SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist

被引:466
作者
Kennett, GA
Wood, MD
Bright, F
Trail, B
Riley, G
Holland, V
Avenell, KY
Stean, T
Upton, N
Bromidge, S
Forbes, IT
Brown, AM
Middlemiss, DN
Blackburn, TP
机构
[1] SMITHKLINE BEECHAM PHARMACEUT, DEPT MED CHEM, HARLOW CM19 5AW, ESSEX, ENGLAND
[2] SMITHKLINE BEECHAM PHARMACEUT, DEPT PSYCHIAT RES, HARLOW CM19 5AW, ESSEX, ENGLAND
关键词
SB; 242084; 5-HT2C receptor; anxiety; feeding; seizures;
D O I
10.1016/S0028-3908(97)00038-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
SB 242084 has a high affinity (pK(i) 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SE 242084 acted as an antagonist with a pK(b) of 9.3, which closely resembled its corresponding receptor binding affinity. SE 242084 potently inhibited m-chIorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SE 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SE 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SE 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SE 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SE 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor. (C) 1997 Elsevier Science Ltd.
引用
收藏
页码:609 / 620
页数:12
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