Unsaturated derivatives of the muscarinic antagonists hexahydro-sila-difenidol (HHSiD) and p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD) with an (E)-Si-CH=CH-CH2-N moiety: syntheses and binding affinities at muscarinic receptor subtypes

Article abstract of DOI:10.1016/0022-328X(95)05584-7

The unsaturated HHSiD (1) and p-F-HHSiD (2) derivatives (E)-cyclohexyl(phenyl)(3-piperidino-1-propen-1-yl)silanol (5, isolated as 5*HCl) and (E)-cyclohexyl(4-fluorophenyl)(3-piperidino-1-propen-1-yl)silanol (6, isolated as 6*HCl) were synthesized in four steps, starting from (CH3O)3SiH.Reaction of 5 and 6 with CH3Cl gave the corresponding methochlorides 7 and 8, respectively.All compounds were obtained as racemic mixtures.The binding affinities at muscarinic receptor subtypes (M1-M4) of the silanols 5-8 were determined and compared with those of the selective muscarinic 1 and 2 and their methiodides 3 and 4.These studies demonstrated that the ammonium compounds 3, 4, 7 and 8 display similar binding affinities at M1-M4 receptors and comparable receptor subtype selectivities.On the other hand, the conformationally restricted amines 5 and 6 ((E)-Si-CH=CH-CH2-N moiety) exhibit higher affinities but lower receptor aubtype selectivities than the more flexible parent compounds 1 and 2 (Si-CH2-CH2-CH2N moiety).Keywords: Hexahydro-sila-difenidol (HHSiD); p-Fluoro-hexahydro-sila-difenidol (p-F-HHSiD); Silanols; Hydrosilylation; Bioorganosilicon chemistry; Muscarinic receptor subtypes