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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33 Citations (Scopus)

Abstract

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
Volume282
Issue number1
Publication statusPublished - 1 Jul 1997

Cite this

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title = "Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 receptors",
abstract = "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.",
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Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 receptors. / Lanzafame, Alfred; Christopoulos, Arthur; Mitchelson, Fred.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 282, No. 1, 01.07.1997, p. 278-285.

Research output: Contribution to journalArticleResearchpeer-review

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AB - 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.

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