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Titolo:
Characterization of SB-271046: A potent, selective and orally active 5-HT6receptor antagonist
Autore:
Routledge, C; Bromidge, SM; Moss, SF; Price, GW; Hirst, W; Newman, H; Riley, G; Gager, T; Stean, T; Upton, N; Clarke, SE; Brown, AM; Middlemiss, DN;
Indirizzi:
SmithKline Beecham Pharmaceut, Dept Neurosci Res, Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AW ssex, England SmithKline Beecham Pharmaceut, Dept Discovery Chem, Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AW ssex, England SmithKline Beecham Pharmaceut, Dept Drug Metab & Pharmacokinet, Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut Harlow Essex England CM19 5AW ssex, England
Titolo Testata:
BRITISH JOURNAL OF PHARMACOLOGY
fascicolo: 7, volume: 130, anno: 2000,
pagine: 1606 - 1612
SICI:
0007-1188(200008)130:7<1606:COSAPS>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
SEROTONIN RECEPTOR; SEIZURE THRESHOLD; RAT-BRAIN; CLONING; LOCALIZATION; RO-04-6790; EXPRESSION; BINDING; RODENTS; PROFILE;
Keywords:
human 5-HT6 receptor; SB-271046; [H-3]-LSD; SB-258585; adenylyl cyclase; rat maximal electroshock seizure; threshold (MEST) test; pharmacokinetics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Routledge, C SmithKline Beecham Pharmaceut, Dept Neurosci Res, New Frontiers Sci Pk,3rdAve, Harlow CM19 5AW, Essex, England SmithKline Beecham Pharmaceut New Frontiers Sci Pk,3rd Ave Harlow Essex England CM19 5AW
Citazione:
C. Routledge et al., "Characterization of SB-271046: A potent, selective and orally active 5-HT6receptor antagonist", BR J PHARM, 130(7), 2000, pp. 1606-1612

Abstract

1 SB-271046, potently displaced [H-3]-LSD and [I-125]-SB-258585 from human5-HT6 receptors recombinantly expressed in HeLa cells in vitro (pK(i) 8.92and 9.09 respectively). SB-271046 also displaced [I-125]-SB-258585 from human caudate putamen and rat and pig striatum membranes (PKi 8.81, 9.02 and 8.55 respectively).2 SB-271046 was over 200 fold selective for the 5-HT6 receptor vs 55 otherreceptors, binding sites and ion channels.3 In functional studies on human 5-HT6 receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA(2) of 8.71.4 SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of less than or equal to 0.1 mg kg(-1) p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC50 of 0.16 mu M) and brain concentrations of 0.01-0.04 mu M at C-max.5 These data, together with the observed anticonvulsant activity of other selective 5-HT6 receptor antagonists, SB-258510 (10 mg kg(-1), 2-6 h pre-test) and Ro 04-6790 (1-30 mg kg(-1), 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT6 receptors.6 Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT6 receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT6 receptors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/08/20 alle ore 07:07:12