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 (f Si/C replacement) were prepared in twostep 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 [ 3 H]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 (pK i ) 7.03-7.14), M 3 (pK i ) 8.04-8.11), M 4 (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 (f 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) g 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 (f 4b) increased the affinities for M 1 -M 5 receptors, this increase being greatest at M 3 and M 5 receptors (4-fold).

Functional characterization of muscarinic autoreceptors in rat and human neocortex

“…(1998); c values for HHSiD were taken from Lambrecht et al . (1989); Tacke et al . (2002), and d values for AQ‐RA‐741 were taken from Gross et al.…”

Pentacoordinate hydrochlorosilanes with lactamomethyl ligand

“…Both compounds (10) and (12) have similar ligand environments at the pentacoordinate silicon atom and closely related 29 Si resonances (À48.66 and À52.50 ppm, respectively). Note that variations in the 29 Si chemical shifts from related silanols to alkoxysilanes are within limits of 2-10 ppm [37,38].…”

Anionic Access to Silylated and Germylated Binuclear Heterocycles

“…[9] The case of the sila-and germa-analogous derivatives of the muscarinic antagonist cycrimines B and C, respectively, which display a higher affinity than the corresponding alcohols, is also worth noting. [10] A spectacular example is given with the silylated analogue of haloperidol: A drug prescribed since the 1950s for the treatment of neuropsychiatric disorders such as schizophrenia, that is, sila-haloperidol D. This compound is not only as powerful as its carbon analogue (with an inhibition constant of 0.85 nm for the hD2 receptors against 4.0 nm in the case of haloperidol), but has also a very different metabolic fate in vivo. [11] Note that silicon-containing odorants like sila-rhubafuran E and disila-galaxolide F have been synthetized very recently in the same laboratory, introducing enthusing possibilities of development in the field.…”