The racemic (2-aminoethyl)cyclohexyl(hydroxymethyl)phenylsilanes [rac-Ph(c-Hex)Si(CH2-OH)CH(2)CH(2)NR(2)] rac-5a (NR(2) = pyrrolidino), rac-5b (NR(2) = piperidino), and rac-5c (NR(2) = hexamethylenimino) were synthesized by a five-step synthesis starting from rac-Ph(c-Hex)Si(CH2Cl)OMe. The (R)- and (S)-enantiomers of 5a-c were obtained by resolution of rac-5a-c using the antipodes of O,O'-di-p-toluoyltartaric acid as resolving agents (resolution by fi adional crystallization of diastereomeric salts). The enantiomeric purities of the resolved antipodes of 5a-c were determined to be greater than or equal to 98% ee (IH NMR) and greater than or equal to 97%, ee (C-13 NMR) respectively (NMR experiments using chiral shift reagents). Reaction of the pure (R)- and (S)-enantiomers of 5a-c with methyl iodide gave the pure (R)- and (S)-enantiomers of the respective quaternary ammonium derivatives 6a-c. The absolute configuration of(R)-6b was determined by single-crystal X-ray diffraction. The crystal data for this compound are as follows: C21H36INOSi, space group P2(1)2(1)2(1), a = 890.5(3) pm, b = 916.2(2) pm, c = 2719.4 (7) pm, V = 2.2187(11) nm(3), T = -130 degrees C, Z = 4, R(F) = 0.0210. On the basis of the experimentally established absolute configuration of(R)-6b, the absolute configurations of all the other aforementioned optically active silicon compounds could be assigned by chemical and optical correlations. The pure (R)- and (S)-enantiomers of 5a-c and 6a-c were studied for their affinities for muscarinic M1, M2, M3, and M4 receptors by functional pharmacological experiments (M1 rabbit vas deferens; M2, guinea-pig atria; M3, guinea-pig ileum) and radioligand binding experiments (M1, human NB-OK 1 cells; M2, rat heart; M3, rat pancreas; M4, rat striatum). According to these studies, the (R)-enantiomers of 5a-c and 6a-c exhibited higher affinities for all four muscarinic receptor subtypes than their corresponding (S)-antipodes. The greatest difference (44-fold, M1 receptors) between the enantiomers was observed for 1-{2-[cyclohexyl(hydroxymethyl)phenylsilyl] ethyl}-1-methylhexamethyleniminium iodide (6c). The highest receptor selectivity was observed for (R)-6c at M1/MB receptors (20-fold) and at M1/M3 receptors (6.9-fold). The potent M1-selective antagonist (R)-6c is considered to be an interesting lead for the development of new receptor-selective muscarinic antagonists.
