2-methylimidazol-1-yl-substituted analogs of hexahydro-difenidol (HHD) and hexahydro-sila-difenidol (HHSiD) as M-3 receptor-preferring muscarinic antagonists: A study on C/Si bioisosterism

摘要

The hexahydro-sila-difenidol (HHSiD, 1b) and p-fluoro-hexahydro-sila-difenidoI (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 M-1, M-2, M-3, M-4, and M-5 receptors stably expressed in CHO-K1 cells by evaluating their ability to inhibit the binding of the muscarinic antagonist [H-3]N-methylscopolamine. These studies revealed that compounds 4a, 4b, 5a, and 5b behave as simple competitive antagonists at M-1-M-5 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 M-3-preferring antimuscarinic agent, compound 4b. The affinities of compounds 4a, 5a, and 5b for muscarinic M-1 (pK(i) = 7.74-7.93), M-2 (PKi = 7.03-7.14), M-3 (pK(i) = 8.04-8.11), M4 (pK(i) = 7.63-7.94), and M-5 receptors (pK(i) = 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 M-1-M-5 receptors up to 8.3-fold. The muscarinic receptor affinity profile of 4b was found to be M-3 (pK(i) = 8.69) > M-1 (pK(i) = 8.39) M-4 (pK(i) = 8.32) > M-5 (pK(i) = 8.02) > M-2 (pK(i) = 7.43). Thus, compound 4b displayed a M-3 versus M-2 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 M-1-M-5 receptors, this increase being greatest at M-3 and M-5 receptors (4-fold). [References: 27]