title: Stereospecific and selective 5-HT2 antagonism in a series of 5-substituted trans-1-piperazino-3-phenylindans.
abstract: 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 stereospecific and selective, centrally acting 5-HT2 antagonists. This goal was fulfilled in 5-chloro- or 5-fluoro-substituted compounds with 2-(3-alkyl-2-oxoimidazolidin-1-yl)ethyl- or 2-(tetrahydro-2-oxo-1H-pyrimidin-1-yl)ethylpiperazine substituents, as well as in their imidazolidine-2-thione or pyrimidine-2-thione analogues. The most interesting derivatives were resolved either directly via diastereomeric salts or by syntheses from resolved starting materials. Optical purity was determined by a 1H NMR method, using the chiral shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. The compound (-)-trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden++ +-1- yl]piperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone ((-)-20) had the overall best profile with a high stereoselectivity (eudismic ratio: 68) and a high selectivity versus D2 and alpha 1 receptors (affinity ratios 182 and 191, respectively). It had a potent central effect but was shorter-acting than the tetrahydropyrimidinone or thione derivatives ((-)-39, (+)-40, (-)-41, and (+)-42). The observed activities of the compounds are settled in perspective in relation to a recently proposed D2 receptor interaction model. While there are no indications so far that trans-1-piperazino-3-phenylindans interact with D2 and 5-HT2 receptors in different conformations, the present study shows important differences in aromatic substitution effects. Only 5-HT2 receptors are able to accommodate a 5-substituent in the indan benzene ring, thus allowing syntheses of highly selective compounds.
authors.affiliation: Research Department, H. Lundbeck A/S, Copenhagen, Valby, Denmark.
authors.forename: K P
authors.initials: KP
authors.lastname: Bøgesø
authors.forename: J
authors.initials: J
authors.lastname: Arnt
authors.forename: J
authors.initials: J
authors.lastname: Hyttel
authors.forename: H
authors.initials: H
authors.lastname: Pedersen
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007189:Indans; D010879:Piperazines; D012702:Serotonin Antagonists