PT  - JOURNAL ARTICLE
AU  - Alfred Lanzafame
AU  - Arthur Christopoulos
AU  - Fred Mitchelson
TI  - Three Allosteric Modulators Act at a Common Site, Distinct from that of Competitive Antagonists, at Muscarinic Acetylcholine M<sub>2</sub> Receptors
DP  - 1997 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 278--285
VI  - 282
IP  - 1
4099  - http://jpet.aspetjournals.org/content/282/1/278.short
4100  - http://jpet.aspetjournals.org/content/282/1/278.full
SO  - J Pharmacol Exp Ther1997 Jul 01; 282
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. The American Society for Pharmacology and Experimental Therapeutics