一种新型的氨四氢萘型血清素(5-HT)2C 受体特异性激动剂和 5-HT2A 竞争性拮抗剂/5-HT2B 反向激动剂,具有治疗精神疾病的临床前疗效。

A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses.

机构信息

Center for Drug Discovery (C.E.C., R.G.B.), Department of Pharmaceutical Sciences (C.E.C., R.G.B.), and Department of Chemistry and Chemical Biology (R.G.B.), Northeastern University, Boston, Massachusetts; Department of Psychiatry (D.M.), Medicinal Chemistry (D.F., R.S., K.K., R.G.B.), and Psychology (N.E.R., K.L.R.), University of Florida, Gainesville, Florida.

出版信息

J Pharmacol Exp Ther. 2014 May;349(2):310-8. doi: 10.1124/jpet.113.212373. Epub 2014 Feb 21.

Abstract

Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (-)-trans-(2S,4R)-4-(3'[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (-)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (-)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (-)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (-)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (-)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (-)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

摘要

用于治疗神经精神疾病(包括精神病、药物滥用和肥胖症)的 5-HT2C 激动剂的开发充满了困难,因为绝大多数报道的 5-HT2C 选择性激动剂也会激活 5-HT2A 和/或 5-HT2B 受体,可能导致幻觉和/或心脏瓣膜病。本文描述了一种新型、有效且强效的人 5-HT2C 受体激动剂,(-)-反式-(2S,4R)-4-(3'[间位]-溴苯基)-N,N-二甲基-1,2,3,4-四氢萘-2-胺(-)-MBP),它分别是人类 5-HT2A 和 5-HT2B 受体的竞争性拮抗剂和反向激动剂。(-)-MBP 在三种 C57Bl/6 小鼠药物诱导的精神病模型中的功效与典型的第二代抗精神病药物氯氮平相当:[2,5]-二甲氧基-4-碘苯丙胺引起的头部抽搐反应;MK-801((5R,10S)-(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸氢盐(地昔帕明马来酸盐))诱导的过度活跃;和安非他命引起的过度活跃。然而,(-)-MBP 单独给药时不会改变运动,这使其与氯氮平区分开来,氯氮平抑制运动。最后,当 (-)-MBP 以在精神病模型中产生至少 50%最大功效的剂量给药时,它不会增加小鼠对高适口性食物的消耗。与(-)-MBP 相比,对映体(+)-MBP 在使用小鼠和人受体的体外亲和力和功能测定中活性要低得多,并且在体内也以类似的低效力和功效转化。结果表明,5-HT2C 受体特异性激动剂,如(-)-MBP,可能是治疗精神病的药物治疗方法,不会引起肥胖症、幻觉、心脏病、镇静或运动障碍的风险。

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