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Analogues of Carbacholine: Synthesis and Relationship between Structure and Affinity for Muscarinic and Nicotinic Acetylcholine Receptors
Author(s) -
Søkilde Birgitte,
Mikkelsen Ivan,
Stensbøl Tine B.,
Andersen Birgit,
Ebdrup Søren,
KrogsgaardLarsen Povl,
Falch Erik
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290207
Subject(s) - muscarinic acetylcholine receptor , chemistry , nicotinic agonist , acetylcholine receptor , tertiary amine , alpha 4 beta 2 nicotinic receptor , agonist , nicotine , stereochemistry , muscarinic acetylcholine receptor m3 , nicotinic acetylcholine receptor , muscarinic acetylcholine receptor m2 , receptor , oxotremorine , biochemistry , biology , organic chemistry , neuroscience
A series of acyclic and heterocyclic analogues of carbacholine ( 1 ) was synthesized using N ‐methylcarbacholine (MCC, 2 ), N , N ‐dimethylcarbacholine (DMCC, 3 ), and the corresponding tertiary amine ( 4 ) as leads. Whereas nicotinic acetylcholine receptor affinity was determined using [ 3 H]nicotine as the radioactive ligand, [ 3 H]oxotremorine‐M ([ 3 H]Oxo‐M) and [ 3 H]quinuclidinyl benzilate ([ 3 H]QNB), in some cases supplemented with [ 3 H]pirenzepine ([ 3 H]PZ), were used as radioligands for muscarinic acetylcholine receptors on rat brain membranes. On the basis of receptor binding data, nicotinic/muscarinic (N/M) selectivity factors were determined, and muscarinic receptor efficacy (M agonist index) and M 1 selectivity (M 2 /M 1 index) estimated. In most cases, quaternized analogues showed higher affinity than the corresponding tertiary amines for muscarinic and, in particular, nicotinic receptor sites. Among the new compounds, N , N ‐diethylcarbacholine ( 9e ) (IC 50 = 0.046 μM), ( S )‐1‐methyl‐2‐( N,N ‐diethyl‐aminocarbonyloxymethyl)pyrrolidine ( 17k ) (IC 50 = 0.068 μM), and the corresponding quaternized analogue, 18k (IC 50 = 0.018 μM) showed the highest nicotinic receptor affinity. The tertiary amine, 17k showed much higher nicotinic receptor affinity than the acyclic analogue, 4 (IC 50 = 5.7 μM), and the N/M selectivity factor determined for 17k (150) is an order of magnitude lower than that of nicotine (1400). The N/M selectivity factors for MCC ( 2 ) and DMCC ( 3 ), previously reported to be highly selective nicotinic receptor ligands, were shown to be 6.5 and 60, respectively, the latter value being comparable with that of 18k (89).