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 [R1(CH2)3SiMe2(CH2)5NMe2(CH2)3R1]Br (3), [R2(CH2)3SiMe2(CH2)5NMe2(CH2)3R2]Br (4), [R1(CH2)3SiMe2(CH2)5NMe2(CH2)3R2]Br (5), and [R2(CH2)3SiMe2(CH2)5NMe2(CH2)3R1]Br (6) (R1=phthalimido; R2=1,8-naphthalimido) were synthesized, starting from chlorodimethylsilane. Compounds 3–6 were studied for their allosteric interaction at porcine heart muscarinic M2 receptors. They inhibited the dissociation of the orthosteric ligand [3H]N-methylscopolamine ([3H]NMS) with similar potency; compounds 4 and 6 yielded steep concentration–effect curves. All compounds enhanced [3H]NMS equilibrium binding, but with different efficacies. The effect of 4 on [3H]NMS binding was studied at cloned M1–M5 receptor subtypes. Compound 4 did not affect [3H]NMS equilibrium binding at M1, M3, M4, and M5 receptors, thus representing an M2-selective allosteric enhancer of [3H]NMS binding.