Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 receptors.
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.
Lanzafame
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A
Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), Parkville, Australia.
Christopoulos
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A
Mitchelson
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F
D000443:Alcuronium / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D005260:Female; D005703:Gallamine Triethiodide / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D019832:N-Methylscopolamine; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012602:Scopolamine Derivatives / Q000494:pharmacology
D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D001285:Atropine; D005703:Gallamine Triethiodide; D000443:Alcuronium; D019832:N-Methylscopolamine