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Titolo:
STEREOSPECIFIC AND SELECTIVE 5-HT2 ANTAGONISM IN A SERIES OF 5-SUBSTITUTED TRANS-1-PIPERAZINO-3-PHENYLINDANS
Autore:
BOGESO KP; ARNT J; HYTTEL J; PEDERSEN H;
Indirizzi:
H LUNDBECK & CO AS,DEPT RES,OTTILIAVEJ 9 DK-2500 COPENHAGEN DENMARK H LUNDBECK & CO AS,DEPT RES & DEV DK-2500 COPENHAGEN DENMARK
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 19, volume: 36, anno: 1993,
pagine: 2761 - 2770
SICI:
0022-2623(1993)36:19<2761:SAS5AI>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEUROLEPTIC INDUCED AKATHISIA; RECEPTOR-INTERACTION-MODEL; THERAPEUTIC APPROACH; DOPAMINE D-2; DRUG-ABUSE; PHARMACOLOGICAL ACTIVITY; CONFORMATIONAL-ANALYSIS; UPTAKE INHIBITION; RITANSERIN; POTENT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
46
Recensione:
Indirizzi per estratti:
Citazione:
K.P. Bogeso et al., "STEREOSPECIFIC AND SELECTIVE 5-HT2 ANTAGONISM IN A SERIES OF 5-SUBSTITUTED TRANS-1-PIPERAZINO-3-PHENYLINDANS", Journal of medicinal chemistry, 36(19), 1993, pp. 2761-2770

Abstract

A study of the effect of aromatic substitution on 5-HT2, D2, and alpha1 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 tetrahydro-2-oxo-1H-pyrimidin-1-yl)ethylpiperazine substituents, as well as in their imidazolidine-2-thione or pyrimidine-2-thione analogoues. The most interesting derivatives were resolved either directly via diastereomeric salts or by syntheses from resolved starting materials. Optical purity was determined by a H-1 NMR method, using the chiral shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. The compound iperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone ((-)-20) had the overall best profile with ahigh stereoselectivity (eudismic ratio: 68) and a high selectivity versus D2 and alpha1 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 09:23:12