Sila-biperiden und endo-Sila-biperiden: Synthesen, Kristallstrukturen und antimuscarinische Eigenschaften

Article abstract of DOI:10.1016/0022-328X(94)88024-7

Starting from trichloro(vinyl)silane (Cl3SiCH=CH2), the muscarinic antagonists sila-biperiden and endo-sila-biperiden were prepared by a seven-step synthesis.Both silanols are configurationally stable in inert organic solvents but undergo slow epimerization in aqueous solution (pH 7.4, 32 deg C) by inversion of the configuration at the silicon atom.The relative configurations of sila-biperiden and endo-sila-biperiden were determined by single-crystal X-ray diffraction.Both compounds form intermolecular O-H...N hydrogen bonds in the crystal leading to the formation of centrosymmetric dimers (sila-biperiden) and infinite chains (endo-sila-biperiden), respectively.Sila-biperiden is a silicon analogue (C/Si exchange) of the antiparkinsonian drug biperiden .In functional pharmacological experiments, as well as in radioligand competition studies, biperiden, sila-biperiden and endo-sila-biperiden behaved as simple competitive antagonists at muscarinic M1-, M2-, M3- and M4-receptors.The three compounds displayed the highest affinity for M1-receptors (pA₂ values: 8.72-8.80; pK_i values: 8.8-9.1), intermediate affinity for M4- and M3-receptors, and lowest affinity for M2-receptors (pA₂ values: 7.57-7.79; pK_i values: 7.7-7.8).The affinity profile (M1 > M4 > M3 > M2) of biperiden, sila-biperiden and endo-sila-biperiden is qualitatively similar to that of the M1-selective muscarinic antagonist pirenzepine.The antimuscarinic properties of the C/Si analogues biperiden and sila-biperiden are almost identical. Key words: Silicon; Silanol; Sila-biperiden; Bioorganosilicon chemistry; Muscarinic antagonist; Muscarinic receptor subtype