3 ALLOSTERIC MODULATORS ACT AT A COMMON SITE, DISTINCT FROM THAT OF COMPETITIVE ANTAGONISTS, AT MUSCARINIC ACETYLCHOLINE M-2 RECEPTORS

Functional studies were conducted on guinea pig atrial muscarinic acet ylcholine M-2 receptors with the allosteric modulators ane-1,7-bis(dim ethyl-3'-phthalimidopropyl)ammonium bromide (C-7/3'-phth), gallamine a nd 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 combinati on, C-7/3'-phth and gallamine or C-7/3'-phth and alcuronium gave dose ratios that were either additive or underadditive. In contrast, the co mbinations of C-7/3'-phth or alcuronium with the competitive antagonis ts, N-methylscopolamine or atropine, yielded supra-additive dose ratio s. The data could be reconciled with a model involving a ternary compl ex between (1) the receptor, (2) carbachol, N-methylscopolamine or atr opine acting at the orthosteric binding site and (3) C-7/3'-phth, alcu ronium or gallamine acting at a common, allosteric site with varying d egrees of heterotropic cooperativity.