title: Stereoselective binding and activity of oxotremorine analogs at muscarinic receptors in rat brain.
abstract: 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 [3H]-(R)-quinuclidinyl benzilate ([3H]-(R)-QNB) to muscarinic receptors in the rat brain. (+)-(R)-BM-5 inhibited [3H]-(R)-QNB binding to rat brain sections at concentrations below 1.0 microM, 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.
authors: Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Ohio 43606.
authors: W S
authors: WS
authors: Messer
authors: D O
authors: DO
authors: Ngur
authors: Y F
authors: YF
authors: Abuh
authors: L A
authors: LA
authors: Dokas
authors: S M
authors: SM
authors: Ting
authors: U
authors: U
authors: Hacksell
authors: B M
authors: BM
authors: Nilsson
authors: P G
authors: PG
authors: Dunbar
authors: W
authors: W
authors: Hoss
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D007700:Kinetics; D010095:Oxotremorine / Q000031:analogs & derivatives*; D010277:Parasympathomimetics / Q000737:chemistry / Q000378:metabolism*; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D010277:Parasympathomimetics; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D010095:Oxotremorine; C038672:N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide; D000262:Adenylyl Cyclases