acetylcholinesterase inhibitors
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MCMP 407
Acetylcholinesterase InhibitorsAcetylcholinesterase Inhibitors
MCMP 407
Types of cholinesterasesTypes 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
HN
Hydrolysis of acetylcholine by AChEHydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
ON
CH3
CH3
CH3
O
OH
Ser 203
Phe 338
Anionic site
CO
OGlu 327
N
HN
His 440
MCMP 407
O
O
HN
Hydrolysis of acetylcholine by AChEHydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic siteHO
N
CH3
CH3
CH3
CO
OGlu 327
N
HN
His 440
MCMP 407
O
O
HN
Hydrolysis of acetylcholine by AChEHydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic siteHO
N
CH3
CH3
CH3
choline
CO
OGlu 327
N
HN
His 440
MCMP 407
O
O
HN
Hydrolysis of acetylcholine by AChEHydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
CO
OGlu 327
N
HN
His 440 HO H
MCMP 407
OH
HN
Hydrolysis of acetylcholine by AChEHydrolysis of acetylcholine by AChE
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic siteOH
Oacetate
CO
OGlu 327
N
HN
His 440
MCMP 407
Action Potential
Na+
Ca 2+
Acetylcholinesterase
Pharmacologic manipulation of AChE: No inhibition
Presynaptic neuronPostsynaptic target
Muscarinic
Receptor
ACH
ACH
Choline Acetate
ACHACH
ACH
ACHACH
ACH
ACHACH
ACH
MCMP 407
Action Potential
Na+
Ca 2+
Acetylcholinesterase
Pharmacologic manipulation of AChE: Inhibition by drugs
Presynaptic neuronPostsynaptic target
Muscarinic
Receptor
ACH
ACH
ACHACH
ACH
ACHACH
ACH
ACHACH
ACH
ACHACH
ACH
ACH
ACH
ACH
MCMP 407
Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
Tetraalkylammonium ions
Simplest structures Bind to anionic site
and block ACh binding
Reversible Non-covalent
R N
R
R
R
R
CH3
C2H5
C3H7
C4H9
Relative Potency
1.0
5.0
100
50
MCMP 407
Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
Quaternary ammonium alcohol
Simplest structures Bind to anionic site
and block ACh binding
Reversible Non-covalent
OH
NH3C C2H5
CH3
Edrophonium(Tensilon)
MCMP 407
Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
Carbamates Quaternary or tertiary
ammonium groups Reversible Covalent modification
to AChE
O
NH3C CH3
CH3
N
O
CH3
CH3
Neostigmine(Prostigmin)
N
N
CH3
H
H3C
CH3
OHN
OPhysostigmine(Antilirium)
H3C
N
O N
O
CH3
CH3
Pyridostigmine(Mestinon)CH3
Most basic Nitrogen;
protonated at physiological pH.
MCMP 407
HN
Inhibition of AChE by NeostigmineInhibition of AChE by Neostigmine
Trp 86
Esteratic site
OH
Ser 203
Phe 338
Anionic site
NON
O
Glu 327
His 440
MCMP 407
ON
O
HN
Inhibition of AChE by NeostigmineInhibition of AChE by Neostigmine
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
NHO
Glu 327
His 440
MCMP 407
ON
O
HN
Inhibition of AChE by NeostigmineInhibition of AChE by Neostigmine
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
NHO
Glu 327
His 440
MCMP 407
ON
O
HN
Inhibition of AChE by NeostigmineInhibition of AChE by Neostigmine
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
Glu 327
His 440
MCMP 407
HN
Inhibition of AChE by NeostigmineInhibition of AChE by Neostigmine
Trp 86
Esteratic site
OH
Ser 203
Phe 338
Anionic site
OHN
O
Glu 327
His 440
MCMP 407
Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
Organophosphates Irreversible Covalent modification
to AChE Longer acting Used in the treatment
of glaucoma
O P
O
O
F
Isofluorophate; DFP(Floropryl)
H3CNH3CCH3
CH2 CH2 S P
O
OC2H5
OC2H5
I-
Echothiophate(Phospholine Iodide)
MCMP 407
Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
Organophosphates Nerve gases Irreversible Covalent modification
to AChE
H3C P
O
O
F
O P
O
CH3
FCHCH3C
CH3
CH3
CH3
Sarin
Soman
MCMP 407
Acetylcholinesterase inhibitorsAcetylcholinesterase inhibitors
Organophosphates Insecticides Irreversible Covalent modification
to AChE Rapidly inactivated in
mammals
O P
S
OC2H5
OC2H5
N
N
CH3
CHH3C
H3C Diazinon
S P
S
OCH3
OCH3
CH
CH2
C
C
O
O
O
OC2H5
C2H5
Malathion
MCMP 407
Biotransformation of insecticidesBiotransformation of insecticides
S P
S
OCH3
OCH3
CH
CH2
C
C
O
O
O
OC2H5
C2H5
Malathion
S P
O
OCH3
OCH3
CH
CH2
C
C
O
O
O
OC2H5
C2H5
Malaoxon
S P
S
OCH3
OCH3
CH
CH2
C
C
O
HO
O
HO
(Inactive)
Cyt P450
Insects
Carboxyesterase
Mammals, Birds
MCMP 407
HN
Inhibition of AChE by OrganophosphatesInhibition of AChE by Organophosphates
Trp 86
Esteratic site
OH
Ser 203
Phe 338
Anionic site
O P
O
F
O
Glu 327
His 440
Why do these drugs selectively
affect the cholinergic
system?
