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Research ArticleArticle

M2 Receptor Binding of the Selective Antagonist AF-DX 384: Possible Involvement of the Common Allosteric Site

C. Tränkle, I. Andresen, G. Lambrecht and K. Mohr
Molecular Pharmacology February 1998, 53 (2) 304-312; DOI: https://doi.org/10.1124/mol.53.2.304
C. Tränkle
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Abstract

The hypothesis was tested that M2-selective antagonists partially utilize the allosteric site of muscarinic M2receptors. The interactions of the allosteric agent W84 (hexane-1,6-bis[dimethyl-3′-phthalimidopropyl-ammonium bromide]) were studied with the M2/M4-selective AF-DX 384 [(±)-5,11-dihydro-11-{[(2-{2-[(dipropylamino)methyl]-1-piperidinyl}ethyl)amino]carbonyl}-6H-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 M2receptor model (W84 binding constantK A ∼ 160 nm) was higher than at M1/M4-like receptors of rabbit vas deferens (K B ∼800 nm) and at M3 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 M2-preferring AF-DX 384 (α = 444). In guinea pig heart homogenates, the equilibrium binding of [3H]NMS was only partially inhibited by W84 (α = 2.4), whereas [3H]AF-DX 384 binding could be suppressed completely (α = 194). The difference in cooperativity reflects that W84 inhibits [3H]NMS dissociation with a ∼40-fold higher potency (ECdiss = 900 nm) than [3H]AF-DX 384 dissociation (ECdiss = 33,300 nm). [3H]NMS dissociation also could be retarded by AF-DX 384 (ECdiss = 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 M2 receptor protein.

Footnotes

    • Received August 6, 1997.
    • Accepted October 24, 1997.
  • Send reprint requests to: Klaus Mohr, Pharmacology & Toxicology, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany. E-mail:k.mohr{at}uni-bonn.de

  • This work was supported by the Deutsche Forschungsgemeinschaft (K.M.) and the Fonds der Chemischen Industrie (G.L.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (2)
Molecular Pharmacology
Vol. 53, Issue 2
1 Feb 1998
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Research ArticleArticle

M2 Receptor Binding of the Selective Antagonist AF-DX 384: Possible Involvement of the Common Allosteric Site

C. Tränkle, I. Andresen, G. Lambrecht and K. Mohr
Molecular Pharmacology February 1, 1998, 53 (2) 304-312; DOI: https://doi.org/10.1124/mol.53.2.304

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Research ArticleArticle

M2 Receptor Binding of the Selective Antagonist AF-DX 384: Possible Involvement of the Common Allosteric Site

C. Tränkle, I. Andresen, G. Lambrecht and K. Mohr
Molecular Pharmacology February 1, 1998, 53 (2) 304-312; DOI: https://doi.org/10.1124/mol.53.2.304
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