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

The unsaturated HHSiD (1) and p-F-HHSiD (2) derivatives lohexyl(phenyl )(3-piperidino-1-propen-1-yl)silanol (5, isolated as 5 HCl) and 4-fluo rophenyl)(3-piperidino-1-propen-1-yl)silanol (6, isolated as 6 . HCl) were synthesized in four steps, starting from (CH3O)(3)SiH. Reaction o f 5 and 6 with CH3Cl gave the corresponding methochlorides 7 and 8, re spectively. All compounds were obtained as racemic mixtures. The bindi ng affinities at muscarinic receptor subtypes (M1-M4) of the silanols 5-8 were determined and compared with those of the selective muscarini c antagonists 1 and 2 and their methiodides 3 and 4. These studies dem onstrated that the ammonium compounds 3, 4, 7 and 8 display similar bi nding affinities at M1-M4 receptors and comparable receptor subtype se lectivities. On the other hand, the conformationally restricted amines 5 and 6 ((E)-Si-CH=CH-CH2-N moiety) exhibit higher affinities but low er receptor subtype selectivities than the more flexible parent compou nds 1 and 2 (Si-CH2-CH2-CH2-N moiety).