M 2 Receptor Binding of the Selective Antagonist AF-DX 384: Possible Involvement of the Common Allosteric Site
1998; American Society for Pharmacology and Experimental Therapeutics; Volume: 53; Issue: 2 Linguagem: Inglês
10.1124/mol.53.2.304
ISSN1521-0111
AutoresChristian Tränkle, Irmgard Andresen, G. Lambrecht, Klaus Mohr,
Tópico(s)Neuroscience and Neuropharmacology Research
ResumoThe hypothesis was tested that M 2 -selective antagonists partially utilize the allosteric site of muscarinic M 2 receptors. The interactions of the allosteric agent W84 (hexane-1,6-bis[dimethyl-3′-phthalimidopropyl-ammonium bromide]) were studied with the M 2 /M 4 -selective AF-DX 384 [(±)-5,11-dihydro-11-{[(2-{2-[(dipropylamino)methyl]-1-piperidinyl}ethyl)amino]carbonyl}-6 H -pyrido(2,3- b )(1,4)-benzodiazepine-6-one], the nonselective N -methylscopolamine (NMS), and a number of other muscarinic antagonists. In isolated paced guinea pig atria, the antagonistic effect of W84 against oxotremorine- and arecaidine propargyl ester-induced negative inotropic actions reached a limiting value at higher W84 concentrations, revealing negative cooperativity (factors of cooperativity α = 311 and α = 495, respectively). The antagonistic potency of W84 in this M 2 receptor model (W84 binding constant K A ∼ 160 nm) was higher than at M 1 /M 4 -like receptors of rabbit vas deferens ( K B ∼800 nm) and at M 3 receptors of guinea pig ileum ( K B ∼4,000 nm). In paced atria, combinations of W84 with muscarinic antagonists yielded more-than-additive antagonistic effects against oxotremorine in case of conventional antagonists such as NMS (α = 18) but less-than-additive effects with the M 2 -preferring AF-DX 384 (α = 444). In guinea pig heart homogenates, the equilibrium binding of [ 3 H]NMS was only partially inhibited by W84 (α = 2.4), whereas [ 3 H]AF-DX 384 binding could be suppressed completely (α = 194). The difference in cooperativity reflects that W84 inhibits [ 3 H]NMS dissociation with a ∼40-fold higher potency (EC diss = 900 nm) than [ 3 H]AF-DX 384 dissociation (EC diss = 33,300 nm). [ 3 H]NMS dissociation also could be retarded by AF-DX 384 (EC diss = 22,000 nm), probably via an interaction with the site used by W84. The results suggest that the binding domain of AF-DX 384 partially overlaps with the common allosteric site of the M 2 receptor protein.
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