Kennett G A, Wood M D, Bright F, Trail B, Riley G, Holland V, Avenell K Y, Stean T, Upton N, Bromidge S, Forbes I T, Brown A M, Middlemiss D N, Blackburn T P
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Harlow, Essex, U.K.
Neuropharmacology. 1997 Apr-May;36(4-5):609-20. doi: 10.1016/s0028-3908(97)00038-5.
SB 242084 has a high affinity (pKi 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, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (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. SB 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. SB 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 SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 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 SB 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.
SB 242084对克隆的人5-HT2C受体具有高亲和力（pKi 9.0），对密切相关的克隆人5-HT2B和5-HT2A亚型的选择性分别为100倍和158倍。SB 242084对一系列其他5-HT、多巴胺和肾上腺素能受体的选择性超过100倍。在使用稳定表达克隆人5-HT2C受体的SH-SY5Y细胞进行的5-HT刺激的磷脂酰肌醇水解研究中，SB 242084作为拮抗剂，pKb为9.3，与其相应的受体结合亲和力非常相似。SB 242084能有效抑制间氯苯哌嗪（mCPP，腹腔注射7 mg/kg，试验前20分钟）诱导的大鼠运动减少，这是一种体内中枢5-HT2C受体功能模型，腹腔注射ID50为0.11 mg/kg，口服为2.0 mg/kg。SB 242084（腹腔注射0.1 - 1 mg/kg）在大鼠社交互动试验中表现出抗焦虑样特征，增加了在社交互动中花费的时间，但对运动没有影响。SB 242084（腹腔注射0.1 - 1 mg/kg）在大鼠焦虑的盖勒-赛弗特冲突试验中也显著增加了惩罚性反应，但对非惩罚性反应没有一致影响。大剂量急性给予SB 242084（口服30 mg/kg）对大鼠最大电休克惊厥阈值试验中的惊厥易感性没有影响。此外，虽然SB 242084（口服2和6 mg/kg，试验前1小时）拮抗了对mCPP的摄食减少反应，但无论是急性还是亚慢性给药（口服2或6 mg/kg，每日两次，持续5天），该药物均不影响食物摄入量或体重增加。结果表明，SB 242084是首次报道的选择性强效且能穿透脑的5-HT2C受体拮抗剂，具有抗焦虑样活性，但不具有缺乏5-HT2C受体的突变小鼠所特有的惊厥或摄食亢进特性。
