Cholinesterase Inhibitors 6x2s2p
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MCMP 407 Acetylcholinesterase Inhibitors
MCMP 407
Types of cholinesterases
Acetylcholinesterase Located in synapses Substrate selectivity: » ACH
Plasma cholinesterase Located in plasma (non-neuronal) Substrate selectivity: » ACH » Succinylcholine » Local anesthetics (procaine)
MCMP 407
Hydrolysis of acetylcholine by AChE
O
Glu 327
C H N
Phe 338 O N
His 440
O
CH3 N CH3 CH3
O OH
Trp 86 Ser 203
Esteratic site
HN
Anionic site
MCMP 407
Hydrolysis of acetylcholine by AChE
O C
Glu 327
O
H N
Phe 338 N
CH3 N CH3 CH3
His 440 O
HO
Anionic site
O
Ser 203
Esteratic site
Trp 86 HN
MCMP 407
Hydrolysis of acetylcholine by AChE
O C
Glu 327
O
H N
Phe 338 N
choline
His 440
O
HO
CH3 N CH3 CH3
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Hydrolysis of acetylcholine by AChE
O C
Glu 327
O
H N
Phe 338 N
O
His 440
O
H
H
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Hydrolysis of acetylcholine by AChE
O
Glu 327
C H N
O
Phe 338 N
O
His 440
acetate OH
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407 Pharmacologic manipulation of AChE: No inhibition
Na+ Muscarinic
ACH
Receptor
ACH
Acetylcholinesterase
Action Potential
ACH ACH ACH
ACH ACH ACH
ACH ACH ACH
Presynaptic neuron
Choline Acetate
Postsynaptic target
MCMP 407 Pharmacologic manipulation of AChE: Inhibition by drugs ACH ACH
Na+ ACH ACH
Muscarinic Receptor
ACH
Acetylcholinesterase
Action Potential
ACH ACH ACH
ACH ACH ACH
ACH ACH ACH ACH
Presynaptic neuron
ACH
ACH
Postsynaptic target
MCMP 407
Acetylcholinesterase inhibitors R
R
N
R
R
R CH3 C 2H 5 C 3H 7 C 4H 9
Relative Potency 1.0 5.0 100 50
Tetraalkylammonium ions Simplest structures Bind to anionic site and block ACh binding Reversible Non-covalent
MCMP 407
Acetylcholinesterase inhibitors OH
H3C
N
C2H5
CH3
Edrophonium (Tensilon)
Quaternary ammonium alcohol Simplest structures Bind to anionic site and block ACh binding Reversible Non-covalent
MCMP 407
Acetylcholinesterase inhibitors CH3 O
N CH3
O N
H3 C
CH3
Neostigmine (Prostigmin)
CH3
CH3 O
N CH3 O
N CH3
H N
O
Pyridostigmine (Mestinon)
Most basic Nitrogen; protonated at physiological pH.
H3 C
H3 C
N O
Physostigmine (Antilirium)
Carbamates Quaternary or tertiary ammonium groups Reversible Covalent modification to AChE
N
H CH3
CH3
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440 O N
N
O
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440
O N
N
HO O
Anionic site Trp 86
Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440
O N
N
HO O
Anionic site Trp 86
Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440
O N
O
Anionic site Trp 86
Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440 O N
OH
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Acetylcholinesterase inhibitors O O
P
F
O
Isofluorophate; DFP (Floropryl)
-
I
O H3 C H3C N CH2 CH2 S CH3
P
OC2H5
OC2H5
Echothiophate (Phospholine Iodide)
Organophosphates Irreversible Covalent modification to AChE Longer acting Used in the treatment of glaucoma
MCMP 407
Acetylcholinesterase inhibitors O H3C
P
F
O
Sarin
H3C
CH3CH3
O
C CH O
P
CH3
CH3
Soman
F
Organophosphates Nerve gases Irreversible Covalent modification to AChE
MCMP 407
Acetylcholinesterase inhibitors O S C2H5 C2H5
O O
C O CH S C
CH2
P
OCH3
OCH3
Malathion
CH3
N H3 C H3 C
CH
S O N
Diazinon
P
OC2H5
OC2H5
Organophosphates Insecticides Irreversible Covalent modification to AChE Rapidly inactivated in mammals
MCMP 407
Biotransformation of insecticides O
O
O
S C2H5
O
C2H5
O
C O CH S
P
C
OCH3
CH2
OCH3
Malathion
Cyt P450 Insects
C2H5
O
C2H5
O
C O CH S
P
C
OCH3
CH2
Malaoxon
Carboxyesterase Mammals, Birds
O S HO HO
C O CH S
P
C
OCH3
CH2
(Inactive)
OCH3
OCH3
MCMP 407
Inhibition of AChE by Organophosphates Why do these drugs selectively affect the cholinergic system? Glu 327 Phe 338
