Trillium, GreatSuccess101, OregonIronCo, Elektrik Shoos, AcidBurn211, Bxj, BGinOC, WickedSpice, Wayne Slam, Glennconti, Astara85, Voxcarnage, Norsci, KazekageTR, L Kensington, Mr. SpiceMan, Deathwishh, Akakeillo34, Lgarcia024, Killerprey23, Dominic Ragbottom, Joshgolf81, Sailsbystars, Tobeprecise, DeirdreNocturne, Limelitespice, Orange Suede Sofa, Stacks19, Keeper0fdahoes, Lagato123, Marioja1, Joey kandewit, Bentway, EdoBot, Quagameefi, AJ12Gamer, E. Fokker, Teaktl17, Redpanda44, ClueBot NG, SpikeTorontoR, Munda8163, Bkane16, AznBurger, Mr. Berty, Dchrguy, Kylesnage, Names are hard to think of, Helpful Pixie Bot, BG19bot, Oliveralbq, Justthinking25, Thirdeye616, Bodhisvaha5, BattyBot, Dereistic, BaeyerDrewson, ComfyKem, Yo222, Schenka, Exesop, Anrnusna, Monkbot, Medgirl131, Amanda Smalls and Anonymous: 432 • 4-HTMPIPO Source: http://en.wikipedia.org/wiki/4-HTMPIPO?oldid=628510777 Contributors: ChemNerd, Enix150, The chemistds, Ad Orientem, BaeyerDrewson and Mrbenzhao • 5F-PB-22 Source: http://en.wikipedia.org/wiki/5F-PB-22?oldid=622763569 Contributors: Meodipt, Anaxial, Yobot, Fraggle81, FrescoBot, The chemistds, BaeyerDrewson, KMAnomalocaris, Gigglepox and Anonymous: 7 • A-40174 Source: http://en.wikipedia.org/wiki/A-40174?oldid=546115716 Contributors: CheMoBot, BogBot, Dcirovic and NotWith
Edgar181, Beetstra, Meodipt, Addbot,
• A-41988 Source: http://en.wikipedia.org/wiki/A-41988?oldid=509594440 Contributors: Pegship, SmackBot, Edgar181, Nuklear, Beetstra, Meodipt, CheMoBot, حسن علي البط, BogBot and NotWith • A-796,260 Source: http://en.wikipedia.org/wiki/A-796,260?oldid=589910504 Contributors: Edgar181, Drphilharmonic, Beetstra, Meodipt, Smartse, Tanevala, Enix150, CheMoBot, Trappist the monk, The chemistds, Skoot13, Stark1987 and Anonymous: 1 • A-834,735 Source: http://en.wikipedia.org/wiki/A-834,735?oldid=589910514 Contributors: Drphilharmonic, Beetstra, Meodipt, Enix150, CheMoBot, FrescoBot, Trappist the monk, The chemistds, Skoot13, Shisha-Tom and Anonymous: 1 • A-836,339 Source: http://en.wikipedia.org/wiki/A-836,339?oldid=578815101 Contributors: Drphilharmonic, Meodipt, Smartse, Enix150, CheMoBot, Anypodetos, حسن علي البط, FrescoBot, BogBot, The chemistds, Stark1987 and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• AB-001 Source: http://en.wikipedia.org/wiki/AB-001?oldid=619562530 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Smartse, Enix150, C6541, CheMoBot, Bamyers99, The chemistds, Skoot13, Stark1987, BaeyerDrewson and Anonymous: 2 • AB-005 Source: http://en.wikipedia.org/wiki/AB-005?oldid=600007387 Contributors: Yobot, SciRambar, Josve05a, BaeyerDrewson, Jimer and Anonymous: 2 • AB-CHMINACA Source: http://en.wikipedia.org/wiki/AB-CHMINACA?oldid=626078386 Contributors: Bearcat, Edgar181, Magioladitis, MrX, Medgirl131, Aethyta, Grandmalanfall, Jamesjbradshaw and Anonymous: 1 • AB-FUBINACA Source: http://en.wikipedia.org/wiki/AB-FUBINACA?oldid=616120128 Contributors: Meodipt, BaeyerDrewson and Anonymous: 4 • AB-PINACA Source: http://en.wikipedia.org/wiki/AB-PINACA?oldid=616218448 Contributors: Edgar181, Meodipt, The chemistds, BaeyerDrewson, Capsaicin and Anonymous: 2 • Abnormal cannabidiol Source: http://en.wikipedia.org/wiki/Abnormal_cannabidiol?oldid=589953504 Contributors: Rjwilmsi, Beetstra, Meodipt, Headbomb, Enix150, Benrr101, EoGuy, Addbot, Yobot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, Nirmos, BogBot, Trappist the monk, 564dude, Dcirovic, Cobaltcigs, DouglasMcHugh, The chemistds, Shisha-Tom, Metilisopropilisergamida and Anonymous: 1 • ADB-FUBINACA Source: http://en.wikipedia.org/wiki/ADB-FUBINACA?oldid=616218510 Contributors: HazyM, AnomieBOT, The chemistds, BaeyerDrewson and Anonymous: 5
Edgar181, Meodipt,
• ADB-PINACA Source: http://en.wikipedia.org/wiki/ADB-PINACA?oldid=618895825 Contributors: Edgar181 and BattyBot • ADBICA Source: http://en.wikipedia.org/wiki/ADBICA?oldid=595202165 Contributors: Meodipt, Yosefxp, Anypodetos, AnomieBOT, BaeyerDrewson and Anonymous: 1 • Ajulemic acid Source: http://en.wikipedia.org/wiki/Ajulemic_acid?oldid=618474671 Contributors: St3vo, Cacycle, Physchim62, Derek.cashman, ERobson, Nuklear, Drphilharmonic, Beetstra, Meodipt, Enix150, Benrr101, Panoramix303, Tictrotactro, Addbot, Yobot, PharmHU, CheMoBot, Anypodetos, Citation bot, حسن علي البط, Joyful rabbit, BogBot, Daviesje, Louisajb, Medgirl131 and Anonymous: 3 • AM-087 Source: http://en.wikipedia.org/wiki/AM-087?oldid=522175575 Contributors: Bearcat, Pegship, Drphilharmonic, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, The chemistds, Skoot13 and BaeyerDrewson • AM-1220 Source: http://en.wikipedia.org/wiki/AM-1220?oldid=544648977 Contributors: Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, BogBot, Jesse V., The chemistds, Skoot13, Destruktor5000, Fuse809 and Anonymous: 1 • AM-1221 Source: http://en.wikipedia.org/wiki/AM-1221?oldid=619562492 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, BogBot, Bamyers99, The chemistds, Skoot13 and Anonymous: 1 • AM-1235 Source: http://en.wikipedia.org/wiki/AM-1235?oldid=517510799 Contributors: CheMoBot, Harbinary, BogBot, Jesse V., The chemistds and Skoot13
Drphilharmonic, Meodipt, Enix150,
• AM-1241 Source: http://en.wikipedia.org/wiki/AM-1241?oldid=590554371 Contributors: Bearcat, Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Headbomb, Enix150, Addbot, C6541, CheMoBot, حسن علي البط, Harbinary, Citation bot 1, Nirmos, BogBot, RjwilmsiBot, Dcirovic, Skoot13, Purple Blanket, Destruktor5000, Shisha-Tom, BaeyerDrewson, Monkbot and Anonymous: 1 • AM-1248 Source: http://en.wikipedia.org/wiki/AM-1248?oldid=590552939 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Smartse, Enix150, Squids and Chips, C6541, CheMoBot, BogBot, Skoot13, Stark1987 and Monkbot • AM-1714 Source: http://en.wikipedia.org/wiki/AM-1714?oldid=557804331 Contributors: Meodipt • AM-2201 Source: http://en.wikipedia.org/wiki/AM-2201?oldid=624831207 Contributors: Jeffhos, Edgar181, Drphilharmonic, Meodipt, ChemNerd, Boghog, Enix150, SamChem7, Glossologist, Wikieditor12, DrakeUnlimited, Addbot, C6541, CheMoBot, AnomieBOT, Harbinary, SD5, FrescoBot, Biker Biker, BogBot, ItsZippy, Vrenator, Товарищ, Jesse V., ZéroBot, The chemistds, ClueBot NG, Ieponumos, D42kn355, Verified72, Ungodlyzilla, BaeyerDrewson, Ezymike, Yougotwarsh, Medgirl131 and Anonymous: 36 • AM-2232 Source: http://en.wikipedia.org/wiki/AM-2232?oldid=587699474 Contributors: Drphilharmonic, Meodipt, Toohool, C6541, CheMoBot, BogBot, The chemistds and Anonymous: 1 • AM-2233 Source: http://en.wikipedia.org/wiki/AM-2233?oldid=619646412 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Smartse, Enix150, C6541, CheMoBot, Citation bot, BogBot, GoingBatty, The chemistds, ClueBot NG, Skoot13, Stark1987, Monkbot and Anonymous: 2 • AM-2389 Source: http://en.wikipedia.org/wiki/AM-2389?oldid=577466486 Contributors: Meodipt, CheMoBot, Anypodetos, Jesse V., The chemistds, Skoot13 and Anonymous: 1 • AM-4030 Source: http://en.wikipedia.org/wiki/AM-4030?oldid=512515874 Contributors: Bearcat, St3vo, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Jesse V. • AM-411 Source: http://en.wikipedia.org/wiki/AM-411?oldid=517503332 Contributors: Bearcat, Pegship, Drphilharmonic, Paradoxsociety, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Skoot13 and Anonymous: 1 • AM-630 Source: http://en.wikipedia.org/wiki/AM-630?oldid=590552979 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Enix150, SamChem7, Addbot, C6541, CheMoBot, Lapuchca, BogBot, Yunshui, Dcirovic, Skoot13, Shisha-Tom, Monkbot and Anonymous: 1 • AM-6545 Source: http://en.wikipedia.org/wiki/AM-6545?oldid=605160648 Contributors: Wavelength, Meodipt, CheMoBot, Tea with toast, Hazard-SJ, The chemistds and ChrisGualtieri • AM-679 (cannabinoid) Source: http://en.wikipedia.org/wiki/AM-679_(cannabinoid)?oldid=590553001 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, BogBot, The chemistds, Skoot13 and Monkbot • AM-694 Source: http://en.wikipedia.org/wiki/AM-694?oldid=541208550 Contributors: Bearcat, Aardark, Rjwilmsi, Edgar181, Drphilharmonic, Beetstra, Meodipt, Enix150, Pdcook, ClueBot, C6541, Ettrig, CheMoBot, AnomieBOT, حسن علي البط, Harbinary, Biker Biker, BogBot, Jesse V., John of Reading, D42kn355, Verified72 and Anonymous: 7
332
CHAPTER 252. TM-38837
• AM-855 Source: http://en.wikipedia.org/wiki/AM-855?oldid=590553033 Contributors: Bearcat, Chris Capoccia, Pegship, Edgar181, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Addihockey10 (automated) and Monkbot • AM-905 Source: http://en.wikipedia.org/wiki/AM-905?oldid=561228668 Contributors: Bearcat, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Addihockey10 (automated) • AM-906 Source: http://en.wikipedia.org/wiki/AM-906?oldid=587215378 Contributors: Bearcat, Pegship, Beetstra, Meodipt, Enix150, Panoramix303, CheMoBot, حسن علي البط, BogBot, Dcirovic and Skoot13 • AM-919 Source: http://en.wikipedia.org/wiki/AM-919?oldid=589343788 Contributors: Bearcat, Pegship, Beetstra, Meodipt, Mblumber, Enix150, CheMoBot, حسن علي البط, BogBot and Anonymous: 1 • AM-938 Source: http://en.wikipedia.org/wiki/AM-938?oldid=480558829 Contributors: Bearcat, Pegship, Meodipt, Enix150, Mentisock, CheMoBot, حسن علي البط, BogBot and The chemistds • AM404 Source: http://en.wikipedia.org/wiki/AM404?oldid=630846827 Contributors: Bearcat, Bk0, Rich Farmbrough, Xezbeth, WhiteTimberwolf, Rjwilmsi, Tavilis, Pegship, SmackBot, Edgar181, Deli nk, Beetstra, Ccroberts, Fvasconcellos, Cydebot, Probios, Magioladitis, Cgingold, ChemNerd, Boghog, The Right Honourable, Enix150, Chemgirl131, Addbot, DOI bot, Yobot, CheMoBot, حسن علي البط, Xasodfuih, Custoo, Kpstewart, Citation bot 1, Tea with toast, BogBot, Trappist the monk, Bushwakko, EmausBot, BG19bot, Monkbot, Medgirl131 and Anonymous: 12 • AMG-1 Source: http://en.wikipedia.org/wiki/AMG-1?oldid=599472934 Contributors: St3vo, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Dcirovic, The chemistds, Lugia2453 and Anonymous: 1 • AMG-3 Source: http://en.wikipedia.org/wiki/AMG-3?oldid=575104646 Contributors: Pegship, Beetstra, Meodipt, Kdaly100, Enix150, CheMoBot, حسن علي البط, BogBot, Jesse V., The chemistds and Anonymous: 1 • AMG-36 Source: http://en.wikipedia.org/wiki/AMG-36?oldid=517504824 Contributors: CheMoBot, حسن علي البط, BogBot and Skoot13
Pegship, Beetstra, Meodipt, Enix150,
• AMG-41 Source: http://en.wikipedia.org/wiki/AMG-41?oldid=570390555 Contributors: Pegship, GoodDay, Beetstra, Meodipt, Enix150, Panoramix303, CheMoBot, حسن علي البط, BogBot, Skoot13 and Anonymous: 1 • APINACA Source: http://en.wikipedia.org/wiki/APINACA?oldid=616218465 Contributors: Edgar181, Dl2000, Meodipt, Enix150, Ziggy Sawdust, Addbot, C6541, Yobot, AnomieBOT, Moscow Connection, EmausBot, ZéroBot, Soimort, Lionratz, The chemistds, AngusWOOF, Bcxfu75k, BaeyerDrewson, Yougotwarsh and Anonymous: 4 • AR-231,453 Source: http://en.wikipedia.org/wiki/AR-231,453?oldid=450845414 Contributors: Bearcat, Malcolma, Beetstra, Meodipt, Chemgirl131, CheMoBot, حسن علي البط, Citation bot 1, Nirmos, Tea with toast, BogBot, RjwilmsiBot and PotatoBot • Arachidonyl-2'-chloroethylamide Source: http://en.wikipedia.org/wiki/Arachidonyl-2'-chloroethylamide?oldid=592115240 Contributors: Rjwilmsi, Edgar181, Beetstra, CheMoBot, Citation bot, Tea with toast, 564dude and The chemistds • Arachidonylcyclopropylamide Source: http://en.wikipedia.org/wiki/Arachidonylcyclopropylamide?oldid=619280789 Contributors: Rjwilmsi, Edgar181, Beetstra, CheMoBot, Citation bot, Tea with toast, The chemistds and Skoot13 • N-Arachidonylglycine Source: http://en.wikipedia.org/wiki/N-Arachidonylglycine?oldid=630748266 Contributors: Edgar181, Citation bot, Trappist the monk, BG19bot, BattyBot, Kjkokesh, Anne Delong, Sanganik, HasteurBot, Monkbot, Medgirl131 and Anonymous: 2 • AZ-11713908 Source: http://en.wikipedia.org/wiki/AZ-11713908?oldid=590724305 Contributors: MZMcBride, Meodipt, Reedy Bot, CheMoBot, Hazard-SJ, The chemistds and Monkbot • BAY 38-7271 Source: http://en.wikipedia.org/wiki/BAY_38-7271?oldid=629306223 Contributors: Wimvandorst, Pegship, Beetstra, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Jesse V., The chemistds, Louisajb, Qixingbao07, Jodosma, BethNaught and Anonymous: 3 • BAY 59-3074 Source: http://en.wikipedia.org/wiki/BAY_59-3074?oldid=577145491 Contributors: CheMoBot, Anypodetos, حسن علي البط, BogBot and The chemistds
Pegship, Meodipt, Enix150,
• BML-190 Source: http://en.wikipedia.org/wiki/BML-190?oldid=588166438 Contributors: Rjwilmsi, Pegship, Edgar181, Drphilharmonic, Meodipt, ChemNerd, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, Dcirovic, MikeyMouse10, The chemistds and Shisha-Tom • (C6)- 47,497 Source: http://en.wikipedia.org/wiki/(C6)-_47,497?oldid=570943973 Contributors: Edgar181, Meodipt, JanetteDoe and Nikos 1993 • (C9)- 47,497 Source: http://en.wikipedia.org/wiki/(C9)-_47,497?oldid=570943911 Contributors: Edgar181, Meodipt, Tikuko, JanetteDoe and Nikos 1993 • Canbisol Source: http://en.wikipedia.org/wiki/Canbisol?oldid=618474701 Contributors: MZMcBride, Drphilharmonic, Meodipt, Reedy Bot, Enix150, CheMoBot, Anypodetos, FrescoBot, BogBot, Peryeat, The chemistds, Louisajb, Skoot13, Monkbot, Medgirl131 and Anonymous: 1 • Cannabichromene Source: http://en.wikipedia.org/wiki/Cannabichromene?oldid=627279471 Contributors: Chris Capoccia, Welsh, SmackBot, Edgar181, Jon513, Chrylis, Beetstra, VolkovBot, MenasimBot, Benrr101, Chem-awb, Mild Bill Hiccup, Plasmic Physics, Addbot, LaaknorBot, CheMoBot, Metalhead94, Citation bot, حسن علي البط, Custoo, A8UDI, RjwilmsiBot, EmausBot, Dcirovic, The chemistds, Louisajb, Nikos 1993, NotWith, Oneultralamewhiteboy and Anonymous: 1 • Cannabicyclohexanol Source: http://en.wikipedia.org/wiki/Cannabicyclohexanol?oldid=618475852 Contributors: Rich Farmbrough, EncMstr, Meodipt, Bobber0001, Boing! said Zebedee, Addbot, MartinezMD, CheMoBot, Biker Biker, BogBot, Dcirovic, ZéroBot, The chemistds, ClueBot NG, Diogenes2000, Skoot13, Robcrowl, Nikos 1993, Verified72, Monkbot, Medgirl131 and Anonymous: 4 • Cannabicyclol Source: http://en.wikipedia.org/wiki/Cannabicyclol?oldid=562446736 Contributors: Cheyinka, JIP, Pumeleon, Pegship, SmackBot, Edgar181, Beetstra, Leyo, Secretservgy, Panoramix303, Chemgirl131, Addbot, Mai-tai-guy, CheMoBot, Anypodetos, حسن علي البط, BenzolBot, Mcrosenstein, BogBot, Nikos 1993 and Anonymous: 5
