Lundbeck Research Denmark, H. Lundbeck A/S, Valby, Denmark.
Int J Neuropsychopharmacol. 2010 Sep;13(8):1021-33. doi: 10.1017/S1461145710000659. Epub 2010 Jun 23.
The in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist Lu AE58054 ([2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine) on impaired cognition were evaluated. Lu AE58054 displayed high affinity to the human 5-HT(6) receptor (5-HT(6)R) with a Ki of 0.83 nm. In a 5-HT(6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic alpha(1A)- and alpha(1B)-adrenoreceptors, Lu AE58054 demonstrated >50-fold selectivity for more than 70 targets examined. Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157 ([(3)H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline), with an ED(50) of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT(6)R occupancy time-course experiment indicated a plasma EC(50) value of 20 ng/ml. Administration of Lu AE58054 in a dose range (5-20 mg/kg p.o.) leading to above 65% striatal 5-HT(6)R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg/kg b.i.d., i.p. for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT(6)Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia. Lu AE58054 may be useful for the pharmacotherapy of cognitive dysfunction in disease states such as schizophrenia and Alzheimer's disease.
评估了 5-HT(6)R 拮抗剂 Lu AE58054([2-(6-氟-1H-吲哚-3-基)-乙基]-[3-(2,2,3,3-四氟丙氧基)-苄基]-胺)对认知障碍的体外效力和选择性、体内结合亲和力和作用。Lu AE58054 对人 5-HT(6)受体 (5-HT(6)R) 具有高亲和力，Ki 为 0.83nm。在 5-HT(6)GTPγS 效价测定中，Lu AE58054 没有表现出激动剂活性，但显示出对 5-HT 介导的激活的有效抑制。除了对肾上腺素能α(1A)-和α(1B)-肾上腺素受体具有中等亲和力外，Lu AE58054 对超过 70 种被检目标表现出 >50 倍的选择性。口服给予 Lu AE58054 可有效抑制纹状体体内 5-HT(6)拮抗剂放射性配体 [(3)H]Lu AE60157([(3)H]8-(4-甲基哌嗪-1-基)-3-苯磺酰基喹啉)的结合，ED(50)为 2.7mg/kg。急性药代动力学/5-HT(6)R 占有率时间过程实验的稳态建模表明，血浆 EC(50)值为 20ng/ml。在一个剂量范围内(5-20mg/kg 口服)给予 Lu AE58054，导致体内纹状体 5-HT(6)R 结合占有率超过 65%，可逆转慢性给予苯环利定(PCP 2mg/kg，每日 2 次，腹腔注射，共 7 天，随后 7 天无药物)7 天后诱导的大鼠新物体识别任务中的认知障碍。结果表明，Lu AE58054 是一种选择性 5-HT(6)R 拮抗剂，具有良好的口服生物利用度和在精神分裂症大鼠认知障碍模型中的强大疗效。Lu AE58054 可用于治疗精神分裂症和阿尔茨海默病等疾病状态下的认知功能障碍的药物治疗。
