MCMP 407 Action Potential Na + Ca 2+ Acetylcholinestera e Pharmacologic manipulation of the cholinergic system Presynaptic neuron Postsynaptic target Nicotinic Receptor Muscarini c Receptor Choline Choline Na + Acetyl CoA + Acetylcholi ne Choline Acetyltransferas e H + ACH ACH Choline Acetate
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MCMP 407
Action Potential
Na+
Ca 2+
Acetylcholinesterase
Pharmacologic manipulation of the cholinergic system
Presynaptic neuronPostsynaptic target
Nicotinic
Receptor
Muscarinic
Receptor
Choline
Choline
Na+
Acetyl CoA
+ Acetylcholine
CholineAcetyltransferase
H+
ACH
ACH
Choline Acetate
MCMP 407
Direct acting cholinergic receptor agonists:Direct acting cholinergic receptor agonists:EstersEsters
COH3C
O
CH2 CH2 N
CH3
CH3
CH3
Acetylcholine(Miochol)
CO
O
CH CH2 N
CH3
CH3
CH3H2N
CH3
Bethanechol(Urecholine)
CO
O
CH2 CH2 N
CH3
CH3
CH3H2N
Carbachol(Isoptocarbachol)
COH3C
O
CH CH2 N
CH3
CH3
CH3
Methacholine
CH3
(Provocholine)
MCMP 407
Direct acting cholinergic receptor agonists:Direct acting cholinergic receptor agonists:Alkaloids and synthetic analogsAlkaloids and synthetic analogs
N
CH3
N
Nicotine(Nicorette)
OO
CH2
H2CH3C
N
NCH3
Pilocarpine(Isoptocarpine)
OH
H
H3CHO
H
N(CH3)3
(+)-Muscarine
MCMP 407
NH3
COOH
Gq
Phospho-lipase C
(+)
PIP2
IP3 Diacylglycerol
Increase Ca2+ Activate ProteinKinase C
Response
Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways
M3 muscarinic
receptor
C O
O
CH2 CH2 N
CH3
CH3
CH3
CH3
Acetylcholine
MCMP 407
HO
OH
Molecular actions of acetylcholineMolecular actions of acetylcholineat muscarinic receptorsat muscarinic receptors
I
II
IV
V
VI
VII
C O
O
IIIAsp105
Thr189
Tyr381
N O
O
MCMP 407
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
+
Acetylcholine
+
trans cis
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
OH
H
H3CHO
H
N(CH3)3
OH
N(CH3)3
O
H3C H3C
OCH3
N(CH3)3
O
H3C H
(+)-muscarine (+)-methacholine
(-)-methacholine
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs
OH
H
H3CHO
H
N(CH3)3
OO
NH
N
H3C
(+)-muscarine Protonated
pilocarpine
MCMP 407
Stereochemistry of cholinergic drugsStereochemistry of cholinergic drugs