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

Glu 327

C
H N

Phe 338
O
N

O O

His 440
OH

CH3 N CH3 CH3

Anionic site

Trp 86 Ser 203

HN

Esteratic site

MCMP 407

Hydrolysis of acetylcholine by AChE

Glu 327

C
H N

Phe 338
N

His 440
O O

HO

CH3 N CH3 CH3

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Hydrolysis of acetylcholine by AChE

Glu 327

C
H N

Phe 338
N

His 440

choline
O

HO
O

CH3 N CH3 CH3

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Hydrolysis of acetylcholine by AChE

Glu 327

C
H N

Phe 338
N

His 440

O
O

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Hydrolysis of acetylcholine by AChE

Glu 327

C
H N

Phe 338
N

His 440

acetate
OH

OH

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407
Pharmacologic manipulation of AChE: No inhibition

Na+
ACH ACH

Muscarinic Receptor
Acetylcholinesterase

Action Potential

ACH ACH ACH

ACH ACH ACH

ACH ACH ACH

Choline Acetate

Presynaptic neuron

Postsynaptic target

MCMP 407
Pharmacologic manipulation of AChE: Inhibition by drugs
ACH ACH

Na+
ACH ACH ACH

Muscarinic Receptor
Acetylcholinesterase

Action Potential

ACH ACH ACH

ACH ACH ACH

ACH

ACH ACH ACH ACH ACH

Presynaptic neuron

Postsynaptic target

MCMP 407

Acetylcholinesterase inhibitors
R

N 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 O H3 C N CH3 N CH3

Neostigmine (Prostigmin)

CH3 CH3 O O N CH3 N CH3

Carbamates Quaternary or tertiary ammonium groups Reversible Covalent modification to AChE

Pyridostigmine (Mestinon)

H N H3 C O

H3 C N N H CH3 CH3

Most basic Nitrogen; protonated at physiological pH.

Physostigmine (Antilirium)

MCMP 407

Inhibition of AChE by Neostigmine

Glu 327 Phe 338

O N O
OH

His 440

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Inhibition of AChE by Neostigmine

Glu 327 Phe 338

His 440
N

O N

HO
O

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Inhibition of AChE by Neostigmine

Glu 327 Phe 338

His 440
N

O N

HO
O

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Inhibition of AChE by Neostigmine

Glu 327 Phe 338

His 440

O N O

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Inhibition of AChE by Neostigmine

Glu 327 Phe 338

O N
OH

His 440

OH

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Acetylcholinesterase inhibitors
O O P O F

Isofluorophate; DFP (Floropryl) I

-

O H3 C H3C N CH2 CH2 S CH3 P OC2H5

Organophosphates Irreversible Covalent modification to AChE Longer acting Used in the treatment of glaucoma

OC2H5

Echothiophate (Phospholine Iodide)

MCMP 407

Acetylcholinesterase inhibitors
O H3C P O F

Sarin

Organophosphates Nerve gases Irreversible Covalent modification to AChE

CH3CH3 H3C C CH O CH3

O P CH3 F

Soman

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 O N S P OC2H5

Organophosphates Insecticides Irreversible Covalent modification to AChE Rapidly inactivated in mammals

Diazinon

OC2H5

MCMP 407

Biotransformation of insecticides
O S C2H5 C2H5 O O C O CH S C CH2 P OCH3 O O

Cyt P450 Insects

C2H5 C2H5

O O

C O CH S C CH2

OCH3

OCH3

OCH3

Malathion

Malaoxon

Carboxyesterase Mammals, Birds

HO HO

O S C O CH S C CH2 P OCH3

OCH3

(Inactive)

MCMP 407

Inhibition of AChE by Organophosphates

Why do these drugs selectively affect the cholinergic system? Glu 327 Phe 338
O O
OH

His 440
P F O

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Inhibition of AChE by Organophosphates

Glu 327 Phe 338

His 440
O O P O O

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Inhibition of AChE by Organophosphates

Aging
Glu 327 Phe 338

His 440
O O P O O

Anionic site
Trp 86
HN

Ser 203

Esteratic site

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

N

His 440
O O P O
O N CH3

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Regeneration of AChE by Pralidoxime

Glu 327 Phe 338

N

His 440
O O P O
O N CH3

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Regeneration of AChE by Pralidoxime

Glu 327

C
H N

Phe 338
O
N

His 440
OH

Anionic site
Trp 86
HN

Ser 203

Esteratic site

MCMP 407

Clinical pharmacology of acetylcholinesterase inhibitors

Type of Route of inhibition administration Clinical Use
Rev Rev Rev Rev Rev Irrev Irrev IM or IV IM, IV, or oral IM, IV, or local Oral Oral Local Local Diagnostic for Myasthenia Gravis Myasthenia Gravis, post-operative ileus and bladder distention, surgical adjunct Glaucoma, Alzheimers disease, antidote to anticholinergic overdose Alzheimers disease Alzheimers disease Glaucoma Glaucoma

Drug
Edrophonium Neostigmine Physostigmine Tacrine Donepezil Isofluorophate Echothiophate

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

Treatment:

Also: Increased sweating Decreased heart rate Pupils constricted CNS activation

Cholinergic receptor antagonist (Atropine) If irreversible AChE inhibitor, 2-PAM (Pralidoxime)

MCMP 407
Clinical Correlation: Alzheimers 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 Alzheimers Disease

NH2

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 Alzheimers Disease

CH3 O O CH3

CH3

H3C

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 Alzheimers Disease

OH H O CH3O H

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 Alzheimers 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 Alzheimers may be related to increased activity of glutamate May slow progression of the disease Favorable adverse effect profile

MCMP 407

Treatment of Alzheimers 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