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• Cannabidiol Source: http://en.wikipedia.org/wiki/Cannabidiol?oldid=630847328 Contributors: Bryan Derksen, MadSurgeon, Andrevan, Selket, Phil Boswell, Robbot, St3vo, Vanished 1234567890, Ary29, Alexrexpvt, Rich Farmbrough, Cacycle, Zaslav, Kwamikagami, Causa sui, Tgeller, Renice, Viriditas, Eric Kvaalen, Benjah-bmm27, Howrealisreal, Thoric, Animated Cascade, Ceyockey, Lofor, Rjwilmsi, Heah, FlaBot, A scientist, Margosbot, SouthernNights, Shao, Physchim62, WriterHound, ThunderPeel2001, Nick, Revaaron, ASmartKid, SmackBot, Alex Ex, Ohnoitsjamie, HartzR, Elixir0219, Zachorious, Frantik, Ioscius, BullRangifer, Drphilharmonic, DMacks, Acdx, Fireemblem555, Gobonobo, Ckatz, Smith609, Beetstra, SandyGeorgia, DeLarge, MessedRobot, ShelfSkewed, Meodipt, Linuxrocks123, Cydebot, Supposed, Mrt50, DumbBOT, Alaibot, Thijs!bot, CopperKettle, Subvertc, Headbomb, Nashmaximus, SummerPhD, Smartse, 18hands, Badgerbear, NLuchs, Noobeditor, Cadsuane Melaidhrin, ChemNerd, Fconaway, Enix150, Funandtrvl, Meiskam, Sergivs-en, MenasimBot, Wikieditor12, Benrr101, LetTheSunshineIn, Cheryladay, Gamesguru2, Vvevo, Yintan, Alexbrn, Danelo, Eplebel, Literaturegeek, Leodmacleod, Panoramix303, Chemgirl131, Dthomsen8, Addbot, C6541, DOI bot, Hermógenes Teixeira Pinto Filho, SamatBot, Pigoutultra, Lightbot, Yobot, CheMoBot, Anypodetos, AnomieBOT, Götz, Royote, Jtmorgan, Citation bot, LilHelpa, Zad68, حسن علي البط, Harbinary, O0Alea0o, P-kun80, Custoo, Citation bot 1, Nirmos, DrM!KEY, A8UDI, Codwiki, Sucrase, Tea with toast, Oldmaneinstein, BogBot, David Hedlund, Gtziavelis, Reach Out to the Truth, RjwilmsiBot, Dustin 3choes, Kefirmonger, Dcirovic, AManWithNoPlan, Eagleye54321, Allethrin, Ehsan soltani, Bayhemp, Rachman321, Louisajb, ClueBot NG, Vjiced, BakuninGoldmanKropotkin, Osterluzei, Soleil mouse, TeXnocrat, Redmitrow, Shabadahabada, Eeroth, Helpful Pixie Bot, Busician, BG19bot, Petrarchan47, Nikos 1993, Exercisephys, MrBill3, NotWith, 123957a, Fuse809, BattyBot, TheBaur, ChrisGualtieri, Qxukhgiels, FoCuSandLeArN, Webclient101, Will Sandberg, Steinsplitter, UseTheCommandLine, ComfyKem, ScoutKnot, Youtalkfunny, Tentinator, ArmbrustBot, Merff, Tired canadian, Tankbank420, Dave Underbridge, HeyItsAedan, JaconaFrere, Zouloum, MissSpade602, Logan Lynn Roberts, C.o.young, Monkbot, Mattdavid22, Silent Singularitarian, Wendywhatnot, Daveyboy9999, Jakens84, JackDemarco 420, Medgirl131, Tristonlarsen, Rowanbiggs, Aethyta, Shirt0ripper0, DystoniaPatient and Anonymous: 156 • Cannabidivarin Source: http://en.wikipedia.org/wiki/Cannabidivarin?oldid=599332824 Contributors: RedWolf, Jorge Stolfi, Foobar, Cacycle, Ceyockey, PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Frantik, Beetstra, Alaibot, Benrr101, GeorgeLTirebiter, Panoramix303, DumZiBoT, Chemgirl131, Addbot, CheMoBot, Anypodetos, Casforty, حسن علي البط, Nirmos, MastiBot, BogBot, EmausBot, Davesynth, Nikos 1993, NotWith, BattyBot and Anonymous: 2 • Cannabigerol Source: http://en.wikipedia.org/wiki/Cannabigerol?oldid=618473245 Contributors: Renice, Cheyinka, Rjwilmsi, Pegship, Edgar181, Beetstra, ChemNerd, Benrr101, Secretservgy, Chem-awb, Panoramix303, Chemgirl131, Addbot, Tide rolls, CheMoBot, Anypodetos, Metalhead94, Citation bot, حسن علي البط, Custoo, Nirmos, MastiBot, Tea with toast, BogBot, PotatoBot, Louisajb, MerlIwBot, Nikos 1993, NotWith, Shisha-Tom, Sedind, Monkbot, Medgirl131 and Anonymous: 3 • Cannabinoidergic Source: http://en.wikipedia.org/wiki/Cannabinoidergic?oldid=630539739 Contributors: Rjwilmsi, Bhny, Fram, Wilhelmina Will, Addbot, The Elves Of Dunsimore, Sunilaggarwal7, CitationCleanerBot, Monkbot and Medgirl131 • Cannabinol Source: http://en.wikipedia.org/wiki/Cannabinol?oldid=618473196 Contributors: Robbot, Cacycle, Pacula, Howrealisreal, Ceyockey, Rjwilmsi, FlaBot, Physchim62, Pegship, SmackBot, Eskimbot, Frymaster, Edgar181, Lieutenant Colonel Frank Slade, Beetstra, Saxbryn, Cydebot, Rifleman 82, Absentis, Alaibot, Subvertc, VolkovBot, MenasimBot, THC Loadee, Benrr101, Chem-awb, Anthonyvidal, Eeekster, Panoramix303, Stevem848, Chemgirl131, Addbot, DOI bot, LaaknorBot, Wormantson, Luckas-bot, Ptbotgourou, Fraggle81, CheMoBot, Anypodetos, Götz, حسن علي البط, P-kun80, Custoo, Micasta, Citation bot 1, A8UDI, RedBot, MastiBot, BogBot, PotatoBot, Peryeat, Osterluzei, Jonfarrimond, Bemopa, Nikos 1993, NotWith, ArmbrustBot, MissSpade602, Monkbot, Sentaloc, Medgirl131 and Anonymous: 15 • Cannabivarin Source: http://en.wikipedia.org/wiki/Cannabivarin?oldid=599333620 Contributors: Jorge Stolfi, Cacycle, Aude, Ceyockey, PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Beetstra, Saxbryn, Alaibot, Benrr101, Chem-awb, Panoramix303, Addbot, CheMoBot, Casforty, حسن علي البط, FrescoBot, EmausBot, Dcirovic, HiW-Bot, Nikos 1993 and Anonymous: 1 • Caryophyllene Source: http://en.wikipedia.org/wiki/Caryophyllene?oldid=622304553 Contributors: Mboverload, Rich Farmbrough, Kwamikagami, Mendaliv, Rjwilmsi, WriterHound, Chris Capoccia, SmackBot, Edgar181, Sesquis, Mwtoews, DMacks, Beetstra, Timothykinney, Meodipt, Cydebot, Calvero JP, Deflective, NEUROtiker, ChemNerd, Arsenal1508, TimofKingsland, Chem-awb, Sensonet, Alexbot, Panoramix303, Addbot, DOI bot, Fothergill Volkensniff IV, LaaknorBot, Luckas-bot, Yobot, CheMoBot, Citation bot, Xqbot, حسن علي البط, Itineranttrader, Andromeas, Custoo, FrescoBot, Citation bot 1, Sorneguer, EmausBot, Dcirovic, NotWith, Bcary, DarafshBot, Mogism, ArmbrustBot, Monkbot, RohdeN and Anonymous: 14 • CB-13 Source: http://en.wikipedia.org/wiki/CB-13?oldid=590870232 Contributors: Meodipt, Enix150, Yobot, CheMoBot, حسن علي البط, BogBot, Hazard-SJ, BaeyerDrewson, Monkbot and Anonymous: 1 • CBS-0550 Source: http://en.wikipedia.org/wiki/CBS-0550?oldid=570619983 Contributors: Meodipt, The chemistds and Skoot13 • 47,497 Source: http://en.wikipedia.org/wiki/_47,497?oldid=610061328 Contributors: Cacycle, Alansohn, Poul818, Pegship, Cybercobra, Valenciano, Beetstra, Meodipt, Cydebot, Thijs!bot, Smartse, Enix150, Funandtrvl, TXiKiBoT, ClueBot, Addbot, C6541, MartinezMD, Ryanjca, حسن علي البط, Custoo, DrilBot, Biker Biker, BogBot, Akerans, LoverOfTheWord, Louisajb, ClueBot NG, Skoot13, Nikos 1993, Verified72, Woo 24, Monkbot and Anonymous: 26 • 55,244 Source: http://en.wikipedia.org/wiki/_55,244?oldid=561022757 Contributors: Rjwilmsi, Pegship, Edgar181, Meodipt, Rhadamante, Enix150, Funandtrvl, CheMoBot, حسن علي البط, BogBot and Anonymous: 1 • 55,940 Source: http://en.wikipedia.org/wiki/_55,940?oldid=618472345 Contributors: DropDeadGorgias, Ktotam, St3vo, Sam Hocevar, Cacycle, Flying Hamster, Ceyockey, Galaxiaad, Pol098, Rjwilmsi, Heah, Physchim62, Muijzo, Kajerm, SmackBot, GoldenXuniversity, Hmains, Tsca.bot, Simonster, Rory096, Saxbryn, Ccroberts, Meodipt, Cydebot, CDrecche, Alaibot, MattTweedell, Astavats, Floaterfluss, Tanevala, Enix150, Funandtrvl, Jonakimmen, Psych0-007, Wertyg, Modern Shaman, Addbot, C6541, Chempedia, AnomieBOT, Citation bot, حسن علي البط, Harbinary, Custoo, FrescoBot, BogBot, RjwilmsiBot, PotatoBot, Louisajb, Skoot13, Yukileoo, Delphine Psychoyos, Medgirl131 and Anonymous: 27 • Dexanabinol Source: http://en.wikipedia.org/wiki/Dexanabinol?oldid=602665690 Contributors: Drphilharmonic, Beetstra, Meodipt, Rod57, Enix150, Panoramix303, Addbot, CheMoBot, Anypodetos, حسن علي البط, Citation bot 1, HRoestBot, Tea with toast, BogBot, The chemistds, ClueBot NG, Skoot13, Monkbot, Madtay and Anonymous: 3 • Dimethylheptylpyran Source: http://en.wikipedia.org/wiki/Dimethylheptylpyran?oldid=629287274 Contributors: Bkell, St3vo, GregorB, Rjwilmsi, Pegship, Chris the speller, Beetstra, Meodipt, Astavats, Funandtrvl, Wikieditor12, Panoramix303, Chemgirl131, C6541, CheMoBot, Anypodetos, Rifter0x0000, Metalhead94, Materialscientist, Citation bot, حسن علي البط, Harbinary, BogBot, Lotje, Dcirovic, K kisses, Daviesje, Nikos 1993, Testem, ChrisGualtieri, Medgirl131 and Anonymous: 7
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• Docosatetraenoylethanolamide Source: http://en.wikipedia.org/wiki/Docosatetraenoylethanolamide?oldid=479428373 Contributors: Edgar181, Beetstra, Cydebot, CheMoBot, Citation bot, Erik9bot, Kpstewart, Citation bot 1, Tea with toast, The chemistds and Anonymous: 1 • Drinabant Source: http://en.wikipedia.org/wiki/Drinabant?oldid=608365837 Contributors: Woohookitty, Rjwilmsi, Edgar181, Meodipt, Chemgirl131, Yobot, A412 and Anonymous: 1 • EAM-2201 Source: http://en.wikipedia.org/wiki/EAM-2201?oldid=602234811 Contributors: Dl2000, Meodipt, Magioladitis, Destruktor5000, D42kn355 and Anonymous: 3 • Endocannabinoid reuptake inhibitor Source: http://en.wikipedia.org/wiki/Endocannabinoid_reuptake_inhibitor?oldid=630847750 Contributors: Firsfron, De728631, Mild Bill Hiccup, SchreiberBike, Custoo, Rideer13, AvicAWB, SaetaSolea, Beedublu, Jpgunner13, Sbuinformation, Medgirl131 and Anonymous: 3 • Endocannabinoid system Source: http://en.wikipedia.org/wiki/Endocannabinoid_system?oldid=630033669 Contributors: Nagelfar, Rich Farmbrough, Lycurgus, Jpgordon, C4 Diesel, Rjwilmsi, Chris Capoccia, Tavilis, Trovatore, Pb30, Winter Light, Banus, SmackBot, Roadnottaken, Mini-Geek, Clicketyclack, Gobonobo, Kimdonndenman, Rhetth, Darthelmo, Inferiority, CopperKettle, Headbomb, Leon7, Nick Number, MarshBot, Thibbs, Marcuj, Nono64, Boghog, Colincbn, Tanevala, Enix150, DragonBot, BDov777, ZuluPapa5, Wnt, DumZiBoT, Chemgirl131, Mjpresson, Ost316, Vojtěch Dostál, Addbot, JayGSXR750, Yobot, Bunnyhop11, Jzlong, Wrightmj, AnomieBOT, Materialscientist, Citation bot, Drilnoth, The myoclonic jerk, Lothar von Richthofen, Citation bot 1, I dream of horses, Tea with toast, David Hedlund, Gtziavelis, virus, Lucas Thoms, Jlb92, ClueBot NG, Vjiced, Osterluzei, SaetaSolea, Bibcode Bot, Snow Blizzard, Glacialfox, Wyliea, BattyBot, Hoodjuice, Ramizein, Meteor sandwich yum, Monkbot, Medgirl131, Mrokiestar and Anonymous: 59 • Endocannabinoid transporters Source: http://en.wikipedia.org/wiki/Endocannabinoid_transporters?oldid=625857200 Contributors: Rjwilmsi, Wavelength, Vigyani, Yobot, Citation bot, Alvin Seville, GoingBatty, Sbuinformation, Anaffen21, Medgirl131 and Anonymous: 1 • GW-405,833 Source: http://en.wikipedia.org/wiki/GW-405,833?oldid=610061444 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Cydebot, Enix150, Addbot, CheMoBot, حسن علي البط, Harbinary, Custoo, BogBot, Dcirovic and Louisajb • GW-842,166X Source: http://en.wikipedia.org/wiki/GW-842,166X?oldid=591559628 Contributors: Meodipt, CheMoBot, BogBot, The chemistds, Louisajb and Monkbot • Hemopressin Source: http://en.wikipedia.org/wiki/Hemopressin?oldid=619651829 Contributors: Kielsky, Arcadian, Rjwilmsi, Meodipt, Boghog, Enix150, Ronhjones, CheMoBot, ScottMHoward, Jesse V., RjwilmsiBot, The chemistds, Monkbot, Medgirl131 and Anonymous: 5 • HU-210 Source: http://en.wikipedia.org/wiki/HU-210?oldid=618472397 Contributors: Fnielsen, Rich Farmbrough, Cacycle, ZayZayEM, SqueakBox, Heah, Margosbot, Physchim62, Fourdee, WriterHound, YurikBot, Gaius Cornelius, Daemon8666, Pegship, SmackBot, C.Löser, GoldenXuniversity, Edgar181, Nuklear, Cybercobra, Drphilharmonic, Ourai, Beetstra, Ccroberts, CmdrObot, Meodipt, Alaibot, Gharmon, Turkeyphant, Smartse, Hoffmeier, ThinkBlue, Enix150, Funandtrvl, VolkovBot, Fences and windows, Altzinn, SPECVLVMSINCERVS, Panoramix303, Addbot, DOI bot, Tide rolls, Alfie66, Luckas-bot, Yobot, CheMoBot, Metalhead94, Götz, Codc, حسن علي البط, Harbinary, FrescoBot, StrawberryCube, Biker Biker, Snazzra, Calmer Waters, JKChandler, BogBot, Gould363, SalviaFan, Nuujinn, Renamed01302013, Daviesje, Phenomenologyx, Louisajb, Doctorarcane, RealMortimir, Skoot13, SubDural12, Verified72, Hmainsbot1, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 51 • HU-243 Source: http://en.wikipedia.org/wiki/HU-243?oldid=536294331 Contributors: Meodipt • HU-308 Source: http://en.wikipedia.org/wiki/HU-308?oldid=610213643 Contributors: St3vo, Wimvandorst, FlaBot, Pegship, Nuklear, Drphilharmonic, Beetstra, Meodipt, Cydebot, Enix150, Panoramix303, Addbot, C6541, CheMoBot, حسن علي البط, Custoo, BogBot, Dcirovic, Jimer and Anonymous: 2 • HU-331 Source: http://en.wikipedia.org/wiki/HU-331?oldid=613064375 Contributors: BD2412, Drphilharmonic, Meodipt, R'n'B, Enix150, SchreiberBike, Addbot, CheMoBot, Anypodetos, KamikazeBot, MALLUS, The chemistds, Skoot13, NotWith and ChrisGualtieri • 11-Hydroxy-THC Source: http://en.wikipedia.org/wiki/11-Hydroxy-THC?oldid=620143359 Contributors: Yidele, Cacycle, Rjwilmsi, Derek.cashman, Edgar181, Beetstra, Suboptimal name, Meodipt, Isilanes, Equazcion, DorganBot, Danelo, Alexbot, Panoramix303, MystBot, Addbot, Yobot, CheMoBot, KamikazeBot, Citation bot, حسن علي البط, Harbinary, Citation bot 1, BogBot, Jynto, Medgirl131 and Anonymous: 3 • 9-nor-9β-Hydroxyhexahydrocannabinol Source: http://en.wikipedia.org/wiki/9-nor-9β-Hydroxyhexahydrocannabinol?oldid= 517509498 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150, Yobot, Citation bot, حسن علي البط, Skoot13 and Anonymous: 1 • Ibipinabant Source: http://en.wikipedia.org/wiki/Ibipinabant?oldid=618474939 Contributors: Rjwilmsi, Pegship, SmackBot, Meodipt, Enix150, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Citation bot, حسن علي البط, BogBot, Peryeat, The chemistds, Louisajb, Pashihiko, Vaccinationist, Medgirl131 and Anonymous: 2 • IDFP Source: http://en.wikipedia.org/wiki/IDFP?oldid=576656123 Contributors: Meodipt • 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene Source: http://en.wikipedia.org/wiki/ Cacycle, Deyyaz, Peg2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene?oldid=545325142 Contributors: ship, Edgar181, Meodipt, Nono64, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, EmausBot and Anonymous: 1 • JTE 7-31 Source: http://en.wikipedia.org/wiki/JTE_7-31?oldid=546233677 Contributors: Meodipt, Enix150, Addbot, CheMoBot, RevelationDirect, Skoot13 and AvocatoBot • JTE-907 Source: http://en.wikipedia.org/wiki/JTE-907?oldid=606454861 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt, Smartse, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, EmausBot, Skoot13, Stark1987, WildCation and Anonymous: 1 • JWH-015 Source: http://en.wikipedia.org/wiki/JWH-015?oldid=616440152 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt, Cydebot, Headbomb, Boghog, Enix150, Addbot, C6541, Queenmomcat, CheMoBot, Citation bot, حسن علي البط, Lapuchca, Custoo, Jonesey95, BogBot, Tisane, Dcirovic, Skoot13, Monkbot, WildCation and Anonymous: 3 • JWH-051 Source: http://en.wikipedia.org/wiki/JWH-051?oldid=606457301 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot, Tisane, WildCation and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• JWH-057 Source: http://en.wikipedia.org/wiki/JWH-057?oldid=606458240 Contributors: Bgwhite, Meodipt, Magioladitis, AnomieBOT, BaeyerDrewson and WildCation • JWH-120 Source: http://en.wikipedia.org/wiki/JWH-120?oldid=606478716 Contributors: Meodipt, BaeyerDrewson and WildCation • JWH-122 Source: http://en.wikipedia.org/wiki/JWH-122?oldid=560783506 Contributors: Bearcat, Edgar181, Beetstra, Meodipt, Katharineamy, Enix150, Cvf-ps, Addbot, C6541, Yobot, CheMoBot, A412, Diogenes2000, Skoot13, Snotbot, JamietwBot and Anonymous: 2 • JWH-133 Source: http://en.wikipedia.org/wiki/JWH-133?oldid=618472603 Contributors: St3vo, Arcadian, SmackBot, Zaphraud, Beetstra, Saxbryn, Ccroberts, CmdrObot, Meodipt, Cydebot, NewEnglandYankee, Tanevala, Enix150, Altzinn, Addbot, CheMoBot, حسن علي البط, Harbinary, Anonabyss, Custoo, BogBot, Tisane, Dcirovic, Frozen Wind, Rich Smith, Managermerrill, AwamerT, Drblizz, Medgirl131 and Anonymous: 16 • JWH-148 Source: http://en.wikipedia.org/wiki/JWH-148?oldid=606481972 Contributors: Meodipt, BaeyerDrewson and WildCation • JWH-149 Source: http://en.wikipedia.org/wiki/JWH-149?oldid=606483315 Contributors: Meodipt, C6541, BaeyerDrewson and WildCation • JWH-161 Source: http://en.wikipedia.org/wiki/JWH-161?oldid=606483553 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150, CheMoBot, حسن علي البط, FrescoBot, BogBot and WildCation • JWH-176 Source: http://en.wikipedia.org/wiki/JWH-176?oldid=606485810 Contributors: Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Tisane, Deathhell77 and WildCation • JWH-359 Source: http://en.wikipedia.org/wiki/JWH-359?oldid=502194790 Contributors: Rjwilmsi, Nuklear, Meodipt, Headbomb, Nono64, Enix150, CheMoBot, Grim23, حسن علي البط, FrescoBot, BogBot, Tisane, Rich Smith, Managermerrill and Anonymous: 4 • JZL184 Source: http://en.wikipedia.org/wiki/JZL184?oldid=591975737 Contributors: Wimvandorst, Roadnottaken, Beetstra, Meodipt, Enix150, Chem-awb, Addbot, CheMoBot, Anypodetos, Jzlong, حسن علي البط, P-kun80, Citation bot 1, Nirmos, EmausBot, PotatoBot, Monkbot and Anonymous: 3 • JZL195 Source: http://en.wikipedia.org/wiki/JZL195?oldid=546258079 Contributors: Enix150, Addbot, The Blade of the Northern Lights and Rezabot • KM-233 Source: http://en.wikipedia.org/wiki/KM-233?oldid=624180345 Contributors: BD2412, Meodipt, Dthomsen8, Yobot, Skoot13 and WildCation • L-759,633 Source: http://en.wikipedia.org/wiki/L-759,633?oldid=610061479 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt, Cydebot, Enix150, Addbot, CheMoBot, Citation bot, حسن علي البط, Custoo, Citation bot 1, BogBot, Dcirovic, Louisajb and Shisha-Tom • L-759,656 Source: http://en.wikipedia.org/wiki/L-759,656?oldid=545322433 Contributors: Pegship, Nuklear, Drphilharmonic, Meodipt, Enix150, ClueBot, Addbot, CheMoBot, حسن علي البط, BogBot, Dcirovic, Louisajb and Anonymous: 1 • LASSBio-881 Source: http://en.wikipedia.org/wiki/LASSBio-881?oldid=489676335 Contributors: Meodipt • LBP-1 (drug) Source: http://en.wikipedia.org/wiki/LBP-1_(drug)?oldid=587855670 Contributors: Meodipt, Hazard-SJ and ChrisGualtieri • Leelamine Source: http://en.wikipedia.org/wiki/Leelamine?oldid=618475826 Contributors: Magioladitis, Eeekster, Sekio and Medgirl131 • Levonantradol Source: http://en.wikipedia.org/wiki/Levonantradol?oldid=618472637 Contributors: Howrealisreal, Wouterstomp, Rjwilmsi, FlaBot, Pegship, Edgar181, Beetstra, Meodipt, Cydebot, Enix150, Funandtrvl, Sam Blacketer, Addbot, CheMoBot, Anypodetos, حسن علي البط, Harbinary, Custoo, BogBot, ZéroBot, Peryeat, Skoot13, BattyBot, Najenager, Monkbot, Medgirl131 and Anonymous: 1 • List of AM cannabinoids Source: http://en.wikipedia.org/wiki/List_of_AM_cannabinoids?oldid=604703358 Contributors: Bearcat, Chris the speller, Meodipt, Enix150, Citation bot, BattyBot, Monkbot and Anonymous: 5 • List of JWH cannabinoids Source: http://en.wikipedia.org/wiki/List_of_JWH_cannabinoids?oldid=607385076 Contributors: Rjwilmsi, Meodipt, Uruiamme, Enix150, The Thing That Should Not Be, Ironholds, Quebec99, RjwilmsiBot, Tisane, 4321acb, BG19bot, BaeyerDrewson and Anonymous: 3 • LY-2183240 Source: http://en.wikipedia.org/wiki/LY-2183240?oldid=630847383 Contributors: Meodipt, Addbot, Rezabot, Fylbecatulous, WildCation, Medgirl131 and Anonymous: 3 • LY-320,135 Source: http://en.wikipedia.org/wiki/LY-320,135?oldid=525861108 Contributors: Pegship, Meodipt, RXPhd, Yobot, CheMoBot, حسن علي البط, BogBot and Anonymous: 1 • MAM-2201 Source: http://en.wikipedia.org/wiki/MAM-2201?oldid=615014022 Contributors: Dl2000, Meodipt, C6541, AnomieBOT, Harbinary and WildCation • MDA-19 Source: http://en.wikipedia.org/wiki/MDA-19?oldid=517576564 Contributors: Drphilharmonic, Beetstra, Meodipt, CheMoBot and Skoot13 • Menabitan Source: http://en.wikipedia.org/wiki/Menabitan?oldid=621328559 Contributors: Rjwilmsi, Edgar181, Meodipt, Chemgirl131, Anypodetos, Braincricket, Monkbot and Medgirl131 • Methanandamide Source: http://en.wikipedia.org/wiki/Methanandamide?oldid=544106189 Contributors: Bearcat, St3vo, Wimvandorst, Stemonitis, Rjwilmsi, SmackBot, Edgar181, Bluebot, Beetstra, Cytocon, Waacstats, STBot, Nono64, Enix150, Plasmic Physics, Addbot, CheMoBot, Anypodetos, Citation bot, حسن علي البط, Erik9bot, Tea with toast, Skoot13, Amolbot and Anonymous: 4 • MK-9470 Source: http://en.wikipedia.org/wiki/MK-9470?oldid=612370825 Contributors: Rjwilmsi, Pegship, Edgar181, DMacks, CmdrObot, Meodipt, MSBOT, Boghog, Chem-awb, Addbot, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, RedBot, Dcirovic and WildCation • N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-methoxyindole-3-carboxamide Source: http://en.wikipedia.org/wiki/N-(S) Edgar181, A5b, Meodipt, -Fenchyl-1-(2-morpholinoethyl)$-$7-methoxyindole-3-carboxamide?oldid=592608780 Contributors: Smartse, Ben MacDui, Enix150, Denisarona, Addbot, CheMoBot, AnomieBOT, Citation bot, Xqbot, SDPatrolBot, Dcirovic, The chemistds, Skoot13, ScottSteiner, Vasiliy 100, Vasiliy 101, ChrisGualtieri, Monkbot and Anonymous: 1
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• Nabazenil Source: http://en.wikipedia.org/wiki/Nabazenil?oldid=628470027 Contributors: Meodipt, ChemNerd, CheMoBot, حسن علي البط, BogBot, Peryeat, Helpful Pixie Bot, WildCation and Medgirl131 • Nabilone Source: http://en.wikipedia.org/wiki/Nabilone?oldid=627639158 Contributors: Selket, IceKarma, St3vo, Cacycle, Arcadian, Kjkolb, E=MC^2, Rad Racer, Rjwilmsi, Heah, FlaBot, Ground Zero, Kerowyn, Bgwhite, Asacarny, Pegship, JRey, Andrew73, SmackBot, Edgar181, Zachorious, Cybercobra, Beetstra, CmdrObot, Meodipt, Guitarmankev1, Anthonyhcole, Alaibot, Tins128, Amontgomery, Gwern, AliaGemma, ChemNerd, Gojo002, Floaterfluss, Enix150, Funandtrvl, McM.bot, Dr.michael.benjamin, Flyer22, Alexbrn, Atdavies, Mlaffs, Zhile, Dr. Anymouse, Chemgirl131, Addbot, DOI bot, Earthguy69, Yobot, CheMoBot, Yngvadottir, AnomieBOT, Metalhead94, Citation bot, Jü, حسن علي البط, Harbinary, Apteekkarin poika, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot, ZéroBot, Peteb4, Louisajb, ClueBot NG, Skoot13, Petrarchan47, PhnomPencil, Scopolaminemethylnitrate, Fuse809, Crocodile100100, Monkbot, Medgirl131, SP1977 and Anonymous: 27 • Nabitan Source: http://en.wikipedia.org/wiki/Nabitan?oldid=618475710 Contributors: St3vo, Pegship, Edgar181, Beetstra, Meodipt, Leftfoot69, Funandtrvl, Addbot, Yobot, CheMoBot, Anypodetos, حسن علي البط, BogBot, Snubcube, NotWith and Medgirl131 • Nabiximols Source: http://en.wikipedia.org/wiki/Nabiximols?oldid=625135113 Contributors: Pfrishauf, Arm, Jfdwolff, Trevor MacInnis, Tribble, Pacula, Eleland, Oasisbob, GJeffery, SidP, Galaxiaad, Urod, Tokek, SqueakBox, Vegaswikian, Aspro, WriterHound, YurikBot, Shalmoo, Andrew73, Anarchist42, Poldavo, Uthbrian, Cybercobra, Beetstra, L'œuf, Yaris678, Anthonyhcole, Psilocin, Path2k6, DB1986, Jamieliz, McM.bot, Martha p, VVVBot, Fibo1123581321, Toddst1, Dala11a, Denisarona, Morton12, Maxxx55, Mjpresson, Addbot, C6541, DOI bot, Armyyo, Luckas-bot, Yobot, CheMoBot, Anypodetos, GrouchoBot, Fuz2y, Dpf90, The myoclonic jerk, RedBot, Tea with toast, EmausBot, ZéroBot, Norsci, Satellizer, Vjiced, TheNoBrainer, Fuse809, Ellomo, Sedind, Medgirl131 and Anonymous: 49 • Naboctate Source: http://en.wikipedia.org/wiki/Naboctate?oldid=618475582 Contributors: Meodipt, Kupirijo, ChemNerd, CheMoBot, حسن علي البط, BogBot, Peryeat, Helpful Pixie Bot and Medgirl131 • NESS-0327 Source: http://en.wikipedia.org/wiki/NESS-0327?oldid=557658516 Contributors: Pegship, SmackBot, Edgar181, Meodipt, Tanevala, Enix150, Yobot, CheMoBot, Rjanag, حسن علي البطand BogBot • NESS-040C5 Source: http://en.wikipedia.org/wiki/NESS-040C5?oldid=581293179 Contributors: Meodipt and Mrbenzhao • NMP-7 Source: http://en.wikipedia.org/wiki/NMP-7?oldid=574549912 Contributors: Meodipt and The chemistds • Nonabine Source: http://en.wikipedia.org/wiki/Nonabine?oldid=618472034 Contributors: Wimvandorst, Pegship, Edgar181, Beetstra, Meodipt, CheMoBot, Anypodetos, حسن علي البط, BogBot, PotatoBot, Peryeat, NotWith, Medgirl131 and Anonymous: 1 • 11-nor-9-Carboxy-THC Source: http://en.wikipedia.org/wiki/11-nor-9-Carboxy-THC?oldid=626249075 Contributors: Cacycle, Rjwilmsi, Edgar181, Beetstra, Meodipt, ChemNerd, Bobber0001, Addbot, Luckas-bot, Legobot II, CheMoBot, Citation bot, حسن علي البط, Harbinary, Custoo, Citation bot 1, A8UDI, BogBot, 564dude, Jynto, EmausBot, Shisha-Tom, Igramudi, Medgirl131 and Anonymous: 10 • O-1057 Source: http://en.wikipedia.org/wiki/O-1057?oldid=608378294 Contributors: Pegship, Closedmouth, Meodipt, Enix150, Panoramix303, CheMoBot, حسن علي البط, BogBot, Gunnanmon, Skoot13 and WildCation • O-1125 Source: http://en.wikipedia.org/wiki/O-1125?oldid=608380315 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and WildCation • O-1238 Source: http://en.wikipedia.org/wiki/O-1238?oldid=513487985 Contributors: Shoefly, Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Shisha-Tom • O-1269 Source: http://en.wikipedia.org/wiki/O-1269?oldid=538765444 Contributors: Meodipt • O-1602 Source: http://en.wikipedia.org/wiki/O-1602?oldid=546479215 Contributors: Meodipt • O-1812 Source: http://en.wikipedia.org/wiki/O-1812?oldid=607130796 Contributors: Drphilharmonic, Meodipt, Enix150, Plasmic Physics, CheMoBot, BogBot, Skoot13 and Monkbot • O-1871 Source: http://en.wikipedia.org/wiki/O-1871?oldid=563934779 Contributors: Meodipt • O-1918 Source: http://en.wikipedia.org/wiki/O-1918?oldid=546480992 Contributors: Meodipt • O-2050 Source: http://en.wikipedia.org/wiki/O-2050?oldid=473933807 Contributors: Meodipt • O-2113 Source: http://en.wikipedia.org/wiki/O-2113?oldid=517511788 Contributors: Meodipt, The chemistds and Skoot13 • O-2372 Source: http://en.wikipedia.org/wiki/O-2372?oldid=591901705 Contributors: Edgar181, Drphilharmonic, Meodipt, Enix150, CheMoBot, BogBot, Skoot13 and Anonymous: 1 • O-2545 Source: http://en.wikipedia.org/wiki/O-2545?oldid=517511924 Contributors: Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, Gunnanmon, Skoot13 and Anonymous: 3 • O-2694 Source: http://en.wikipedia.org/wiki/O-2694?oldid=517511601 Contributors: Pegship, Drphilharmonic, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot and Skoot13 • O-774 Source: http://en.wikipedia.org/wiki/O-774?oldid=607131131 Contributors: Meodipt, Enix150, Anypodetos, The chemistds and Skoot13 • O-806 Source: http://en.wikipedia.org/wiki/O-806?oldid=448105477 Contributors: Pegship, Nuklear, Meodipt, Marek69, Enix150, CheMoBot, حسن علي البط, BogBot and The chemistds • O-823 Source: http://en.wikipedia.org/wiki/O-823?oldid=513577948 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, حسن علي البط, BogBot, The chemistds and Shisha-Tom • Org 27569 Source: http://en.wikipedia.org/wiki/Org_27569?oldid=592717766 Contributors: Meodipt, Addbot, CheMoBot, BogBot, Dcirovic, The chemistds and Monkbot • Org 28312 Source: http://en.wikipedia.org/wiki/Org_28312?oldid=592716560 Contributors: Beetstra, Meodipt, Enix150, CheMoBot, BogBot, The chemistds and Monkbot • Org 28611 Source: http://en.wikipedia.org/wiki/Org_28611?oldid=592716578 Contributors: Beetstra, Meodipt, Enix150, CheMoBot, BogBot, The chemistds and Monkbot
