title: Evidence for a multiple binding mode of bispyridinium-type allosteric modulators of muscarinic receptors.
abstract: 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.
authors.affiliation: Institute of Pharmacy, University of Bonn, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Kostenis
authors.forename: H M
authors.initials: HM
authors.lastname: Botero Cid
authors.forename: Y
authors.initials: Y
authors.lastname: Holzgrabe
authors.forename: K
authors.initials: K
authors.lastname: Mohr
mesh_terms: D000494:Allosteric Regulation; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013329:Structure-Activity Relationship
chemical_list: D001593:Benzyl Compounds; D010797:Phthalimides; D011726:Pyridinium Compounds; D011976:Receptors, Muscarinic