His 440 O O
P
O
F
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Organophosphates
Glu 327 Phe 338
His 440 O O
P
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Organophosphates Aging Glu 327 Phe 338
His 440 O O
P
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Antidote for AChE “poisoning”
N HO
N
Cl
-
CH3
Pralidoxime Chloride (Protopam; 2-pyridine aldoxime methyl chloride; 2-PAM) Antidote for pesticide or nerve gas poisoning Most effective if given within a few hours of exposure
MCMP 407
Regeneration of AChE by Pralidoxime
Glu 327 Phe 338
His 440 N
O O
P
N
O
CH3
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Regeneration of AChE by Pralidoxime
Glu 327 Phe 338
His 440 N
O O
P
N
O
CH3
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Regeneration of AChE by Pralidoxime
O
Glu 327
C H N
Phe 338 O N
His 440
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Clinical pharmacology of acetylcholinesterase inhibitors
Drug
Type of Route of inhibition istration Clinical Use
Edrophonium Neostigmine
Rev Rev
IM or IV IM, IV, or oral
Physostigmine
Rev
IM, IV, or local
Tacrine Donepezil Isofluorophate Echothiophate
Rev Rev Irrev Irrev
Oral Oral Local Local
Diagnostic for Myasthenia Gravis Myasthenia Gravis, post-operative ileus and bladder distention, surgical adjunct Glaucoma, Alzheimer’s disease, antidote to anticholinergic overdose Alzheimer’s disease Alzheimer’s disease Glaucoma Glaucoma
MCMP 407
Contraindications to the use of parasympathomimetic drugs
Asthma COPD Peptic ulcer Obstruction of the urinary or GI tract
MCMP 407 Cholinergic agent side effects and toxicity
SLUD Salivation Lacrimation Urination Defecation
Also: Increased sweating Decreased heart rate Pupils constricted CNS activation
Treatment: Cholinergic receptor antagonist (Atropine) If irreversible AChE inhibitor, 2-PAM (Pralidoxime)
MCMP 407 Clinical Correlation: Alzheimer’s Disease
Most common cause of dementia after age 50 Atrophy of brain Widening of sulci and thinning of gyri Improper processing of bamyloid precursor protein (b-APP) leads to toxic form (b-A42) that promotes apoptosis On pathological exam: Senile plaques: b-amyloid Neurofibrillary tangles
Loss of cholinergic neurons in brain
MCMP 407
Treatment of Alzheimer’s Disease NH2
N
Tacrine (Cognex)
Bind to anionic site and block ACh binding Reversible Non-covalent Enhances cognitive ability Does not slow progression of disease Newer agent: Donepezil (Aricept)
MCMP 407
Treatment of Alzheimer’s Disease CH3 O
N
CH3
O
H3C
N
CH3
CH3
Rivastigmine (Exelon)
Reversible carbamate AChE inhibitor Enhances cognitive ability by increasing cholinergic function Loses effectiveness as disease progresses Side Effects: Nausea, vomiting, anorexia, and weight loss Newer long-acting carbamate: Eptastigmine
MCMP 407
Treatment of Alzheimer’s Disease OH H
H
O CH3O
N
Reminyl (Galantamine)
CH3
Reversible competitive AChE inhibitor Extract from daffodil (Narcissus pseudonarcissus) bulbs Loses effectiveness as disease progresses May be a nicotinic receptor agonist Inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability
MCMP 407
Treatment of Alzheimer’s Disease
NH2
CH3
H3C Memantine (Namenda)
N-methyl-D-aspartate (NMDA) receptor antagonist NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory Neuronal loss in Alzheimer’s may be related to increased activity of glutamate May slow progression of the disease Favorable adverse effect profile
MCMP 407
Treatment of Alzheimer’s Disease On The Horizon: Acetyl-L-carnitine - neuroprotective agent b-amyloid fibrillogenesis inhibitor (Alzhemed) - disease-modifying inhibitor of b-amyloid fibril formation Cerebrolysin – neurotrophic and neuroprotective agent Phenserine – acetylcholinesterase and bamyloid precursor protein inhibitor Xaliproden – neurotrophic agent