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• Otenabant Source: http://en.wikipedia.org/wiki/Otenabant?oldid=618474885 Contributors: Pegship, SmackBot, Meodipt, Chemgirl131, CheMoBot, Anypodetos, Rjanag, حسن علي البط, Harbinary, Custoo, Citation bot 1, Jonesey95, BogBot, RjwilmsiBot, Peryeat, Louisajb, Pashihiko, Skoot13, WildCation and Medgirl131 • Parahexyl Source: http://en.wikipedia.org/wiki/Parahexyl?oldid=618474777 Contributors: SqueakBox, Pegship, Beetstra, Meodipt, JaGa, Funandtrvl, Panoramix303, DumZiBoT, Addbot, DOI bot, CheMoBot, Anypodetos, Citation bot, حسن علي البط, BogBot, Nikos 1993, Medgirl131 and Anonymous: 5 • UR-144 Source: http://en.wikipedia.org/wiki/UR-144?oldid=627620534 Contributors: Discospinster, Wainblatrobert, MZMcBride, Vegaswikian, Edgar181, Myxsoma, Beetstra, Meodipt, Smartse, JamesBWatson, ChemNerd, Boghog, Reedy Bot, Enix150, Yikrazuul, Carriearchdale, C6541, , CheMoBot, AnomieBOT, SDPatrolBot, AManWithNoPlan, ClueBot NG, Skoot13, Frietjes, O.Koslowski, Ieponumos, Dipankan001, Vasiliy 100, Stark1987, ChrisGualtieri, BaeyerDrewson, Luxemoxie, Yougotwarsh, Rebrewind, Monkbot, Rusty Lugnuts and Anonymous: 22 • Perrottetinene Source: http://en.wikipedia.org/wiki/Perrottetinene?oldid=518915209 Contributors: Meodipt, Benrr101, CheMoBot, Anypodetos, حسن علي البط, BogBot and Anonymous: 2 • PF-03550096 Source: http://en.wikipedia.org/wiki/PF-03550096?oldid=618824275 Contributors: Meodipt, FreddysFun and WildCation • PF-514273 Source: http://en.wikipedia.org/wiki/PF-514273?oldid=583222914 Contributors: Meodipt, Anypodetos and The chemistds • PipISB Source: http://en.wikipedia.org/wiki/PipISB?oldid=538846629 Contributors: Meodipt • Pirnabine Source: http://en.wikipedia.org/wiki/Pirnabine?oldid=618818792 Contributors: Beetstra, Meodipt, CheMoBot, حسن علي البط, BogBot, WildCation and Medgirl131 • PSB-SB-1202 Source: http://en.wikipedia.org/wiki/PSB-SB-1202?oldid=575732178 Contributors: Meodipt, Fraggle81 and Mrbenzhao • PSB-SB-487 Source: http://en.wikipedia.org/wiki/PSB-SB-487?oldid=557656947 Contributors: Meodipt • QUCHIC Source: http://en.wikipedia.org/wiki/QUCHIC?oldid=617182468 Contributors: Meodipt, Yobot, SciRambar, The chemistds, BaeyerDrewson, Yougotwarsh and Anonymous: 7 • QUPIC Source: http://en.wikipedia.org/wiki/QUPIC?oldid=619859946 Contributors: Velella, Rjwilmsi, Meodipt, Enix150, Earcanal, Yobot, AnomieBOT, SciRambar, AManWithNoPlan, The chemistds, BG19bot, BaeyerDrewson, Dr J.Rozen, Yougotwarsh and Anonymous: 12 • Rimonabant Source: http://en.wikipedia.org/wiki/Rimonabant?oldid=628033220 Contributors: Kpjas, MadSurgeon, David spector, Tpbradbury, Francs2000, Schutz, ZimZalaBim, Obli, Fjarlq, St3vo, Geni, BozMo, Beland, Nowster, M1ss1ontomars2k4, Monkeyman, Rich Farmbrough, Cacycle, Peak Freak, Jtact, Remuel, Arcadian, Pacula, Wouterstomp, Malo, Versageek, Siafu, Scjessey, Eras-mus, SDC, Rjwilmsi, Darguz Parsilvan, Miserlou, Margosbot, Stevenfruitsmaak, Hydrargyrum, Janke, Semperf, Syldaril, Smaines, Yonidebest, Bdell555, Zzuuzz, Closedmouth, Colin, Kajerm, Jeffreymcmanus, SmackBot, Edgar181, Gilliam, Amatulic, Deli nk, Cormagh, JanesDaddy, Oltsw, KaiserbBot, Roadnottaken, JonHarder, Apexprim8, JHe, Cybercobra, Drphilharmonic, Lobster101, Simonster, Beetstra, Bwalters, Az1568, Linkspamremover, Fvasconcellos, DoctorFuQang, Cytocon, DrPiotroski, Give Peace A Chance, Ward3001, Thijs!bot, Sacxnz, Adjespers, Link Spam Remover, Mcscmd, AntiVandalBot, Yupik, Dextrovert, João Carvalho, Postlewaight, Astavats, Kgbveg, Rkwwkr, Krunalc, It2media, DietGurl, .anacondabot, OM, MaxPont, Jackboogie, Mtiffany71, Crazy-Chemist, Rettetast, Kkeane, Boghog, Mikael Häggström, Tanevala, Enix150, Danbearsea, TXiKiBoT, Celtus, Mikeaubert, GPryce, Nadsozinc, Eve Teschlemacher, Poterala, Oreiser, Le feu, Vcare, Lightmouse, Phillymutt, Sabne, Rimonabant, Sisalgs, ClueBot, Schaea, Osm agha, Carlo Banez, Panoramix303, Pharmankur, BlackHoleSon, DumZiBoT, Chemgirl131, Gazimoff, Addbot, DOI bot, SpBot, Shankkark, Nizil Shah, TALKO, CheMoBot, Anypodetos, AnomieBOT, Casforty, Rjanag, LilHelpa, Dagrun, Gigemag76, حسن علي البط, Custoo, Citation bot 1, Teenmd, Tea with toast, BogBot, David Hedlund, Peacedance, RjwilmsiBot, Yid, Dcirovic, ZéroBot, H3llBot, Timetraveler3.14, Peryeat, Skoot13, BG19bot, BattyBot, Vaccinationist, Monkbot, Medgirl131 and Anonymous: 108 • Rosonabant Source: http://en.wikipedia.org/wiki/Rosonabant?oldid=618474987 Contributors: Rjwilmsi, Edgar181, Chemgirl131, Anypodetos, BG19bot, Monkbot and Medgirl131 • S-444,823 Source: http://en.wikipedia.org/wiki/S-444,823?oldid=628622349 Contributors: Meodipt, Skoot13 and WildCation • SDB-001 Source: http://en.wikipedia.org/wiki/SDB-001?oldid=557806974 Contributors: Meodipt, Magioladitis, C6541, BaeyerDrewson and Anonymous: 2 • SDB-006 Source: http://en.wikipedia.org/wiki/SDB-006?oldid=585445393 Contributors: Meodipt, BaeyerDrewson, Mrbenzhao and Anonymous: 2 • SER-601 Source: http://en.wikipedia.org/wiki/SER-601?oldid=607679714 Contributors: Beetstra, Meodipt, Enix150, Davecrosby uk, CheMoBot, BogBot, The chemistds, Skoot13, Monkbot and Anonymous: 1 • Serinolamide A Source: http://en.wikipedia.org/wiki/Serinolamide_A?oldid=579444765 Contributors: Edgar181, Meodipt, John of Reading and RichardsonsRSC • SR-144,528 Source: http://en.wikipedia.org/wiki/SR-144,528?oldid=618472544 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Enix150, Addbot, CheMoBot, BogBot, Dcirovic, Louisajb, Skoot13, Monkbot and Medgirl131 • Stearoylethanolamide Source: http://en.wikipedia.org/wiki/Stearoylethanolamide?oldid=630989213 Contributors: Bearcat, Malcolma, Jatlas and Medgirl131 • STS-135 (drug) Source: http://en.wikipedia.org/wiki/STS-135_(drug)?oldid=628883259 Contributors: Edgar181, Meodipt, Jim1138, SciRambar, BaeyerDrewson, Yougotwarsh and Anonymous: 3 • Surinabant Source: http://en.wikipedia.org/wiki/Surinabant?oldid=618475012 Contributors: Edward, St3vo, Pegship, Beetstra, Meodipt, R'n'B, Enix150, Carlo Banez, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Dagrun, حسن علي البط, BogBot, PotatoBot, Peryeat, ChrisGualtieri and Medgirl131 • Taranabant Source: http://en.wikipedia.org/wiki/Taranabant?oldid=618475039 Contributors: St3vo, Woohookitty, OrphanBot, Meodipt, Magioladitis, ChemNerd, Enix150, Kizly, Carlo Banez, Panoramix303, Chemgirl131, Yobot, CheMoBot, Rjanag, Dagrun, حسن علي البط, P-kun80, BogBot, PotatoBot, Peryeat, Monkbot, Medgirl131 and Anonymous: 2 • Tedalinab Source: http://en.wikipedia.org/wiki/Tedalinab?oldid=491266810 Contributors: Meodipt
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• Tetrad test Source: http://en.wikipedia.org/wiki/Tetrad_test?oldid=443471240 Contributors: Chick Bowen, Roadnottaken, Jzlong, AloysiusLiliusBot, Aaron Kauppi and Anonymous: 1 • Tetrahydrocannabinol Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinol?oldid=630780019 Contributors: Damian Yerrick, AxelBoldt, Kpjas, Bryan Derksen, The Anome, Tarquin, Malcolm Farmer, SimonP, Pit, Gabbe, Chinju, Paul A, MichaelJanich, Mkweise, Ahoerstemeier, HarmonicSphere, TUF-KAT, JWSchmidt, Evercat, Iorsh, SaveThePoint, Andrevan, Furrykef, Gutsul, Robbot, Astronautics, Mirv, UtherSRG, Hif, DocWatson42, Nunh-huh, BenFrantzDale, Bradeos Graphon, Guanaco, St3vo, Eequor, Richard Myers, Andycjp, Geus, Sonjaaa, Ferre, Antandrus, HistoryBA, AlexanderWinston, OwenBlacker, Gene s, Bk0, Rlcantwell, Joyous!, Mearlon, Gerrit, Tonik, Idolcrash, Lynto008, Adashiel, Porges, Stevenmattern, Discospinster, Rich Farmbrough, Guanabot, Cacycle, Pie4all88, Bender235, Mykhal, Calair, Jensbn, Livajo, Cedders, Kwamikagami, Dennis Brown, Jpgordon, Jonathan Drain, Bobo192, Timon, Flying Hamster, Smalljim, Shenme, Viriditas, Mrdude, NotAbel, ZayZayEM, Giraffedata, Alansohn, Eleland, PopUpPirate, Eric Kvaalen, Atlant, Benjah-bmm27, Andrew Gray, Howrealisreal, Thoric, Ransack, Ynhockey, Hu, Velella, Keziah, Gene Nygaard, Netkinetic, Ceyockey, Japanese Searobin, Ron Ritzman, Mindmatrix, Lunar Jesters, Rajiv Varma, Kzollman, CiTrusD, GregorB, Jon Harald Søby, Palica, SqueakBox, Magister Mathematicae, Mendaliv, Canderson7, Sjö, Rjwilmsi, Londonbroil, Soakologist, Pabix, Heah, Rpinz, Nneonneo, DirkvdM, X1987x, FlaBot, Ground Zero, Mister Matt, AJR, Vayne, TheDJ, Wgfcrafty, Diza, Consumed Crustacean, Butros, WriterHound, Joseph11h, YurikBot, NTBot, Petiatil, Pacaro, Chris Capoccia, Ansell, Shaddack, NawlinWiki, Ytcracker, Johann Wolfgang, Belkov, ONEder Boy, Nad, Afiler, Xdenizen, Moe Epsilon, DeadEyeArrow, Bota47, BraneJ, Louieduvall, Max Schwarz, Mike Serfas, Zzuuzz, TheMadBaron, KGasso, Jolt76, BorgQueen, JRey, LeonardoRob0t, JLaTondre, CIreland, SmackBot, Mitchan, Brammers, Slashme, Anarchist42, Unyoyega, ParkerHiggins, Davewild, WookieInHeat, Jrockley, Jab843, Edgar181, HalfShadow, Gilliam, Ohnoitsjamie, Hmains, Shaggorama, Iain.dalton, Ksenon, Dolive21, Master of Puppets, GregRM, MalafayaBot, Domthedude001, SchfiftyThree, Zachorious, Mladifilozof, MaxSem, Muboshgu, Can't sleep, clown will eat me, Chlewbot, OrphanBot, Addshore, Bulbous, Cybercobra, T-borg, Drphilharmonic, DMacks, A5b, Lambiam, AThing, John, Jidanni, Gobonobo, Shlomke, Stwalkerster, Beetstra, Waggers, SandyGeorgia, Nialsh, Iridescent, Camb15, Newone, Igoldste, LadyofShalott, Nalco, Courcelles, Tawkerbot2, OS2Warp, Switchercat, CmdrObot, ArmyOfFluoride, Rikva, WeggeBot, T23c, Meodipt, Karmak, Cydebot, Rifleman 82, Gogo Dodo, D666D, A Softer Answer, Odie5533, Tawkerbot4, Carstensen, Codetiger, Dyakofborneo, Daven200520, Pinky sl, Epbr123, Legolas558, Loudsox, Bendroz, Yukichigai, Subvertc, Headbomb, Chrisdab, Rhrad, Matthew Proctor, Pfranson, Dawnseeker2000, Noclevername, Escarbot, Porqin, Exhilaration157, AntiVandalBot, The Obento Musubi, RobotG, DarkAudit, Smartse, GodGell, Spencer, Elaragirl, Deflective, MSBOT, Iownutopia, .anacondabot, Acroterion, Mattb112885, Bongwarrior, VoABot II, Jeff Dahl, JNW, JamesBWatson, Gold3nrul3, Balloonguy, Hiplibrarianship, Mreaster, Allstarecho, Tins128, Ajgregory, Pax:Vobiscum, MartinBot, By97aa, ChemNerd, Anaxial, Nono64, Leyo, Hairchrm, Fconaway, Lilac Soul, Tgeairn, J.delanoy, Bogey97, Boghog, Cocoaguy, Alwaysasking, Solidach, Afluegel, Mikael Häggström, L'Aquatique, Alphapeta, Plasticup, SJP, Enix150, Cometstyles, Bondo 6464, HazyM, Martial75, Halmstad, Signalhead, Gothbag, Deor, Hammersoft, VolkovBot, Rtdixon86, Philip Trueman, DoorsAjar, TXiKiBoT, A4bot, Qxz, Victimofleisure, Ph33rspace, Martin451, Wikieditor12, Tpk5010, Jsteinhoefel, Dvmedis, Vaubin, Nadsozinc, Falcon8765, Puusq, LetTheSunshineIn, Fischer.sebastian, Skepticignorant, Tbg connor, Peter Fleet, SieBot, Coffee, Da Joe, YourEyesOnly, Aswad87, Yintan, Agador, BrienIsSexy4, Flyer22, Alexbrn, Oneku201, Oxymoron83, Hello71, Poindexter Propellerhead, WacoJacko, La Parka Your Car, StaticGull, Mike2vil, DaDrought3, Dala11a, Mygerardromance, PerryTachett, Nn123645, 30SEC2, DRTllbrg, Chem-awb, Kanonkas, Tanvir Ahmmed, ClueBot, PipepBot, Anthonyvidal, The Thing That Should Not Be, Voxpuppet, MedialLateral, Yikrazuul, Drmies, Mild Bill Hiccup, Shinpah1, Redspades, Leodmacleod, Niceguyedc, Chiosu, Flubecabot, Excirial, Jusdafax, Ltnemo2000, John Nevard, Paymaun, Panoramix303, Jophis, Alchemist01010101, Cenarium, Iohannes Animosus, XeroX16, Williadb, BlackHoleSon, Thingg, Aitias, 7, Versus22, NJGW, BlueDevil, 0Chance, DumZiBoT, Skunkboy74, Chemgirl131, JS747, Ost316, SilvonenBot, NellieBly, NHJG, LikeHolyWater, Conversationalskills, Addbot, Piz d'Es-Cha, RH420, C6541, DOI bot, Tcncv, Eltone, Binary TSO, Ronhjones, Dnnisrdz, Skyezx, Protonk, Glass Sword, AndersBot, Roux, WikiDegausser, Sepulwiki, Adam Willenbrecht, Aldrich Hanssen, Pnpointer, Tide rolls, OlEnglish, Alfie66, Ben Ben, Drpickem, Slayer14666, Yobot, Andreasmperu, Ptbotgourou, CheMoBot, Whiskeydog, TestEditBot, Tempodivalse, Synchronism, Slowgenius, TheHighTree, AnomieBOT, Tryptofish, Metalhead94, Casforty, Götz, Choij, Message From Xenu, Modanung, Ulric1313, Bluerasberry, Mahmudmasri, Materialscientist, Citation bot, BlurTento, LilHelpa, Simultaneous movement, The Firewall, Apothecia, Jason.Singer, Capricorn42, Millahnna, Br77rino, حسن علي البط, Harbinary, Xxkeeenxx, Malbano17, Inferno, Lord of Penguins, Coretheapple, Cmerlin2, Anand droog, Shit Goes Here, Lapuchca, Crabjuicer, SassoBot, RomanHunt, Kyng, Tony12893, X172, C4andrei, Psychonaught, Neolith100, Evangelika, Ajax151, Custoo, Jatlas, Lothar von Richthofen, StaticVision, Vishnu2011, Ryan.rota, Laff able, Citation bot 1, Izzardthegizzard, Pinethicket, Jrew86, A8UDI, Jschnur, SpaceFlight89, Tea with toast, BogBot, Bioextra, Smatrese, DadOfBeanAndBug, MemphisUPEI, David Hedlund, Diannaa, 4ndyD, Suffusion of Yellow, Dungeonscaper, Gtziavelis, Dick blixen, Kanelbulle, DARTH SIDIOUS 2, Ashox D-Shay, Realizen, Moshasaurus, RjwilmsiBot, Ripchip Bot, FetchcommsAWB, Dizanl, Beyond My Ken, NerdyScienceDude, SeeKatethisisme, EmausBot, Franfran2010, Rbaselt, RA0808, 4meter4, Slightsmile, Tommy2010, John Cline, Jaydiem, ElationAviation, GZ-Bot, H3llBot, Cimmerian praetor, Dpdrums, L Kensington, Bayhemp, Tick avenger, DASHBotAV, Hetoi, Louisajb, ClueBot NG, Gaujo, Mini.knowledge.pea, Nielswillems26, FarmDee, Billyrubin2008, Skoot13, Hempknight121, Cj005257, Avagad2, Mesoderm, O.Koslowski, Widr, Helpful Pixie Bot, Psychonaut25, Bibcode Bot, Kenan133, DBigXray, BG19bot, Petrarchan47, Northamerica1000, Stuartteal, Spy12190, Nikos 1993, TheMan4000, Cbakker, Snow Blizzard, NotWith, Zujua, Wyliea, Zmbonvallat, Fuse809, TheBaur, LegacyWeapon, Indirectantagonist, EuroCarGT, 14jay69, Jeschjesch, Blazedbuddha, 00AgentBond93, Gareth CHEBI, Kilasic, Craigcrawford1988, CannaWikibiss, K-ronzagwarn, MidnightRequestLine, Babapcck, Rainyhemptree, JulianaPacheco, Camyoung54, ScoutKnot, Youtalkfunny, DavidLeighEllis, ArmbrustBot, PreCambrianBunny, Seppi333, Mjlphd, BOBBOBLEYBOBSON, Die Antwoorde, Korean181, Meteor sandwich yum, Lyschamb, Monkbot, 235N, Formerly 98, A915, Joshuabumbarger, Santavy2014, JoPhoenix, Fuzznerdees, Medgirl131, Amc98, GP10698 and Anonymous: 949 • Tetrahydrocannabinol-C4 Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinol-C4?oldid=618601612 Contributors: Cacycle, Natalya, BD2412, Pegship, Meodipt, Astavats, Benrr101, Mild Bill Hiccup, Phil Ian Manning, Chemgirl131, Yobot, CheMoBot, حسن علي البط, ZackRegit, BogBot, Nikos 1993, NotWith, Monkbot and Jakenowatzke • Tetrahydrocannabinolic acid Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinolic_acid?oldid=614212282 Contributors: Rjwilmsi, Meodipt, Wikieditor12, Benrr101, Götz, Jim1138, Monkbot and Anonymous: 4 • Tetrahydrocannabivarin Source: http://en.wikipedia.org/wiki/Tetrahydrocannabivarin?oldid=630568385 Contributors: William Avery, St3vo, Rich Farmbrough, Cacycle, Ceyockey, Amire80, Fred Bradstadt, Physchim62, WriterHound, YurikBot, Gaius Cornelius, Pegship, Edgar181, Naturalsol, Chris the speller, Fireemblem555, Smith609, Beetstra, Meodipt, Alaibot, Probios, VolkovBot, GeorgeLTirebiter, Chem-awb, Panoramix303, Burner0718, Chemgirl131, MystBot, Addbot, DOI bot, Wormantson, CheMoBot, Casforty, Obersachsebot, حسن علي البط, Custoo, Citation bot 1, UFO Reporter, MastiBot, BogBot, CrowzRSA, Jynto, ClueBot NG, Nikos 1993, NotWith, Sfgiants1995, Jakenowatzke, Medgirl131, Mplanine and Anonymous: 20 • THC-O-acetate Source: http://en.wikipedia.org/wiki/THC-O-acetate?oldid=586788432 Contributors: Cacycle, Pegship, SmackBot, Edgar181, Afasmit, Beetstra, Meodipt, JaGa, CheMoBot, حسن علي البط, BogBot, Helpful Pixie Bot, ChrisGualtieri and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
