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.
Footnotes
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Send reprint requests to: Dr. Fred Mitchelson, Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), Parkville, Victoria, Australia, 3052.
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↵1 This work was conducted under a grant from The National Health and Medical Research Council of Australia.
- Abbreviations:
- C-R
- concentration-response
- C7/3′-phth
- heptane-1,7-bis(dimethyl-3′-phthalimidopropyl)ammonium bromide
- and NMS
- N-methylscopolamine
- Received October 7, 1996.
- Accepted March 12, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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