STEREOSPECIFIC AND SELECTIVE 5-HT2 ANTAGONISM IN A SERIES OF 5-SUBSTITUTED TRANS-1-PIPERAZINO-3-PHENYLINDANS

A study of the effect of aromatic substitution on 5-HT2, D2, and alpha 1 receptor affinity in a subseries of new and previously synthesized 1 -piperazino-3-phenylindans indicated that high 5-HT2 selectivity could be obtained in 5-substituted derivatives. Accordingly, a series of 5- substituted derivatives was synthesized with the goal of obtaining ste reospecific and selective, centrally acting 5-HT2 antagonists. This go al was fulfilled in 5-chloro- or 5-fluoro-substituted compounds with 2 (3-alkyl-2-oxoimidazolidin-1-yl)ethyl- or tetrahydro-2-oxo-1H-pyrimidi n-1-yl)ethylpiperazine substituents, as well as in their imidazolidine -2-thione or pyrimidine-2-thione analogoues. The most interesting deri vatives were resolved either directly via diastereomeric salts or by s yntheses from resolved starting materials. Optical purity was determin ed by a H-1 NMR method, using the chiral shift reagent (R)-(-)-2,2,2-t rifluoro-1-(9-anthryl)ethanol. The compound iperazin-1-yl]ethyl]-3-iso propyl-2-imidazolidinone ((-)-20) had the overall best profile with a high stereoselectivity (eudismic ratio: 68) and a high selectivity ver sus D2 and alpha1 receptors (affinity ratios 182 and 191, respectively ). It had a potent central effect but was shorter-acting than the tetr ahydropyrimidinone or thione derivatives ((-)-39, (+)-40, (-)-41, and (+)-42). The observed activities of the compounds are settled in persp ective in relation to a recently proposed D2 receptor interaction mode l. While there are no indications so far that trans-1-piperazino-3-phe nylindans interact with D2 and 5-HT2 receptors in different conformati ons, the present study shows important differences in aromatic substit ution effects. Only 5-HT2 receptors are able to accommodate a 5-substi tuent in the indan benzene ring, thus allowing syntheses of highly sel ective compounds.