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

Eur J Pharmacol. 1996 Nov 28;316(1):27-32. doi: 10.1016/s0014-2999(96)00639-5.


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 (alpha values) and the dissociation constant of C7/3'-phth (KB). In all cases, the KB estimates for C7/3'-phth were not significantly different. Increasing the carbachol contact time 10-fold did not significantly influence the KB or the alpha value obtained with C7/3'-phth. Changing from Krebs to Tyrode solution did not significantly alter the KB for C7/3'-phth, although alpha 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Acetylcholine / pharmacology
  • Animals
  • Binding, Competitive
  • Bis-Trimethylammonium Compounds / metabolism
  • Bis-Trimethylammonium Compounds / pharmacology*
  • Buffers
  • Carbachol / metabolism
  • Carbachol / pharmacology
  • Dioxolanes / metabolism
  • Dioxolanes / pharmacology
  • Drug Interactions
  • Female
  • Guinea Pigs
  • In Vitro Techniques
  • Isoindoles
  • Kinetics
  • Male
  • Muscarinic Agonists / metabolism
  • Muscarinic Agonists / pharmacology*
  • Muscarinic Antagonists / metabolism
  • Muscarinic Antagonists / pharmacology*
  • Oxotremorine / analogs & derivatives
  • Oxotremorine / metabolism
  • Oxotremorine / pharmacology
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism


  • Bis-Trimethylammonium Compounds
  • Buffers
  • Dioxolanes
  • Isoindoles
  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • heptane-1,7-bis(dimethyl-3'-phthalimidopropylammonium)
  • Oxotremorine
  • oxotremorine M
  • Carbachol
  • Acetylcholine
  • formal glycol