MCMP 407
Types of cholinesterases
Acetylcholinesterase Located in synapses Substrate selectivity: » ACH
Plasma cholinesterase Located in plasma (non-neuronal) Substrate selectivity: » ACH » Succinylcholine » Local anesthetics (procaine)
MCMP 407
Hydrolysis of acetylcholine by AChE
O
Glu 327
C H N
Phe 338 O N
His 440
O
CH3 N CH3 CH3
O OH
Trp 86 Ser 203
Esteratic site
HN
Anionic site
MCMP 407
Hydrolysis of acetylcholine by AChE
O C
Glu 327
O
H N
Phe 338 N
CH3 N CH3 CH3
His 440 O
HO
Anionic site
O
Ser 203
Esteratic site
Trp 86 HN
MCMP 407
Hydrolysis of acetylcholine by AChE
O C
Glu 327
O
H N
Phe 338 N
choline
His 440
O
HO
CH3 N CH3 CH3
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Hydrolysis of acetylcholine by AChE
O C
Glu 327
O
H N
Phe 338 N
O
His 440
O
H
H
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Hydrolysis of acetylcholine by AChE
O
Glu 327
C H N
O
Phe 338 N
O
His 440
acetate OH
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407 Pharmacologic manipulation of AChE: No inhibition
Na+ Muscarinic
ACH
Receptor
ACH
Acetylcholinesterase
Action Potential
ACH ACH ACH
ACH ACH ACH
ACH ACH ACH
Presynaptic neuron
Choline Acetate
Postsynaptic target
MCMP 407 Pharmacologic manipulation of AChE: Inhibition by drugs ACH ACH
Na+ ACH ACH
Muscarinic Receptor
ACH
Acetylcholinesterase
Action Potential
ACH ACH ACH
ACH ACH ACH
ACH ACH ACH ACH
Presynaptic neuron
ACH
ACH
Postsynaptic target
MCMP 407
Acetylcholinesterase inhibitors R
R
N
R
R
R CH3 C 2H 5 C 3H 7 C 4H 9
Relative Potency 1.0 5.0 100 50
Tetraalkylammonium ions Simplest structures Bind to anionic site and block ACh binding Reversible Non-covalent
MCMP 407
Acetylcholinesterase inhibitors OH
H3C
N
C2H5
CH3
Edrophonium (Tensilon)
Quaternary ammonium alcohol Simplest structures Bind to anionic site and block ACh binding Reversible Non-covalent
MCMP 407
Acetylcholinesterase inhibitors CH3 O
N CH3
O N
H3 C
CH3
Neostigmine (Prostigmin)
CH3
CH3 O
N CH3 O
N CH3
H N
O
Pyridostigmine (Mestinon)
Most basic Nitrogen; protonated at physiological pH.
H3 C
H3 C
N O
Physostigmine (Antilirium)
Carbamates Quaternary or tertiary ammonium groups Reversible Covalent modification to AChE
N
H CH3
CH3
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440 O N
N
O
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440
O N
N
HO O
Anionic site Trp 86
Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440
O N
N
HO O
Anionic site Trp 86
Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440
O N
O
Anionic site Trp 86
Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Neostigmine
Glu 327 Phe 338
His 440 O N
OH
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Acetylcholinesterase inhibitors O O
P
F
O
Isofluorophate; DFP (Floropryl)
-
I
O H3 C H3C N CH2 CH2 S CH3
P
OC2H5
OC2H5
Echothiophate (Phospholine Iodide)
Organophosphates Irreversible Covalent modification to AChE Longer acting Used in the treatment of glaucoma
MCMP 407
Acetylcholinesterase inhibitors O H3C
P
F
O
Sarin
H3C
CH3CH3
O
C CH O
P
CH3
CH3
Soman
F
Organophosphates Nerve gases Irreversible Covalent modification to AChE
MCMP 407
Acetylcholinesterase inhibitors O S C2H5 C2H5
O O
C O CH S C
CH2
P
OCH3
OCH3
Malathion
CH3
N H3 C H3 C
CH
S O N
Diazinon
P
OC2H5
OC2H5
Organophosphates Insecticides Irreversible Covalent modification to AChE Rapidly inactivated in mammals
MCMP 407
Biotransformation of insecticides O
O
O
S C2H5
O
C2H5
O
C O CH S
P
C
OCH3
CH2
OCH3
Malathion
Cyt P450 Insects
C2H5
O
C2H5
O
C O CH S
P
C
OCH3
CH2
Malaoxon
Carboxyesterase Mammals, Birds
O S HO HO
C O CH S
P
C
OCH3
CH2
(Inactive)
OCH3
OCH3
MCMP 407
Inhibition of AChE by Organophosphates Why do these drugs selectively affect the cholinergic system? Glu 327 Phe 338
His 440 O O
P
O
F
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Organophosphates