MCMP 407
HN
Inhibition of AChE by OrganophosphatesInhibition of AChE by Organophosphates
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic siteO P
O
O
O
Glu 327
His 440
MCMP 407
HN
Inhibition of AChE by OrganophosphatesInhibition of AChE by Organophosphates
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic site
Aging
O P
O
O
O
Glu 327
His 440
MCMP 407
Antidote for AChE “poisoning”Antidote for AChE “poisoning”
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
N
CH3
NHO
Cl-
MCMP 407
HN
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic siteO P
O
O
O
N
CH3
NO
Regeneration of AChE by PralidoximeRegeneration of AChE by Pralidoxime
Glu 327
His 440
MCMP 407
HN
Trp 86
Esteratic site
Ser 203
Phe 338
Anionic siteO P
O
O
O
N
CH3
NO
Regeneration of AChE by PralidoximeRegeneration of AChE by Pralidoxime
Glu 327
His 440
MCMP 407
HN
Trp 86
Esteratic site
OH
Ser 203
Phe 338
Anionic site
CO
OGlu 327
N
HN
His 440
Regeneration of AChE by PralidoximeRegeneration of AChE by Pralidoxime
MCMP 407
Clinical pharmacology of acetylcholinesterase inhibitorsClinical pharmacology of acetylcholinesterase inhibitors
DrugType ofinhibition
Route ofadministration Clinical Use
Edrophonium Rev IM or IV Diagnostic for Myasthenia GravisNeostigmine Rev IM, IV, or oral Myasthenia Gravis, post-operative ileus and
bladder distention, surgical adjunctPhysostigmine Rev IM, IV, or local Glaucoma, Alzheimer’s disease, antidote to
anticholinergic overdoseTacrine Rev Oral Alzheimer’s diseaseDonepezil Rev Oral Alzheimer’s diseaseIsofluorophate Irrev Local GlaucomaEchothiophate Irrev Local Glaucoma
MCMP 407
Contraindications to the use of Contraindications to the use of parasympathomimetic drugsparasympathomimetic drugs
Asthma COPD Peptic ulcer Obstruction of the urinary or GI tract
MCMP 407
Cholinergic agent side effects and toxicityCholinergic 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:Clinical Correlation:Alzheimer’s DiseaseAlzheimer’s Disease
Most common cause of dementia after age 50
Atrophy of brain Widening of sulci and
thinning of gyri Improper processing of -
amyloid precursor protein (-APP) leads to toxic form (-A42) that promotes apoptosis
On pathological exam: Senile plaques: -amyloid Neurofibrillary tangles
Loss of cholinergic neurons in brain
MCMP 407
Bind to anionic site and block ACh binding
Reversible Non-covalent Enhances cognitive
ability Does not slow
progression of disease Newer agent:
Donepezil (Aricept)
N
NH2
Tacrine(Cognex)
Treatment of Alzheimer’s DiseaseTreatment of Alzheimer’s Disease
MCMP 407
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
Treatment of Alzheimer’s DiseaseTreatment of Alzheimer’s Disease
O N
O
CH3
CH3
H3C NCH3
CH3
Rivastigmine(Exelon)
MCMP 407
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
Treatment of Alzheimer’s DiseaseTreatment of Alzheimer’s Disease
CH3O
NCH3
O
OH
H H
Reminyl(Galantamine)
MCMP 407
Treatment of Alzheimer’s DiseaseTreatment of Alzheimer’s Disease 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
H3C
CH3
NH2
Memantine (Namenda)
MCMP 407
On The Horizon: Acetyl-L-carnitine - neuroprotective agent -amyloid fibrillogenesis inhibitor
(Alzhemed) - disease-modifying inhibitor of -amyloid fibril formation
Cerebrolysin – neurotrophic and neuroprotective agent
Phenserine – acetylcholinesterase and -amyloid precursor protein inhibitor
Xaliproden – neurotrophic agent
Treatment of Alzheimer’s DiseaseTreatment of Alzheimer’s Disease
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