339
• THC-O-phosphate Source: http://en.wikipedia.org/wiki/THC-O-phosphate?oldid=447734263 Contributors: Koavf, Pegship, Edgar181, Beetstra, Meodipt, Alaibot, Mojo Hand, Greatmajor55, CheMoBot, حسن علي البطand BogBot • Tinabinol Source: http://en.wikipedia.org/wiki/Tinabinol?oldid=618475536 Contributors: Meodipt, OrenBochman, Chemgirl131, Anypodetos, Braincricket, BG19bot and Medgirl131 • URB602 Source: http://en.wikipedia.org/wiki/URB602?oldid=600974517 Contributors: Rjwilmsi, Edgar181, Beetstra, Smartse, MSBOT, Addbot, Yobot, CheMoBot, Citation bot, Tea with toast, The chemistds and Stark1987 • URB754 Source: http://en.wikipedia.org/wiki/URB754?oldid=618360159 Contributors: Arcadian, Fred Bradstadt, Itub, SmackBot, Bluebot, Roadnottaken, Bwduca, Beetstra, Smartse, Isilanes, Tanevala, Danelo, Chem-awb, Panoramix303, DOI bot, CheMoBot, حسن علي البط, P-kun80, RjwilmsiBot, GoingBatty, PotatoBot, Stark1987, Vaccinationist, Monkbot and Anonymous: 4 • VCHSR Source: http://en.wikipedia.org/wiki/VCHSR?oldid=600803681 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, BogBot and Anonymous: 1 • VDM-11 Source: http://en.wikipedia.org/wiki/VDM-11?oldid=630848440 Contributors: RussBot, Edgar181, CommonsDelinker, Enix150, Auntof6, Addbot, Yobot, CheMoBot, Rideer13, The chemistds, AvocatoBot, Medgirl131 and Anonymous: 2 • WIN 54,461 Source: http://en.wikipedia.org/wiki/WIN_54,461?oldid=593323168 Contributors: Drphilharmonic, Enix150, Anypodetos, BogBot, Skoot13 and Monkbot • WIN 55,212-2 Source: http://en.wikipedia.org/wiki/WIN_55,212-2?oldid=618472575 Contributors: GTBacchus, Howrealisreal, ^demon, Mandarax, Zachjones4, Fred Bradstadt, WriterHound, Pegship, SmackBot, Edgar181, Bluebot, Mirshafie, Phaedriel, Nuklear, Drphilharmonic, Saxbryn, Iridescent, Ccroberts, Meodipt, Cydebot, RelentlessRecusant, D666D, CopperKettle, Sony 1, Tanevala, Enix150, Funandtrvl, Altzinn, Panoramix303, Yuhong wang, Addbot, Maclia, Yobot, CheMoBot, حسن علي البط, Harbinary, Lapuchca, Custoo, FrescoBot, BogBot, RjwilmsiBot, Gould363, DASHBot, ZéroBot, Louisajb, Skoot13, Jeff.keyser, Fuse809, Testem, Gareth CHEBI, Medgirl131 and Anonymous: 12 • WIN 56,098 Source: http://en.wikipedia.org/wiki/WIN_56,098?oldid=605489228 Contributors: Enix150, Anypodetos, SwisterTwister, BogBot, Snotbot, Crosstemplejay, BattyBot and Monkbot • XLR-11 (drug) Source: http://en.wikipedia.org/wiki/XLR-11_(drug)?oldid=626107904 Contributors: Wainblatrobert, Dl2000, Meodipt, Boghog, Enix150, Balst32, CMBJ, Yobot, AnomieBOT, SciRambar, The chemistds, Skoot13, BattyBot, Testem, ChrisGualtieri, BaeyerDrewson, Epicgenius, KMAnomalocaris, Rebrewind, Monkbot and Anonymous: 5 • AM251 Source: http://en.wikipedia.org/wiki/AM251?oldid=544204589 Contributors: Bearcat, Circeus, Vanky, BorisTM, Rjwilmsi, Laminado, Beetstra, Ccroberts, Meodipt, Calvero JP, Astavats, Cgingold, Tanevala, Enix150, Panoramix303, Addbot, CheMoBot, Gongshow, Rjanag, حسن علي البط, BogBot, PotatoBot and Anonymous: 3 • Aminoalkylindole Source: http://en.wikipedia.org/wiki/Aminoalkylindole?oldid=582043905 Contributors: John Vandenberg, Smartse and AnomieBOT • Cannabipiperidiethanone Source: http://en.wikipedia.org/wiki/Cannabipiperidiethanone?oldid=618475932 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Addbot, Dcirovic, The chemistds, BaeyerDrewson, Medgirl131 and Anonymous: 1 • JWH-193 Source: http://en.wikipedia.org/wiki/JWH-193?oldid=606478297 Contributors: CheMoBot, BogBot, Skoot13, Monkbot and WildCation
Rjwilmsi, Meodipt, Enix150, C6541,
• JWH-198 Source: http://en.wikipedia.org/wiki/JWH-198?oldid=606597688 Contributors: CheMoBot, BogBot, Skoot13, Monkbot and WildCation
Rjwilmsi, Meodipt, Enix150, C6541,
• JWH-200 Source: http://en.wikipedia.org/wiki/JWH-200?oldid=606475531 Contributors: Rich Farmbrough, John Vandenberg, Velella, Rjwilmsi, Pegship, Edgar181, Drphilharmonic, Meodipt, Smartse, Enix150, Funandtrvl, Addbot, C6541, Favonian, CheMoBot, AnomieBOT, Citation bot, Grim23, حسن علي البط, BogBot, Unceasing, Tisane, HarDNox, SmokingNewton, Frozen Wind, Caponex, Silver Harshy, Managermerrill, Skoot13, Exercisephys, Fuse809, WildCation and Anonymous: 15 • Pravadoline Source: http://en.wikipedia.org/wiki/Pravadoline?oldid=607406644 Contributors: Rich Farmbrough, Wimvandorst, Natalya, Pegship, Drphilharmonic, Beetstra, Hu12, Meodipt, Enix150, Lamro, Panoramix303, CheMoBot, Anypodetos, Citation bot, حسن علي البط, Citation bot 1, Jonesey95, BogBot, Peryeat, S1lv3rblad3, Skoot13, Snotbot, Yukileoo, ChrisGualtieri and Anonymous: 2 • RCS-4 Source: http://en.wikipedia.org/wiki/RCS-4?oldid=525171484 Contributors: Aardark, XLerate, SmackBot, Shoy, Beetstra, Meodipt, Bobber0001, Enix150, C6541, CheMoBot, AnomieBOT, BogBot, Renamed01302013, The chemistds, ClueBot NG, Bped1985, VeiledReference, Pan Czy Pani and Anonymous: 2 • Anandamide Source: http://en.wikipedia.org/wiki/Anandamide?oldid=629335365 Contributors: MadSurgeon, Olivier, MartinHarper, Sugarfish, Robbot, Sanders muc, Fuelbottle, Unfree, Giftlite, SoCal, Mearlon, Rich Farmbrough, Cacycle, Van Flamm, Mjpieters, Bitplane, Mykhal, El C, Arcadian, Eritain, M7, Max rspct, Reaverdrop, Mahanga, Josh Parris, Rjwilmsi, Fred Bradstadt, FlaBot, Doc glasgow, RexNL, WriterHound, YurikBot, RobotE, Tavilis, El Cazangero, A314268, Joncolvin, Gamerider, Laminado, SmackBot, Saravask, AlexNordeen, Edgar181, Lennert B, Colonies Chris, Oatmeal batman, Roadnottaken, Drphilharmonic, Beetstra, Saxbryn, Chirality, Fvasconcellos, Mellery, Icek, Cydebot, Bendroz, Dream Focus, Trapezoidal, Belizefan3000, Lumir, .José, Boghog, Mikael Häggström, Pmallet, Tanevala, Enix150, DorganBot, VolkovBot, Chango369w, Cotard, Hertz1888, Djadvance, Chem-awb, Orbitalcombustion, ClueBot, Plastikspork, Redspades, Ltnemo2000, Nettacog, Yonskii, Chemgirl131, Dthomsen8, Addbot, DOI bot, Chempedia, Lightbot, Jarble, Gaberdine2, Yobot, Legobot II, CheMoBot, Götz, Citation bot, حسن علي البط, Jyffeh, GrouchoBot, Xasodfuih, Custoo, FrescoBot, Akshatrathi294, Tea with toast, BogBot, 564dude, RjwilmsiBot, Dcirovic, Tomásdearg92, Ronhirzmd, ClueBot NG, Gilderien, Vjiced, Skoot13, BG19bot, Lifeformnoho, Enomai, Valera123, Vjiced1, Anaffen21, JaconaFrere, Monkbot, Medgirl131 and Anonymous: 76 • N-Arachidonoyl dopamine Source: http://en.wikipedia.org/wiki/N-Arachidonoyl_dopamine?oldid=618471241 Contributors: St3vo, Rich Farmbrough, Rjwilmsi, Edgar181, Beetstra, Rhetth, Cydebot, ChemNerd, Enix150, Benrr101, ing4Taste, PookeyMaster, Chem-awb, Panoramix303, Chemgirl131, Addbot, DOI bot, CheMoBot, حسن علي البط, Custoo, Nirmos, Tea with toast, ZéroBot, The chemistds, Brainiacal, Monkbot, Medgirl131 and Anonymous: 3 • 2-Arachidonoylglycerol Source: http://en.wikipedia.org/wiki/2-Arachidonoylglycerol?oldid=618471104 Contributors: Rich Farmbrough, Rjwilmsi, WriterHound, Shaddack, El Cazangero, SmackBot, Edgar181, Roadnottaken, Beetstra, Rhetth, Cydebot, Astavats, Kilrothi, ChemNerd, Tanevala, Enix150, Michaël George, SieBot, Chem-awb, Drmies, Panoramix303, ChemSpiderMan, Chemgirl131, Addbot, K-MUS, DOI bot, Ginosbot, Yobot, CheMoBot, Jzlong, Citation bot, Xasodfuih, Custoo, Citation bot 1, RedBot, BogBot, CrowzRSA, 564dude, Dcirovic, ZéroBot, Helpful Pixie Bot, Shisha-Tom, Cotedesneiges, Austinpk, Jianhui67, Anaffen21, Monkbot, Medgirl131 and Anonymous: 15
340
CHAPTER 252. TM-38837
• 2-Arachidonyl glyceryl ether Source: http://en.wikipedia.org/wiki/2-Arachidonyl_glyceryl_ether?oldid=618471126 Contributors: St3vo, Rich Farmbrough, Physchim62, WriterHound, Slashme, Edgar181, Beetstra, Cydebot, Benrr101, Chem-awb, Panoramix303, ChemSpiderMan, Chemgirl131, Addbot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, CrowzRSA, Dcirovic, Cimmerian praetor, ChrisGualtieri, Gareth CHEBI, Medgirl131 and Anonymous: 5 • Oleamide Source: http://en.wikipedia.org/wiki/Oleamide?oldid=618471264 Contributors: AxelBoldt, Richard Taytor, Henrik, Rjwilmsi, WriterHound, SmackBot, Edgar181, Roadnottaken, Beetstra, Meodipt, Scouse123, ChemNerd, Ejhoekstra, TXiKiBoT, Benrr101, Living under a rock, Chem-awb, Yikrazuul, DumZiBoT, Chemgirl131, Addbot, DOI bot, CheMoBot, Neoligand, Citation bot, Custoo, Citation bot 1, Abductive, Tea with toast, BogBot, ZéroBot, Cimmerian praetor, Skoot13, Rezabot, Drpainless, Makecat-bot, Monkbot, Medgirl131 and Anonymous: 15 • RVD-Hpα Source: http://en.wikipedia.org/wiki/RVD-Hpα?oldid=618471413 Contributors: Meodipt, Magioladitis, Boghog, Yobot, Custoo, BG19bot, Medgirl131 and Anonymous: 1 • Virodhamine Source: http://en.wikipedia.org/wiki/Virodhamine?oldid=618471494 Contributors: Rich Farmbrough, Arcadian, Natalya, WriterHound, BlueZenith, Edgar181, David.Throop, Drphilharmonic, Beetstra, Rhetth, Cydebot, Enix150, Benrr101, Chem-awb, Plasmic Physics, Chemgirl131, Addbot, Luckas-bot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, ZéroBot, Medgirl131 and Anonymous: 1 • HU-320 Source: http://en.wikipedia.org/wiki/HU-320?oldid=517594060 Contributors: Rjwilmsi, Meodipt, Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13 • HU-336 Source: http://en.wikipedia.org/wiki/HU-336?oldid=580010784 Contributors: Rjwilmsi, Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13 • HU-345 Source: http://en.wikipedia.org/wiki/HU-345?oldid=580010824 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt, Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13 • Raphael Mechoulam Source: http://en.wikipedia.org/wiki/Raphael_Mechoulam?oldid=621871273 Contributors: GreatWhiteNortherner, Andycjp, WadeSimMiser, SqueakBox, Rjwilmsi, Bgwhite, RussBot, El Cazangero, Shuki, Mqzspa, Meodipt, Cydebot, Dougweller, J.delanoy, Enix150, Juliancolton, Tzahy, Panoramix303, Qwfp, Addbot, Lightbot, דוד55, Luckas-bot, Yobot, Amirobot, Davshul, Almabot, FrescoBot, Anti-Nationalist, ZéroBot, Cimmerian praetor, Vjiced, Drkup(IMJ), Cyberbot II, Jethro B, Reverend Mick man34, VIAFbot, Looppushh, Monkbot, Jonarnold1985 and Anonymous: 15 • John W. Huffman Source: http://en.wikipedia.org/wiki/John_W._Huffman?oldid=604651417 Contributors: Delirium, Wdfarmer, Dismas, Patken4, Stormbay, KGasso, SmackBot, Meodipt, Lugnuts, Spyder Monkey, Smartse, Trusilver, NewEnglandYankee, KudzuVine, Jackfork, Panoramix303, Addbot, Yobot, AVB, AnomieBOT, OlYeller21, Grim23, Sgravn, Gunnanmon, Tisane, ZéroBot, Andyman1125, Dagko, Allethrin, Frozen Wind, ClueBot NG, Skoot13, 4321acb, Nickt0963, Wiki magnet, Touchhole97 and Anonymous: 19 • JWH-007 Source: http://en.wikipedia.org/wiki/JWH-007?oldid=606455199 Contributors: Meodipt, Enix150, Ziggy Sawdust, C6541, CheMoBot, حسن علي البط, FrescoBot, BogBot, John of Reading, Tisane, Kabutop, Pan Czy Pani, D42kn355, NotWith and WildCation • JWH-018 Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch, Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser, Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilharmonic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT, Nirigihimu, Turkeyphant, Zefiel, Smartse, Theguy0000, MER-C, Grimelab, Iownutopia, JamesBWatson, Monosodious, Bradgib, ChemNerd, Leyo, Boghog, Malkuth1, Gutterkitty, Enix150, Pdcook, CardinalDan, Funandtrvl, Msrbl49, Fbifriday, Philip Trueman, Flux12n21, Flopster2, Wikieditor12, Jpaliano, Guldenat, Falcon8765, Living under a rock, Pjoef, Dlfreem, Dheau, Hobartimus, ClueBot, GorillaWarfare, Tomas e, Drmies, Yuubi, Auntof6, Ktr101, Alexbot, Dr.Koljan, Panoramix303, Sun Creator, Christopherbrian, XLinkBot, Fastily, ErgoSum88, ESO Fan, PurrfectPeach, Addbot, C6541, MartinezMD, Fieldday-sunday, Fluffernutter, LaaknorBot, DFS454, Favonian, Tide rolls, Wax025, Ben Ben, Legobot, Luckas-bot, Yobot, Legobot II, CheMoBot, Daddyrob81, Anypodetos, AnomieBOT, XLocal, Vinyl Ketone, Piano non troppo, Citation bot, GB fan, Intelati, OlYeller21, Δζ, Pontificalibus, Nasnema, Rhoodey, حسن علي البط, Harbinary, Shirik, Amaury, Psychonaught, Shadowjams, Custoo, FrescoBot, Nageh, RicHard-59, Metallica3790, Borguebabe, Weetoddid, Boylechem, Citation bot 1, Biker Biker, Calmer Waters, MastiBot, Sw1ngOnTheSp1ral, BogBot, CrowzRSA, Clickpop, David