Glu 327 Phe 338
His 440 O O
P
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Inhibition of AChE by Organophosphates Aging Glu 327 Phe 338
His 440 O O
P
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Antidote for AChE “poisoning”
N HO
N
Cl
-
CH3
Pralidoxime Chloride (Protopam; 2-pyridine aldoxime methyl chloride; 2-PAM) Antidote for pesticide or nerve gas poisoning Most effective if given within a few hours of exposure
MCMP 407
Regeneration of AChE by Pralidoxime
Glu 327 Phe 338
His 440 N
O O
P
N
O
CH3
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Regeneration of AChE by Pralidoxime
Glu 327 Phe 338
His 440 N
O O
P
N
O
CH3
O
Anionic site
O
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Regeneration of AChE by Pralidoxime
O
Glu 327
C H N
Phe 338 O N
His 440
Anionic site
OH
Trp 86 Ser 203
Esteratic site
HN
MCMP 407
Clinical pharmacology of acetylcholinesterase inhibitors
Drug
Type of Route of inhibition istration Clinical Use
Edrophonium Neostigmine
Rev Rev
IM or IV IM, IV, or oral
Physostigmine
Rev
IM, IV, or local
Tacrine Donepezil Isofluorophate Echothiophate
Rev Rev Irrev Irrev
Oral Oral Local Local
Diagnostic for Myasthenia Gravis Myasthenia Gravis, post-operative ileus and bladder distention, surgical adjunct Glaucoma, Alzheimer’s disease, antidote to anticholinergic overdose Alzheimer’s disease Alzheimer’s disease Glaucoma Glaucoma
MCMP 407
Contraindications to the use of parasympathomimetic drugs
Asthma COPD Peptic ulcer Obstruction of the urinary or GI tract
MCMP 407 Cholinergic agent side effects and toxicity
SLUD Salivation Lacrimation Urination Defecation
Also: Increased sweating Decreased heart rate Pupils constricted CNS activation
Treatment: Cholinergic receptor antagonist (Atropine) If irreversible AChE inhibitor, 2-PAM (Pralidoxime)
MCMP 407 Clinical Correlation: Alzheimer’s Disease
Most common cause of dementia after age 50 Atrophy of brain Widening of sulci and thinning of gyri Improper processing of bamyloid precursor protein (b-APP) leads to toxic form (b-A42) that promotes apoptosis On pathological exam: Senile plaques: b-amyloid Neurofibrillary tangles
Loss of cholinergic neurons in brain
MCMP 407
Treatment of Alzheimer’s Disease NH2
N
Tacrine (Cognex)
Bind to anionic site and block ACh binding Reversible Non-covalent Enhances cognitive ability Does not slow progression of disease Newer agent: Donepezil (Aricept)
MCMP 407
Treatment of Alzheimer’s Disease CH3 O
N
CH3
O
H3C
N
CH3
CH3
Rivastigmine (Exelon)
Reversible carbamate AChE inhibitor Enhances cognitive ability by increasing cholinergic function Loses effectiveness as disease progresses Side Effects: Nausea, vomiting, anorexia, and weight loss Newer long-acting carbamate: Eptastigmine
MCMP 407
Treatment of Alzheimer’s Disease OH H
H
O CH3O
N
Reminyl (Galantamine)
CH3
Reversible competitive AChE inhibitor Extract from daffodil (Narcissus pseudonarcissus) bulbs Loses effectiveness as disease progresses May be a nicotinic receptor agonist Inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability
MCMP 407
Treatment of Alzheimer’s Disease
NH2
CH3
H3C Memantine (Namenda)
N-methyl-D-aspartate (NMDA) receptor antagonist NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory Neuronal loss in Alzheimer’s may be related to increased activity of glutamate May slow progression of the disease Favorable adverse effect profile
MCMP 407
Treatment of Alzheimer’s Disease On The Horizon: Acetyl-L-carnitine - neuroprotective agent b-amyloid fibrillogenesis inhibitor (Alzhemed) - disease-modifying inhibitor of b-amyloid fibril formation Cerebrolysin – neurotrophic and neuroprotective agent Phenserine – acetylcholinesterase and bamyloid precursor protein inhibitor Xaliproden – neurotrophic agent
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