Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 receptors

Alfred Lanzafame, Arthur Christopoulos, Fred Mitchelson

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Functional studies were conducted on guinea pig atrial muscarinic acetylcholine M2 receptors with the allosteric modulators heptane-1,7- bis(dimethyl-3'-phthalimidopropyl)ammonium bromide (C7/3'-phth), gallamine and alcuronium to determine whether these ligands are able to recognize a common accessory site. The three modulators inhibited the negative inotropic response to carbachol in this tissue. When used in combination, C7/3'-phth and gallamine or C7/3'-phth and alcuronium gave dose ratios that were either additive or underadditive. In contrast, the combinations of C7/3'-phth or alcuronium with the competitive antagonists, N-methylscopolamine or atropine, yielded supra-additive dose ratios. The data could be reconciled with a model involving a ternary complex between (1) the receptor, (2) carbachol, N- methylscopolamine or atropine acting at the orthosteric binding site and (3) C7/3'-phth, alcuronium or gallamine acting at a common, allosteric site with varying degrees of heterotropic cooperativity.

Original languageEnglish
Pages (from-to)278-285
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
Publication statusPublished - 1 Jul 1997

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