title: Bisquaternary caracurine V derivatives as allosteric modulators of ligand binding to M2 acetylcholine receptors.
abstract: The allosteric effect on muscarinic acetylcholine M2 receptors of 11 bisquaternary salts of the Strychnos alkaloid caracurine V was determined. The effect was indicated by the concentration which retarded the rate of dissociation of the antagonist [3H]-N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC50). The most potent compounds carry allyl and propargyl substituents, respectively. Introduction of more bulky substituents (e.g., benzyl groups) resulted in a considerably reduced allosteric potency. The wide range of EC50 values (3 nM for R = allyl. 1750 nM for R = 2-naphthyl) suggests a sterically restricted binding pocket. Molecular modeling studies indicated that the caracurine V ring system satisfies the pharmacophore model for the allosteric interaction.
authors.affiliation: Pharmaceutical Institute, University of Würzburg, Germany. zlotos@pharmazie.uni-wuerzburg.de
authors.forename: D P
authors.initials: DP
authors.lastname: Zlotos
authors.forename: S
authors.initials: S
authors.lastname: Buller
authors.forename: C
authors.initials: C
authors.lastname: Tränkle
authors.forename: K
authors.initials: K
authors.lastname: Mohr
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000494:Allosteric Regulation; D000818:Animals; D008024:Ligands; D011485:Protein Binding; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
chemical_list: D000470:Alkaloids; D008024:Ligands; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C041536:caracurine V