Interactions of agonists with an allosteric antagonist at muscarinic acetylcholine M2 receptors

Alfred Lanzafame, Arthur Christopoulos, Fred Mitchelson

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The interaction of heptane-1,7-bis(dimethyl-3'-phthalimidopropylammonium bromide) (C7/3'-phth), with several agonists, was investigated at the muscarinic M2 receptor in guinea-pig left atria. C7/3'-phth shifted concentration-response curves for the agonists, carbachol, oxotremorine-M and (+)-cis-dioxolane, to the right in a parallel fashion. Arunlakshana-Schild regressions of the data yielded slopes significantly different to unity, suggesting non-competitive antagonism. Non-linear regression analysis, using an equation based on allosteric modulation, gave quantitative estimates of co-operativity (α values) and the dissociation constant of C7/3'-phth (K(B)). In all cases, the K(B) estimates for C7/3'-phth were not significantly different. Increasing the carbachol contact time 10-fold did not significantly influence the K(B) or the α value obtained with C7/3'-phth. Changing from Krebs to Tyrode solution did not significantly alter the K(B) for C7/3'-phth, although α values obtained were consistently lower in Tyrode solution, suggesting that the allosteric action may be sensitive to buffer composition. A 4-fold higher degree of negative, heterotropic co-operativity between C7/3'-phth and agonists than between C7/3'-phth and competitive antagonists was also found.

Original languageEnglish
Pages (from-to)27-32
Number of pages6
JournalEuropean Journal of Pharmacology
Issue number1
Publication statusPublished - 28 Nov 1996


  • Bisquaternary allosteric antagonist
  • Muscarinic acetylcholine receptor agonist

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