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[3H]pirenzepine and (-)-[3H]quinuclidinyl benzilate binding to rat cerebral cortical and cardiac muscarinic cholinergic sites. I. Characterization and regulation of agonist binding to putative muscarinic subtypes

M Watson, HI Yamamura and WR Roeske

The binding and regulation of selected muscarinic agonists to putative subtypes in rat cerebral cortex and heart were studied. Parallel inhibition studies of [3H]pirenzepine ([3H]PZ) and (-)- [3H]quinuclidinylbenzilate [(-)-[3H]QNB]-labeled membranes were done with and without 30 microM guanyl-5'-yl imidodiphosphate [Gpp(NH)p] at 25 degrees C in 10 mM Na-K-phosphate buffer which enhances PZ binding affinity and in modified Krebs-phosphate buffer, which mimics physiological conditions. Classical agonists such as carbachol, oxotremorine and acetylcholine inhibited (-)-[3H]QNB binding to membranes with shallow Hill values (nH less than 1), were better fit to a 2-state model, were Gpp(NH)p-regulated and showed lower affinity in modified Krebs-phosphate buffer than in 10 mM Na-K-phosphate buffer. Some agonists were not significantly better fit to a 2-state model in [3H]PZ-labeled cortical membranes, especially in 10 mM Na-K-phosphate buffer. Whereas putative M1 and M2 binding sites distinguished by PZ possessed multiple agonist affinity states, as judged by carbachol, and agonist binding to [3H]PZ-labeled sites were Gpp(NH)p modulated, the partial agonist pilocarpine and nonclassical agonist McN-A-343 [3-(m- chlorophenylcarbamoyloxy)-2-butynyl trimethylammonium chloride] showed little Gpp(NH)p-induced shift in [3H]PZ-labeled cortical membranes in physiological conditions. Agonist binding to (-)-[3H]QNB-labeled putative M2 cardiac sites was more sensitive to Gpp(NH)p than (-)- [3H]QNB-labeled cortical sites. Carbachol and acetylcholine showed significant selectivity for putative M2 sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 237, Issue 2, pp. 411-418, 05/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics




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