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Stereoselective binding and activity of oxotremorine analogs at muscarinic receptors in rat brain
Author(s) -
Messer, William S.,
Ngur Dan O.,
Abuh Yahaya F.,
Dokas Linda A.,
Ting ShuMei,
Hacksell Uli,
Nilsson Bjorn M.,
Dunbar Philip G.,
Hoss Wayne
Publication year - 1992
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530040802
Subject(s) - oxotremorine , muscarinic acetylcholine receptor , chemistry , quinuclidinyl benzilate , adenylyl cyclase , muscarinic acetylcholine receptor m2 , medicine , receptor , endocrinology , cholinergic , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor m4 , biochemistry , biology
The activities of the enantiomers of BM‐5 were examined to measure muscarinic cholinergic selectivity in the central nervous system. Autoradiographic studies assessed the ability of each enantiomer to inhibit the binding of [ 3 H]‐(R)‐quinuclidinyl benzilate ([ 3 H]‐(R)‐QNB) to muscarinic receptors in the rat brain. (+)‐(R)‐BM‐5 inhibited [ 3 H]‐(R)‐QNB binding to rat brain sections at concentrations below 1.0 μ M , while 100‐fold higher concentrations of (—)‐(S)‐BM‐5 were required for comparable levels of inhibition. Analysis of the autoradiograms indicated that both stereoisomers had a similar distribution of high affinity binding sites. Each enantiomer displayed higher affinity for muscarinic receptors in the superior colliculi and lower affinity for receptors in the cerebral cortex and hippocampus. (+)‐(R)‐BM‐5 and oxotremorine inhibited adenylyl cyclase activity in the cerebral cortex with efficacies comparable to that for acetylcholine. (+)‐(R)‐BM‐5 was 26‐fold more potent than (—)‐(S)‐BM‐5 in inhibiting adenylyl cyclase. Oxotremorine‐M and carbamylcholine stimulated phosphoinositide turnover in the cerebral cortex. Oxotremorine had lower activity and (+)‐(R)‐BM‐5 was essentially inactive at comparable concentrations. The difference in activity of the two enantiomers indicates a remarkable stereochemical selectivity for muscarinic receptors. The stereoselectivity index is comparable for both the autoradiographic assays (48) and measures of adenylyl cyclase activity (26) in the cerebral cortex. © 1992 Wiley‐Liss, Inc.