| Abstract: | The enantiomers of 1-methyl-3-(10H-phenothiazine-10-ylmethyl)-1-azoniabicyclo[2,2,2]octane iodide ( 1 ) were prepared by chiral chromatographic resolution of the precursor mequitazine ( 2 ). The (+)-(S)-enantiomer 1b is 10-fold more potent than (?)-(R)-enantiomer 1a as a histamine antagonist, while the two enantiomers show the same antimuscarinic activity in vitro. The absolute configuration of the more active dextrorotatory isomer has been determined by X-ray analysis. Conformational analysis and molecular modeling suggest that the (+)-(S)-enantiomer can adopt a conformation similar to that attributed to the receptor binding conformers of classical antihistamines. © 1994 Wiley-Liss, Inc. |