Hedlund, Tbhotch, RjwilmsiBot, Dustin 3choes, Jwh018, Rsharpe28, John of Reading, Gunnanmon, Katherine, Tisane, Clayman1976, Atropinesulfate, Tommy2010, Sraab2, Wikipelli, White Trillium, Fæ, Josve05a, James.dynamite, Hereforhomework2, H3llBot, Darkwire89, Drhjort, ALANON54, Wayne Slam, Ocaasi, OnePt618, Scema, PeterGriffinJK, Akacypress, Demetrius259, Corei7Maniac, Del nerius, Lagato123, Tjiseclipsed, ClamDip, HaydenBeck, W5NLbrian, Handsum53, DASHBotAV, Hetoi, Abnorml1, Louisajb, Mikhail Ryazanov, ClueBot NG, Agents of The Free, Easyzeh, Dualdj1, Tesacrynheart, EnvyCo, Diogenes2000, Skoot13, 4321acb, Jacobso4, Murraysymes, 1989Exley1989, Exercisephys, Verified72, Snow Blizzard, Boobs4fun, Justthinking25, Shisha-Tom, Fuse809, PhoenixPie, Kid squid, BattyBot, BaeyerDrewson, Rawrfaceace, KMAnomalocaris, Rebrewind, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 417 • JWH-019 Source: http://en.wikipedia.org/wiki/JWH-019?oldid=606455993 Contributors: Drphilharmonic, Meodipt, Leyo, Enix150, Alexbot, Addbot, C6541, CheMoBot, Citation bot, حسن علي البط, Citation bot 1, Biker Biker, BogBot, Skoot13, Pan Czy Pani, Verified72, Shisha-Tom, Monkbot, WildCation and Anonymous: 2 • JWH-030 Source: http://en.wikipedia.org/wiki/JWH-030?oldid=628060353 Contributors: Wimvandorst, Pegship, Nuklear, Beetstra, Meodipt, Enix150, Funandtrvl, CheMoBot, حسن علي البط, BogBot, Tisane, Louisajb, WildCation and Anonymous: 4 • JWH-047 Source: http://en.wikipedia.org/wiki/JWH-047?oldid=540030725 Contributors: Rjwilmsi, RjwilmsiBot and BaeyerDrewson • JWH-048 Source: http://en.wikipedia.org/wiki/JWH-048?oldid=606457011 Contributors: Rjwilmsi, Wikieditor12, C6541, RjwilmsiBot, BaeyerDrewson and WildCation • JWH-073 Source: http://en.wikipedia.org/wiki/JWH-073?oldid=618472305 Contributors: Rich Farmbrough, Cacycle, LindsayH, Blaxthos, Grafen, Pegship, SmackBot, Cybercobra, Drphilharmonic, Meodipt, Cydebot, Marek69, Turkeyphant, Theguy0000, Iownutopia, Leyo, Enix150, Funandtrvl, X!, Krakaet, ClueBot, Panoramix303, Alibobar, Yoman82, ErgoSum88, Addbot, C6541, MartinezMD, Luckas-bot, Yobot, CheMoBot, XLocal, Piano non troppo, Addihockey10, OlYeller21, Grim23, حسن علي البط, Custoo, Weetoddid, Citation bot 1, Biker Biker, BogBot, Noraft, Tisane, Ocaasi, PeterGriffinJK, Darksp000n, Caponex, ClueBot NG, Dvsbmx, Skoot13, Exercisephys, Verified72, Cerabot, Woo 24, Monkbot, WildCation, Cbmacewan, Medgirl131 and Anonymous: 36
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
341
• JWH-081 Source: http://en.wikipedia.org/wiki/JWH-081?oldid=627566683 Contributors: Pegship, Beetstra, Meodipt, Turkeyphant, Terrek, Enix150, TopGun, Funandtrvl, Svick, Michał Sobkowski, Addbot, C6541, CheMoBot, Grim23, حسن علي البط, Biker Biker, BogBot, Tisane, ZéroBot, Frozen Wind, Caponex, ClueBot NG, Skoot13, Pan Czy Pani, Verified72, WildCation and Anonymous: 10 • JWH-098 Source: http://en.wikipedia.org/wiki/JWH-098?oldid=606459363 Contributors: Meodipt, Enix150, C6541, CheMoBot, حسن علي البط, BogBot, Skoot13 and WildCation • JWH-116 Source: http://en.wikipedia.org/wiki/JWH-116?oldid=608540716 Contributors: Rjwilmsi, C6541, BaeyerDrewson and WildCation • JWH-147 Source: http://en.wikipedia.org/wiki/JWH-147?oldid=606479371 Contributors: Pegship, Meodipt, Enix150, Yobot, CheMoBot, حسن علي البط, BogBot, Tisane, Destruktor5000, WildCation and Anonymous: 1 • JWH-164 Source: http://en.wikipedia.org/wiki/JWH-164?oldid=606483862 Contributors: Meodipt, Enix150, CheMoBot, حسن علي البط, FrescoBot, BogBot, Skoot13 and WildCation • JWH-167 Source: http://en.wikipedia.org/wiki/JWH-167?oldid=600826360 Contributors: Stephen, Rjwilmsi, Shoy, Beetstra, Boghog, Enix150, Jsfouche, C6541, Ben Ben, CheMoBot, Citation bot, EmausBot, The chemistds, Rezabot and Anonymous: 1 • JWH-175 Source: http://en.wikipedia.org/wiki/JWH-175?oldid=607110954 Contributors: Jorge Stolfi, Meodipt, Enix150, CheMoBot and WildCation • JWH-184 Source: http://en.wikipedia.org/wiki/JWH-184?oldid=608540728 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson • JWH-185 Source: http://en.wikipedia.org/wiki/JWH-185?oldid=608540720 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson • JWH-196 Source: http://en.wikipedia.org/wiki/JWH-196?oldid=608540711 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson • JWH-203 Source: http://en.wikipedia.org/wiki/JWH-203?oldid=607451648 Contributors: Rich Farmbrough, Rjwilmsi, Bazonka, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, Citation bot, Grim23, حسن علي البط, BogBot, Gunnanmon, Tisane, Caponex, Skoot13, Pan Czy Pani, Monkbot, WildCation and Anonymous: 3 • JWH-210 Source: http://en.wikipedia.org/wiki/JWH-210?oldid=625525612 Contributors: Mike Rosoft, KGasso, Edgar181, Meodipt, Christian75, DumbBOT, MER-C, Enix150, Addbot, C6541, Luckas-bot, CheMoBot, Anypodetos, Mdog228, Grim23, حسن علي البط, FrescoBot, BogBot, NotAnonymous0, Tisane, ZéroBot, DASHBotAV, Caponex, Tryptamines, Pan Czy Pani, WildCation and Anonymous: 16 • JWH-249 Source: http://en.wikipedia.org/wiki/JWH-249?oldid=600743349 Contributors: Rjwilmsi, Shoy, Beetstra, Meodipt, Enix150, Squids and Chips, Ben Ben, CheMoBot, Citation bot, BogBot and The chemistds • JWH-250 Source: http://en.wikipedia.org/wiki/JWH-250?oldid=606791115 Contributors: Mike Rosoft, Blaxthos, Rjwilmsi, WriterHound, KGasso, Edgar181, Drphilharmonic, Meodipt, Smartse, Salih, Enix150, Panoramix303, Chemgirl131, Addbot, C6541, Yobot, CheMoBot, Sarrus, XLocal, Citation bot, ArthurBot, OlYeller21, Grim23, حسن علي البط, Harbinary, Citation bot 1, BogBot, Tbhotch, EmausBot, Tisane, PotatoBot, Joseph3311, IGeMiNix, ChuispastonBot, DASHBotAV, Caponex, Louisajb, MelbourneStar, Skoot13, Names are hard to think of, Purple Blanket, Rebrewind, WildCation and Anonymous: 17 • JWH-251 Source: http://en.wikipedia.org/wiki/JWH-251?oldid=600909501 Contributors: Rjwilmsi, Bazonka, Beetstra, Meodipt, Enix150, Addbot, C6541, CheMoBot, Citation bot, The chemistds and AvocatoBot • JWH-302 Source: http://en.wikipedia.org/wiki/JWH-302?oldid=517587317 Contributors: Rjwilmsi, Beetstra, Meodipt, CheMoBot, BogBot, The chemistds and Skoot13 • JWH-307 Source: http://en.wikipedia.org/wiki/JWH-307?oldid=606472694 Contributors: Cacycle, NawlinWiki, Pegship, KGasso, Edgar181, Meodipt, Smartse, MER-C, Enix150, Addbot, CheMoBot, Sarrus, Grim23, حسن علي البط, Biker Biker, BogBot, Dinamikbot, Tbhotch, Tisane, Somerwind, Caponex, ClueBot NG, Verified72, WildCation and Anonymous: 14 • JWH-398 Source: http://en.wikipedia.org/wiki/JWH-398?oldid=622353964 Contributors: Rjwilmsi, Meodipt, Enix150, C6541, CheMoBot, Grim23, حسن علي البط, Harbinary, BogBot, Tisane, Skoot13, WildCation and Anonymous: 1 • JWH-424 Source: http://en.wikipedia.org/wiki/JWH-424?oldid=606469047 Contributors: Meodipt, Enix150, C6541, CheMoBot, Gongshow, FrescoBot, BogBot, Skoot13, BaeyerDrewson and WildCation • Naphthoylindole Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch, Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser, Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilharmonic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT, Nirigihimu, Turkeyphant, Zefiel, Smartse, Theguy0000, MER-C, Grimelab, Iownutopia, JamesBWatson, Monosodious, Bradgib, ChemNerd, Leyo, Boghog, Malkuth1, Gutterkitty, Enix150, Pdcook, CardinalDan, Funandtrvl, Msrbl49, Fbifriday, Philip Trueman, Flux12n21, Flopster2, Wikieditor12, Jpaliano, Guldenat, Falcon8765, Living under a rock, Pjoef, Dlfreem, Dheau, Hobartimus, ClueBot, GorillaWarfare, Tomas e, Drmies, Yuubi, Auntof6, Ktr101, Alexbot, Dr.Koljan, Panoramix303, Sun Creator, Christopherbrian, XLinkBot, Fastily, ErgoSum88, ESO Fan, PurrfectPeach, Addbot, C6541, MartinezMD, Fieldday-sunday, Fluffernutter, LaaknorBot, DFS454, Favonian, Tide rolls, Wax025, Ben Ben, Legobot, Luckas-bot, Yobot, Legobot II, CheMoBot, Daddyrob81, Anypodetos, AnomieBOT, XLocal, Vinyl Ketone, Piano non troppo, Citation bot, GB fan, Intelati, OlYeller21, Δζ, Pontificalibus, Nasnema, Rhoodey, حسن علي البط, Harbinary, Shirik, Amaury, Psychonaught, Shadowjams, Custoo, FrescoBot, Nageh, RicHard-59, Metallica3790, Borguebabe, Weetoddid, Boylechem, Citation bot 1, Biker Biker, Calmer Waters, MastiBot, Sw1ngOnTheSp1ral, BogBot, CrowzRSA, Clickpop, David Hedlund, Tbhotch, RjwilmsiBot, Dustin 3choes, Jwh018, Rsharpe28, John of Reading, Gunnanmon, Katherine, Tisane, Clayman1976, Atropinesulfate, Tommy2010, Sraab2, Wikipelli, White Trillium, Fæ, Josve05a, James.dynamite, Hereforhomework2, H3llBot, Darkwire89, Drhjort, ALANON54, Wayne Slam, Ocaasi, OnePt618, Scema, PeterGriffinJK, Akacypress, Demetrius259, Corei7Maniac, Del nerius, Lagato123, Tjiseclipsed, ClamDip, HaydenBeck, W5NLbrian, Handsum53, DASHBotAV, Hetoi, Abnorml1, Louisajb, Mikhail Ryazanov, ClueBot NG, Agents of The Free, Easyzeh, Dualdj1, Tesacrynheart, EnvyCo, Diogenes2000, Skoot13, 4321acb, Jacobso4, Murraysymes, 1989Exley1989, Exercisephys, Verified72, Snow Blizzard, Boobs4fun, Justthinking25, Shisha-Tom, Fuse809, PhoenixPie, Kid squid, BattyBot, BaeyerDrewson, Rawrfaceace, KMAnomalocaris, Rebrewind, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 417 • Phenylacetylindole Source: http://en.wikipedia.org/wiki/JWH-167?oldid=600826360 Contributors: Stephen, Rjwilmsi, Shoy, Beetstra, Boghog, Enix150, Jsfouche, C6541, Ben Ben, CheMoBot, Citation bot, EmausBot, The chemistds, Rezabot and Anonymous: 1
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• RCS-8 Source: http://en.wikipedia.org/wiki/RCS-8?oldid=568307281 Contributors: Shoy, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, AnomieBOT, BogBot, The chemistds, Bped1985 and BaeyerDrewson • Intravenous Marijuana Syndrome Source: http://en.wikipedia.org/wiki/Intravenous_Marijuana_Syndrome?oldid=619005877 Contributors: Nagelfar, ESkog, TheoClarke, GregorB, SqueakBox, Rjwilmsi, Wavelength, Kirix, Sadads, Slakr, Fences and windows, Another Believer, NJGW, Mjpresson, C6541, Anypodetos, ThaddeusB, Blueharvest26, Citation bot, Haeinous, Donner60, BG19bot, Darthgreg and Anonymous: 9 • Mellow Yellow coffeeshop Source: http://en.wikipedia.org/wiki/Mellow_Yellow_coffeeshop?oldid=606996853 Contributors: Rpyle731, SqueakBox, MrSativa, Katharineamy, Addbot, Diannaa, Ihakeycakeyabreak, Emayv, BattyBot, Mrt3366, Comatmebro, Mogism, Smokey McSmokealot, Tough brown zealot and Anonymous: 1 • The Night Train Seizure Source: http://en.wikipedia.org/wiki/The_Night_Train_Seizure?oldid=627809729 Contributors: Bearcat, ChrisCork, Slazenger, Katharineamy, Themoodyblue, Pjoef, Mcrabb23 and Ca2flbroker • PSN-375,963 Source: http://en.wikipedia.org/wiki/PSN-375,963?oldid=450845362 Contributors: Meodipt, Chemgirl131, CheMoBot, حسن علي البط, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot and PotatoBot • PSN-632,408 Source: http://en.wikipedia.org/wiki/PSN-632,408?oldid=450845292 Contributors: Meodipt, Chemgirl131, CheMoBot, حسن علي البط, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot and PotatoBot • Soma Seeds Source: http://en.wikipedia.org/wiki/Soma_Seeds?oldid=608038890 Contributors: Bearcat, Rpyle731, Alexf, Grafen, SmackBot, Berean Hunter, Guygoldman, Yobot, Hahamgaon, Soma Seeds, WeedFreak, Bakuto459, BitcoinSeeds and Anonymous: 1 • TM-38837 Source: http://en.wikipedia.org/wiki/TM-38837?oldid=608356887 Contributors: BD2412, Racklever, Meodipt, Enix150, Yobot, Custoo, The chemistds, Paul269, BG19bot, Vaccinationist and Anonymous: 1
252.4.2
Images
• File:(+)-(6aR,10aS)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/2/20/%28%2B%29-%286aR%2C10aS%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_shown%29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:(+)-(6aS,10aS)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/b/b1/%28%2B%29-%286aS%2C10aS%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_shown%29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:(+)-trans-cannabitriol.png Source: http://.wikimedia.org/wikipedia/commons/1/12/%28%2B%29-trans-cannabitriol.png License: CC-BY-SA-3.0 Contributors: Self-published work by Cacycle Original artist: Cacycle • File:(-)-trans-cannabitriol.png Source: http://.wikimedia.org/wikipedia/commons/a/a2/%28-%29-trans-cannabitriol.png License: CC-BY-SA-3.0 Contributors: Self-published work by Cacycle Original artist: Cacycle • File:(C6)-_47,497.png Source: http://.wikimedia.org/wikipedia/commons/d/d8/%28C6%29-_47%2C497.png License: Public domain Contributors: ChemSpider Original artist: ChemSpider • File:(C9)-_47,497.png Source: http://.wikimedia.org/wikipedia/commons/c/cb/%28C9%29-_47%2C497.png License: Public domain Contributors: ChemSpider Original artist: ChemSpider • File:(−)-(6aR,10aR)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/3/39/%28%E2%88%92%29-%286aR%2C10aR%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_ shown%29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:(−)-(6aS,10aR)-Δ9-Tetrahydrocannabinol_(with_hydrogen_atoms_shown).svg Source: http://.wikimedia.org/wikipedia/ commons/1/1d/%28%E2%88%92%29-%286aS%2C10aR%29-%CE%949-Tetrahydrocannabinol_%28with_hydrogen_atoms_shown% 29.svg License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:10-oxo-delta-6a(10a)-tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/f/f5/ 10-oxo-delta-6a%2810a%29-tetrahydrocannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:11-COOH-THC.svg Source: http://.wikimedia.org/wikipedia/commons/8/8d/11-COOH-THC.svg License: Public domain Contributors: Own work Original artist: Harbin • File:11-Hydroxy-THC-3D-balls.png Source: http://.wikimedia.org/wikipedia/commons/e/e3/11-Hydroxy-THC-3D-balls.png License: CC0 Contributors: This chemical image was created with Discovery Studio Visualizer. Original artist: Jynto (talk) • File:11-OH-THC.svg Source: http://.wikimedia.org/wikipedia/commons/6/6e/11-OH-THC.svg License: Public domain Contributors: Own work Original artist: Harbin • File:2-(6-Isopropenyl-3-methyl-1-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ CC0 wikipedia/commons/b/b4/2-%286-Isopropenyl-3-methyl-1-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-2-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/5/5d/2-%286-Isopropenyl-3-methyl-2-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-3-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/d/d2/2-%286-Isopropenyl-3-methyl-3-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-4-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/6/67/2-%286-Isopropenyl-3-methyl-4-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• File:2-(6-Isopropenyl-3-methyl-5-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/a/a2/2-%286-Isopropenyl-3-methyl-5-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methyl-6-cyclohexen-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/ wikipedia/commons/4/4c/2-%286-Isopropenyl-3-methyl-6-cyclohexen-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-(6-Isopropenyl-3-methylenecyclohex-1-yl)$-$5-pentyl-1,3-benzenediol.png Source: http://.wikimedia.org/wikipedia/ commons/a/af/2-%286-Isopropenyl-3-methylenecyclohex-1-yl%29-5-pentyl-1%2C3-benzenediol.png License: CC0 Contributors: Own work Original artist: Nikos 1993 • File:2-Arachidonyl_glyceryl_ether.svg Source: http://.wikimedia.org/wikipedia/commons/4/47/2-Arachidonyl_glyceryl_ether. svg License: Public domain Contributors: Own work Original artist: Benrr101 • File:2ag.svg Source: http://.wikimedia.org/wikipedia/commons/5/55/2ag.svg License: CC-BY-SA-3.0 Contributors: Own work in chemdraw/illustrator and originally from en.wikipedia; description page is/was here. 