Bisquaternary caracurine V derivatives as allosteric modulators of ligand binding to M-2 acetylcholine receptors

The allosteric effect on muscarinic acetylcholine M-2 receptors of 11 bisqu aternary salts of the Strychnos alkaloid caracurine V was determined. The e ffect was indicated by the concentration which retarded the rate of dissoci ation of the antagonist [H-3]-N-methylscopolamine from porcine cardiac chol inoceptors by a factor of 2 (EC50). The most potent compounds carry allyl a nd propargyl substituents, respectively. Introduction of more bulky substit uents (e.g., benzyl groups) resulted in a considerably reduced allosteric p otency. The wide range of EC50 Values (3 nM for R = allyl, 1750 nM for R = 2-naphthyl) suggests a sterically restricted binding pocket. Molecular mode ling studies indicated that the caracurine V ring system satisfies the phar macophore model for the allosteric interaction. (C) 2000 Elsevier Science L td. All rights reserved.