2-Methylimidazol-1-yl-Substituted Analogs of Hexahydro-difenidol (HHD) and Hexahydro-sila-difenidol (HHSiD) as M3 Receptor-Preferring Muscarinic Antagonists: A Study on C/Si Bioisosterism

Abstract

The hexahydro-sila-difenidol (HHSiD, 1b) and p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD, 2b) derivatives cyclohexyl[3-(2-methylimidazol-1-yl)propyl]phenylsilanol (4b) and cyclohexyl(4-fluorophenyl)[3-(2-methylimidazol-1-yl)propyl]silanol (5b) were synthesized in three-step syntheses, starting from (3-chloropropyl)cyclohexyldimethoxysilane. In addition, the corresponding carbon analogs 4a and 5a (→ Si/C replacement) were prepared in two-step syntheses, starting from 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane, respectively. The C/Si pairs 4a/4b and 5a/5b were studied for their affinities at recombinant human muscarinic M1, M2, M3, M4, and M5 receptors stably expressed in CHO-K1 cells by evaluating their ability to inhibit the binding of the muscarinic antagonist [3H]N-methylscopolamine. These studies revealed that compounds 4a, 4b, 5a, and 5b behave as simple competitive antagonists at M1−M5 receptors. The exchange of the piperidin-1-yl group of the parent compounds HHD (1a), HHSiD (1b), p-F-HHD (2a), and p-F-HHSiD (2b) by a 2-methylimidazol-1-yl moiety resulted in a novel, potent, and M3-preferring antimuscarinic agent, compound 4b. The affinities of compounds 4a, 5a, and 5b for muscarinic M1 (pKi = 7.74−7.93), M2 (pKi = 7.03−7.14), M3 (pKi = 8.04−8.11), M4 (pKi = 7.63−7.94), and M5 receptors (pKi = 7.29−7.52) were very similar at the individual receptor subtypes and in turn very similar to those of the parent compounds 1a, 2a, and 2b. In contrast, replacement of the piperidin-1-yl substituent of 1b by a 2-methylimidazol-1-yl group (→ 4b) increased the affinity for M1−M5 receptors up to 8.3-fold. The muscarinic receptor affinity profile of 4b was found to be M3 (pKi = 8.69) > M1 (pKi = 8.39) ≥ M4 (pKi = 8.32) > M5 (pKi = 8.02) > M2 (pKi = 7.43). Thus, compound 4b displayed a M3 versus M2 receptor selectivity (18.2-fold). The receptor subtype affinities of the carbon compound 5a were very similar to those of the corresponding silicon analog 5b, whereas sila-substitution of 4a (→ 4b) increased the affinities for M1−M5 receptors, this increase being greatest at M3 and M5 receptors (4-fold).