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• File:AM-6545_structure.png Source: http://.wikimedia.org/wikipedia/commons/c/c2/AM-6545_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:AM-679_structure.png Source: http://.wikimedia.org/wikipedia/commons/4/4c/AM-679_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:AM-855.svg Source: http://.wikimedia.org/wikipedia/commons/3/33/AM-855.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Panoramix303 • File:AM-905.svg Source: http://.wikimedia.org/wikipedia/commons/6/69/AM-905.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Panoramix303 • File:AM-906.svg Source: http://.wikimedia.org/wikipedia/commons/5/50/AM-906.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Panoramix303 • File:AM-919.png Source: http://.wikimedia.org/wikipedia/commons/a/a8/AM-919.png License: Public domain Contributors: Transferred from en.wikipedia by Ronhjones Original artist: Meodipt at en.wikipedia • File:AM-938.png Source: http://.wikimedia.org/wikipedia/commons/a/a6/AM-938.png License: Public domain Contributors: Transferred from en.wikipedia by Ronhjones Original artist: Meodipt at en.wikipedia • File:AM1220heterocycles.png Source: http://.wikimedia.org/wikipedia/commons/b/bd/AM1220heterocycles.png License: Public domain Contributors: Own work Original artist: Meodipt • File:AM2512d.png Source: http://.wikimedia.org/wikipedia/commons/e/e0/AM2512d.png License: Public domain Contributors: Own work Original artist: Ccroberts • File:AM2513d.png Source: http://.wikimedia.org/wikipedia/commons/b/b8/AM2513d.png License: Public domain Contributors: Own work Original artist: Ccroberts • File:AM404_skel.svg Source: http://.wikimedia.org/wikipedia/commons/b/ba/AM404_skel.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: WhiteTimberwolf, PNG version: Xasodfuih • File:AMG-1.png Source: http://.wikimedia.org/wikipedia/commons/5/5a/AMG-1.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Addihockey10 using CommonsHelper. 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Original artist: ? • File:Ambox_wikify.svg Source: http://.wikimedia.org/wikipedia/commons/e/e1/Ambox_wikify.svg License: Public domain Contributors: Own work Original artist: penubag • File:Anandamid.svg Source: http://.wikimedia.org/wikipedia/commons/1/1f/Anandamid.svg License: Public domain Contributors: Own work Original artist: NEUROtiker • File:Anandamide_skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/b/b7/Anandamide_skeletal.svg License: Public domain Contributors: Own work Original artist: Fvasconcellos 23:45, 27 May 2007 (UTC) • File:Arachidonyl-2-chloroethylamide.svg Source: http://.wikimedia.org/wikipedia/commons/a/ad/ Arachidonyl-2-chloroethylamide.svg License: Public domain Contributors: Own work Original artist: Ed (Edgar181) • File:Arachidonylcyclopropylamide.svg Source: http://.wikimedia.org/wikipedia/commons/c/c0/Arachidonylcyclopropylamide. svg License: Public domain Contributors: Own work Original artist: Ed (Edgar181)
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
345
• File:BAY38-7271.svg Source: http://.wikimedia.org/wikipedia/commons/f/f0/BAY38-7271.svg License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia. Later version(s) were ed by Edgar181 at en.wikipedia. • File:BAY59-3074.svg Source: http://.wikimedia.org/wikipedia/commons/d/da/BAY59-3074.svg License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia. Later version(s) were ed by Edgar181 at en.wikipedia. • File:BB-22.png Source: http://.wikimedia.org/wikipedia/commons/4/4b/BB-22.png License: Public domain Contributors: Own work Original artist: BaeyerDrewson • File:Beta-Caryophyllen.svg Source: http://.wikimedia.org/wikipedia/commons/b/b4/Beta-Caryophyllen.svg License: Public domain Contributors: Own work Original artist: NEUROtiker (talk) • File:C3-cannabielsoic_acid_B.png Source: http://.wikimedia.org/wikipedia/commons/b/b7/C3-cannabielsoic_acid_B.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:C3-cannabielsoin.png Source: http://.wikimedia.org/wikipedia/commons/3/37/C3-cannabielsoin.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:CB-13_structure.png Source: http://.wikimedia.org/wikipedia/commons/1/10/CB-13_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia • File:CBC-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/7/7a/CBC-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBC-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/0/08/CBC-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBD-3D-balls.png Source: http://.wikimedia.org/wikipedia/commons/e/e1/CBD-3D-balls.png License: Public domain Contributors: Own work Original artist: Ben Mills • File:CBD-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/2/26/CBD-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBD-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/d/dc/CBD-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBE-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/8/87/CBE-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBE-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/2/2c/CBE-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBG-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/8/87/CBG-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: Own work Original artist: Cacycle • File:CBG-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/6/67/CBG-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBL-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/d/d6/CBL-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBL-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/3/3b/CBL-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBN-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/2/2a/CBN-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBN-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/3/35/CBN-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBS-0550_structure.png Source: http://.wikimedia.org/wikipedia/commons/7/79/CBS-0550_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:CBT-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/4/4b/CBT-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:CBT-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/9/93/CBT-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:-47,497.svg Source: http://.wikimedia.org/wikipedia/commons/a/a0/-47%2C497.svg License: Public domain Contributors: Transferred from en.wikipedia Original artist: Original er was Meodipt at en.wikipedia • File:-55,244.svg Source: http://.wikimedia.org/wikipedia/commons/6/6d/-55%2C244.svg License: Public domain Contributors: Transferred from en.wikipedia Original artist: Original er was Meodipt at en.wikipedia • File:_55,940-2D-skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/d/d7/_55%2C940-2D-skeletal.svg License: Public domain Contributors: Own work Original artist: Harbin • File:Cannabichromanone-C3.png Source: http://.wikimedia.org/wikipedia/commons/5/58/Cannabichromanone-C3.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromanone.png Source: http://.wikimedia.org/wikipedia/commons/a/aa/Cannabichromanone.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromene-skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/0/0b/Cannabichromene-skeletal.svg License: Public domain Contributors: Own work Original artist: Benrr101
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• File:Cannabichromene.png Source: http://.wikimedia.org/wikipedia/commons/c/cd/Cannabichromene.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:Cannabichromenic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/a/af/Cannabichromenic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromevarine.png Source: http://.wikimedia.org/wikipedia/commons/3/34/Cannabichromevarine.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromevarinic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/4/4c/Cannabichromevarinic_acid_ A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicitran.png Source: http://.wikimedia.org/wikipedia/commons/8/83/Cannabicitran.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicoumaronone.png Source: http://.wikimedia.org/wikipedia/commons/8/8a/Cannabicoumaronone.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicyclohexanol.png Source: http://.wikimedia.org/wikipedia/commons/6/6c/Cannabicyclohexanol.png License: Public domain Contributors: Transferred from en.wikipedia Original artist: Meodipt at en.wikipedia • File:Cannabicyclol.png Source: http://.wikimedia.org/wikipedia/commons/4/49/Cannabicyclol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicyclolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/e/e9/Cannabicyclolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicyclovarin.png Source: http://.wikimedia.org/wikipedia/commons/0/01/Cannabicyclovarin.png License: CC-BYSA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol-C4.png Source: http://.wikimedia.org/wikipedia/commons/a/a7/Cannabidiol-C4.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol.png Source: http://.wikimedia.org/wikipedia/commons/3/3f/Cannabidiol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol.svg Source: http://.wikimedia.org/wikipedia/commons/9/9a/Cannabidiol.svg License: Public domain Contributors: Own work Original artist: Harbin • File:Cannabidiol3Dan.gif Source: http://.wikimedia.org/wikipedia/commons/4/44/Cannabidiol3Dan.gif License: CC-BY-SA3.0 Contributors: QuteMol Original artist: Fuse809 • File:Cannabidiol_momomethyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/5/54/Cannabidiol_momomethyl_ ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiol_numbering.png Source: http://.wikimedia.org/wikipedia/commons/9/9f/Cannabidiol_numbering.png License: Public domain Contributors: SYNTHESIS OF DELTA-3-CANNABIDIOL AND THE DERIVED RIGID ANALOGS, 1987, p. 20 (37 in PDF file) Original artist: NAGARAJA, KODIHALLI NANJAPPA • File:Cannabidiolic_acid.png Source: http://.wikimedia.org/wikipedia/commons/d/d2/Cannabidiolic_acid.png License: CC-BYSA-3.0 Contributors: ? Original artist: ? • File:Cannabidiolic_acid_A_cannabitriol_ester.png Source: http://.wikimedia.org/wikipedia/commons/b/b8/Cannabidiolic_ acid_A_cannabitriol_ester.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidiorcol.png Source: http://.wikimedia.org/wikipedia/commons/2/20/Cannabidiorcol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidivarin.png Source: http://.wikimedia.org/wikipedia/commons/4/40/Cannabidivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabidivarin.svg Source: http://.wikimedia.org/wikipedia/commons/8/8a/Cannabidivarin.svg License: Public domain Contributors: Own work Original artist: Benrr101 • File:Cannabidivarinic_acid.png Source: http://.wikimedia.org/wikipedia/commons/5/55/Cannabidivarinic_acid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabielsoic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/2/22/Cannabielsoic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabielsoic_acid_B.png Source: http://.wikimedia.org/wikipedia/commons/9/90/Cannabielsoic_acid_B.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabielsoin.png Source: http://.wikimedia.org/wikipedia/commons/2/21/Cannabielsoin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabifuran.png Source: http://.wikimedia.org/wikipedia/commons/7/7f/Cannabifuran.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerol.png Source: http://.wikimedia.org/wikipedia/commons/b/bd/Cannabigerol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerol_monomethyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/6/6c/Cannabigerol_ monomethyl_ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/4/40/Cannabigerolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabigerolic_acid_A_monomethyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/9/9e/Cannabigerolic_ acid_A_monomethyl_ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ?
