Evidence for a multiple binding mode of bispyridinium-type allosteric modulators of muscarinic receptors

Eur J Pharmacol. 1996 Oct 31;314(3):385-92. doi: 10.1016/s0014-2999(96)00568-7.


The ligand binding properties of muscarinic receptors can be modulated by allosterically acting compounds. Here, a set of novel bispyridinium-type compounds was investigated which were designed to study structure-activity relationships and to provide more insight into the molecular events underlying the allosteric delay of the dissociation of [3H]N-methylscopolamine from muscarinic M2 receptors in porcine cardiac membranes. The parent compound, a non-substituted bispyridinium oxime, displayed a weak allosteric potency and was unable to prevent radioligand dissociation at maximum concentrations. Introduction of either a phthalimidomethyl-moiety or a dichlorobenzyl-moiety at one end of the parent compound led to a considerable increase of the allosteric activity with regard to both the potency and the maximum effect. In these unilaterally ring-substituted bispyridiniums, homologous contralateral non-aromatic modifications were accompanied by divergent potency shifts depending on whether the unilateral ring was phthalimidomethyl or dichlorobenzyl. The findings point to a multiple binding mode of bispyridinium compounds at M2 receptors in the [3H]N-methylscopolamine-occupied state, i.e., different orientations of the compounds at the allosteric binding area or even an interaction with distinct allosteric recognition sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Benzyl Compounds / chemical synthesis
  • Benzyl Compounds / chemistry
  • Benzyl Compounds / metabolism*
  • Methylation
  • Phthalimides / chemical synthesis
  • Phthalimides / chemistry
  • Phthalimides / metabolism*
  • Pyridinium Compounds / chemical synthesis
  • Pyridinium Compounds / chemistry
  • Pyridinium Compounds / metabolism*
  • Radioligand Assay
  • Receptors, Muscarinic / metabolism*
  • Statistics, Nonparametric
  • Structure-Activity Relationship


  • Benzyl Compounds
  • Phthalimides
  • Pyridinium Compounds
  • Receptors, Muscarinic