Synthesis and pharmacological characterization of new silicon-based W84-type allosteric modulators for ligand binding to muscarinic M2 receptors

The silicon-based allosteric modulators of ligand binding to muscarinic acetylcholine receptors [R-1-(CH2)(3)-SiMe2-(CH2)(5)- NMe2-(CH2)(3)-R-1]Br (3), [R-2-(CH2)(3)-SiMe2 (CH2)(5)-NMe2-(CH2)(3)-R-2]Br (4), [R-1-(CH2)(3)-SiMe2-(CH2)(3)-NMe2-(CH2)(3)- R-2]Br (5), and [R-2-(CH2)(3)-SiMe2- (CH2)(5)-NMe2-(CH2)(3)-R-1]Br (6) (R-1 = phthalimido; R-2 = 1,8-naphthalimido) were sythesized, starting from chlorodimethylsilane. Compounds 3-6 were studied for their allosteric interaction at porcine heart muscarinic M-2 receptors. They inhibited the dissociation of the orthosteric ligand [H-3]N-methylscopolamine ([H-3]NMS) with similar potency; compounds 4 and 6 yielded steep concentration-effect curves. All compounds enhanced [H-3]NMS equilibrium binding, but with different efficacies. The effect of 4 on [H-3]NMS binding was studied at cloned M-1-M-5 receptor subtypes. Compound 4 did not affect [H-3]NMS equilibrium binding at M-1, M-3, M-4, and M-5 receptors, thus representing an M-2-selective allosteric enhancer of [H-3]NMS binding. (C) 2003 Elsevier B.V. All rights reserved.