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
347
• File:Cannabigerovarin.png Source: http://.wikimedia.org/wikipedia/commons/2/20/Cannabigerovarin.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:Cannabigerovarinic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/6/63/Cannabigerovarinic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabiglendol-C3.png Source: http://.wikimedia.org/wikipedia/commons/2/23/Cannabiglendol-C3.png License: CC-BYSA-3.0 Contributors: ? Original artist: ? • File:Cannabinerolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/a/ae/Cannabinerolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinodiol.png Source: http://.wikimedia.org/wikipedia/commons/d/dd/Cannabinodiol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinodivarin.png Source: http://.wikimedia.org/wikipedia/commons/9/96/Cannabinodivarin.png License: CC-BY-SA3.0 Contributors: ? Original artist: ? • File:Cannabinol-C2.png Source: http://.wikimedia.org/wikipedia/commons/f/f0/Cannabinol-C2.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinol-C4.png Source: http://.wikimedia.org/wikipedia/commons/8/8d/Cannabinol-C4.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinol.png Source: http://.wikimedia.org/wikipedia/commons/1/1c/Cannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinol_methyl_ether.png Source: http://.wikimedia.org/wikipedia/commons/d/d4/Cannabinol_methyl_ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabinolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/5/54/Cannabinolic_acid_A.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabiorcol.png Source: http://.wikimedia.org/wikipedia/commons/9/90/Cannabiorcol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabiripsol.png Source: http://.wikimedia.org/wikipedia/commons/e/ea/Cannabiripsol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabis_indica.jpg Source: http://.wikimedia.org/wikipedia/commons/7/77/Cannabis_indica.jpg License: FAL Contributors: 1. Ward, A Holmes, B (1985): Nabilone: a preliminary review of its pharmacological properties and therapeutic use. Drugs 30, 127-144. 2. Gagnon,B Bruera,E (1998): A review of the drug treatment of cachexia associated with cancer. Drugs 55, 675-688. 3. Nahas,G Sutin,K Bennett,WM (2000): Review of Marihuana and medicine. N Engl J Med 343, 514-515. 4. Tinklenberg,JR (1975): What a physician should know about marihuana. Rat Drug Ther 9/7, 1-6. 5. Grinspoon,L Bakalar,JB (1995): Marihuana as medicine. A plea for reconsideration. JAMA 273, 1875©1876. 6. Voth,EA Schwartz,RH (1997): Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 126, 791©798. 7. Merritt,JC Crawford,WJ Alexander,PC Anduze,AL Gelbart,SS (1980): Effect of marijuana on intraocular and blood pressure in glaucoma. Ophthalmology 87, 222©228. 8. Morris,K (1997): The cannabis remedy- wonder worker or evil weed? Lancet 350, 1828. Original artist: Axsadi Sánchez de Tagle • File:Cannabis_leaf.svg Source: http://.wikimedia.org/wikipedia/commons/a/a8/Cannabis_leaf.svg License: CC-BY-SA-3.0 Contributors: This vector image was created with Inkscape. Original artist: Oren neu dag • File:Cannabitetrol.png Source: http://.wikimedia.org/wikipedia/commons/b/b8/Cannabitetrol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabivarin.png Source: http://.wikimedia.org/wikipedia/commons/6/6f/Cannabivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabivarin.svg Source: http://.wikimedia.org/wikipedia/commons/9/97/Cannabivarin.svg License: Public domain Contributors: Own work Original artist: Benrr101 • File:Cis-cannabitriol.png Source: http://.wikimedia.org/wikipedia/commons/6/65/Cis-cannabitriol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cis-delta-9-tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/c/cc/ Cis-delta-9-tetrahydrocannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Commons-logo.svg Source: http://.wikimedia.org/wikipedia/en/4/4a/Commons-logo.svg License: ? Contributors: ? Original artist: ? • File:Dehydrocannabifuran.png Source: http://.wikimedia.org/wikipedia/commons/e/ec/Dehydrocannabifuran.png License: CCBY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-7-cis-isotetrahydrocannabivarin.png Source: http://.wikimedia.org/wikipedia/commons/3/31/ Delta-7-cis-isotetrahydrocannabivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-7-trans-isotetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/c/ce/ Delta-7-trans-isotetrahydrocannabinol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ?
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• File:Delta-7-trans-isotetrahydrocannabivarin.png Source: http://.wikimedia.org/wikipedia/commons/1/19/ Delta-7-trans-isotetrahydrocannabivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-8-tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/c/cd/Delta-8-tetrahydrocannabinol. png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-8-tetrahydrocannabinolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/0/07/ Delta-8-tetrahydrocannabinolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabinol-C4.png Source: http://.wikimedia.org/wikipedia/commons/3/32/ Delta-9-tetrahydrocannabinol-C4.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabinol-from-tosylate-xtal-3D-balls.png Source: http://.wikimedia.org/wikipedia/commons/e/ef/ Delta-9-tetrahydrocannabinol-from-tosylate-xtal-3D-balls.png License: Public domain Contributors: Own work Original artist: Ben Mills • File:Delta-9-tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/b/b5/Delta-9-tetrahydrocannabinol. png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabinolic_acid-C4.png Source: http://.wikimedia.org/wikipedia/commons/f/f3/ Delta-9-tetrahydrocannabinolic_acid-C4.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabinolic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/9/9c/ Delta-9-tetrahydrocannabinolic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabinolic_acid_B.png Source: http://.wikimedia.org/wikipedia/commons/6/6f/ Delta-9-tetrahydrocannabinolic_acid_B.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabiorcolic_acid.png Source: http://.wikimedia.org/wikipedia/commons/a/a6/ Delta-9-tetrahydrocannabiorcolic_acid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabivarin.png Source: http://.wikimedia.org/wikipedia/commons/c/ce/ Delta-9-tetrahydrocannabivarin.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta-9-tetrahydrocannabivarinic_acid_A.png Source: http://.wikimedia.org/wikipedia/commons/8/8a/ Delta-9-tetrahydrocannabivarinic_acid_A.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Delta10-Tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/0/06/ Delta10-Tetrahydrocannabinol.png License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:Delta6a,10a-Tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/a/aa/Delta6a% 2C10a-Tetrahydrocannabinol.png License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:Delta6a,7-Tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/a/a6/Delta6a% 2C7-Tetrahydrocannabinol.png License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:Delta7-Tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/a/af/Delta7-Tetrahydrocannabinol. png License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:Delta8-Tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/9/9b/Delta8-Tetrahydrocannabinol. png License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:Delta9,11-Tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/a/a5/Delta9% 2C11-Tetrahydrocannabinol.png License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:Delta9-Tetrahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/e/eb/Delta9-Tetrahydrocannabinol. png License: Public domain Contributors: Own work Original artist: Nikos 1993 • File:Diagram_human_cell_nucleus_no_text.png Source: http://.wikimedia.org/wikipedia/commons/f/f9/Diagram_human_ cell_nucleus_no_text.png License: Public domain Contributors: Originally from en.wikipedia; description page is/was here. Original artist: Mariana Ruiz Villarreal LadyofHats. Original er was Peter Znamenskiy at en.wikipedia • File:Diazepam-from-xtal-3D-vdW.png Source: http://.wikimedia.org/wikipedia/commons/c/cf/Diazepam-from-xtal-3D-vdW. png License: Public domain Contributors: Own work Original artist: Ben Mills
• File:Dibenzopyran_and_monoterpenoid_numbering_of_tetrahydrocannabinol.png Source: http://.wikimedia. org/wikipedia/commons/5/52/Dibenzopyran_and_monoterpenoid_numbering_of_tetrahydrocannabinol.png License: Public domain Contributors: Ronhjones (Talk) • File:Hu210_bns.png Source: http://.wikimedia.org/wikipedia/commons/7/7c/Hu210_bns.png License: CC0 Contributors: Own work Original artist: SubDural12 • File:Hydroxyhexahydrocannabinol.png Source: http://.wikimedia.org/wikipedia/commons/3/3e/Hydroxyhexahydrocannabinol. png License: Public domain Contributors: Transferred from en.wikipedia Original artist: Meodipt at en.wikipedia • File:IDFP_structure.png Source: http://.wikimedia.org/wikipedia/commons/6/6d/IDFP_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:IPMDHNPC.png Source: http://.wikimedia.org/wikipedia/commons/2/2b/IPMDHNPC.png License: Public domain Contributors: :Meodipt Original artist: :Meodipt • File:Ibipinabant.svg Source: http://.wikimedia.org/wikipedia/commons/4/43/Ibipinabant.svg License: Public domain Contributors: Own work Original artist: Vaccinationist • File:Imbox_content.png Source: http://.wikimedia.org/wikipedia/en/3/38/Imbox_content.png License: ? Contributors: Derived from Image:Information icon.svg Original artist: El T (original icon); David Levy (modified design); Penubag (modified color) • File:Iso-CBN-type_cannabinoid.png Source: http://.wikimedia.org/wikipedia/commons/8/82/Iso-CBN-type_cannabinoid.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Iso-CBN-type_cyclization_of_cannabinoids.png Source: http://.wikimedia.org/wikipedia/commons/e/e5/Iso-CBN-type_ cyclization_of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:JMC2003_46_2110compound4b.png Source: http://.wikimedia.org/wikipedia/commons/5/57/JMC2003_46_ 2110compound4b.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JTE_7-31_molecular_structure.png Source: http://.wikimedia.org/wikipedia/commons/d/d6/JTE_7-31_molecular_ structure.png License: Public domain Contributors: Own work Original artist: Enix150 • File:JWH-018.jpg Source: http://.wikimedia.org/wikipedia/commons/7/7a/JWH-018.jpg License: Public domain Contributors: Own work Original artist: Psychonaught • File:JWH-018_synthesis.svg Source: http://.wikimedia.org/wikipedia/commons/9/96/JWH-018_synthesis.svg License: CC-BYSA-4.0 Contributors: Own work Original artist: Boghog • File:JWH-030.svg Source: http://.wikimedia.org/wikipedia/commons/1/16/JWH-030.svg License: Public domain Contributors: Own work Original artist: Harbinary • File:JWH-051.png Source: http://.wikimedia.org/wikipedia/commons/c/c7/JWH-051.png License: Public domain Contributors: :Meodipt Original artist: :Meodipt • File:JWH-133-2D-skeletal.svg Source: http://.wikimedia.org/wikipedia/commons/a/ae/JWH-133-2D-skeletal.svg License: Public domain Contributors: Own work Original artist: Harbin • File:JWH-161_structure.png Source: http://.wikimedia.org/wikipedia/commons/0/09/JWH-161_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Meodipt. Original er was Meodipt at en.wikipedia • File:JWH-167_molecular_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/e6/JWH-167_molecular_ structure.png License: Public domain Contributors: Own work Original artist: Enix150
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• File:JWH-171.png Source: http://.wikimedia.org/wikipedia/commons/f/fc/JWH-171.png License: Public domain Contributors: :Meodipt Original artist: :Meodipt • File:JWH-175_structure.png Source: http://.wikimedia.org/wikipedia/commons/2/25/JWH-175_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-193_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/ec/JWH-193_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-198_structure.png Source: http://.wikimedia.org/wikipedia/commons/6/67/JWH-198_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-200.svg Source: http://.wikimedia.org/wikipedia/commons/f/fc/JWH-200.svg License: Public domain Contributors: Own work Original artist: Harbinary • File:JWH-204_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/e0/JWH-204_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-251_molecular_structure.png Source: http://.wikimedia.org/wikipedia/commons/3/3f/JWH-251_molecular_ structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:JWH-359_structure.png Source: http://.wikimedia.org/wikipedia/commons/c/c9/JWH-359_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. 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Original artist: Psychonaught (talk). Original er was Psychonaught at en.wikipedia • File:L-759,633.png Source: http://.wikimedia.org/wikipedia/commons/e/ed/L-759%2C633.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia • File:L-759,656.png Source: http://.wikimedia.org/wikipedia/commons/e/ee/L-759%2C656.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Original er was Meodipt at en.wikipedia • File:LASSBio-881_structure.png Source: http://.wikimedia.org/wikipedia/commons/e/e2/LASSBio-881_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:LBP-1_structure.png Source: http://.wikimedia.org/wikipedia/commons/9/91/LBP-1_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:LY-2183240_structure.png Source: http://.wikimedia.org/wikipedia/commons/6/65/LY-2183240_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:Leelamine_structure.png Source: http://.wikimedia.org/wikipedia/commons/5/59/Leelamine_structure.png License: Public domain Contributors: made in chemdraw Original artist: sekio • File:Levonantradol.svg Source: http://.wikimedia.org/wikipedia/commons/e/e8/Levonantradol.svg License: Public domain Contributors: Own work Original artist: Harbinary • File:MDA-19_structure.png Source: http://.wikimedia.org/wikipedia/commons/5/51/MDA-19_structure.png License: Public domain Contributors: Own work Original artist: Meodipt • File:MK-9470.png Source: http://.wikimedia.org/wikipedia/commons/4/41/MK-9470.png License: Public domain Contributors: Transferred from en.wikipedia to Commons by :Ronhjones using CommonsHelper. 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Original artist:
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES
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• File:Nabilone2D.svg Source: http://.wikimedia.org/wikipedia/commons/7/73/Nabilone2D.svg License: Public domain Contributors: MarvinSketch 6.0.0 Original artist: Fuse809 Fuse809 at en.wikipedia • File:Nabilone3Dan2.gif Source: http://.wikimedia.org/wikipedia/commons/0/04/Nabilone3Dan2.gif License: CC-BY-SA-3.0 Contributors: QuteMol Original artist: Fuse809 • File:Nabitan.svg Source: http://.wikimedia.org/wikipedia/commons/f/f5/Nabitan.svg License: Public domain Contributors: Own work Original artist: Snubcube ( talk) • File:Naboctate_structure.png Source: http://.wikimedia.org/wikipedia/commons/1/1a/Naboctate_structure.png License: Public domain Contributors: Transferred from en.wikipedia; transferred to Commons by :Ronhjones using CommonsHelper. Original artist: Meodipt. 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• File:Padlock-silver.svg Source: http://.wikimedia.org/wikipedia/commons/f/fc/Padlock-silver.svg License: ? Contributors: http: //openclipart.org/people/Anonymous/padlock_aj_ashton_01.svg Original artist: This image file was created by AJ Ashton. ed from English WP by :Eleassar. Converted by :AzaToth to a silver color. • File:Pancreatic_stellate_cell_cropped.png Source: cropped.png License: CC-BY-2.5 Contributors:
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