HTS and Rational Drug Design to Generate a Class of 5-HT2C-Selective Ligands for Possible Use in Schizophrenia
HTS and Rational Drug Design to Generate a Class of 5-HT2C-Selective Ligands for Possible Use in Schizophrenia
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DOI：
10.1002/cmdc.201000186
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发表时间：
2010-07-01
期刊：
影响因子：
3.4
通讯作者：
Roth, Bryan L.
中科院分区：
文献类型：
--
作者：
Kozikowski, Alan P.;Cho, Sung Jin;Roth, Bryan L.
5-羟色胺(1，5-HT2C)受体(5-HT2C)是一种重要的中枢5-羟色胺受体亚型，广泛分布于中枢神经系统(CNS)，被认为在调节多种行为过程中发挥作用，如情绪、食欲和性行为。[1-4]5-HT2A型受体介导药物的致幻活性，如麦角酸二乙胺(LSD)，是治疗精神分裂症的主要靶点。失眠和其他疾病。[5-8]5-HT2B受体介导了几种用作处方药的化合物潜在的致命的心脏瓣膜病副作用。[9，10]5-HT2C激动剂已在抑郁症、肥胖症、成瘾和精神病的临床前模型中证明有效。[11-13]因此，靶向5-HT2C受体似乎为开发治疗中枢神经系统相关疾病的新疗法提供了一种有前途的手段。然而，由于该受体与另外两个家族成员5-HT2A和5-HT2B同源，[14]正在开发用于临床的5-HT2C激动剂对这些亚型的活性即使有，也很少。[15]到目前为止，几种5-HT2C激动剂已经在临床前动物模型中显示出有效性(2-8)，[16-18]，目前正在进行人体试验。[16]尤其是，最先进的5-HT2C配体之一是氯酪蛋白(2)，它正由Arena制药公司开发，并已在两个III期试验中被证明具有口服活性，抗肥胖药物。[19]根据使用FDA批准的药库的HTS活动的初步结果，我们开展了结构优化活动，产生了一种有效的、但中等选择性的激动剂(8)，其选择性分别是5-HT2A和5-HT2B的120和14倍(在2A、2B和2C亚型上，EC50分别为585、65和4.8 nM)。化合物8(10-60 mg·kg~(-1))在常用的行为测试中也显示出中等的抗抑郁药样作用。[18]然而，由于化合物8不能对5-HT2B受体表现出足够的选择性，进一步的优化被重新优化。
The 5-hydroxytryptamine (1, 5-HT) 2C receptor (5-HT2C), a prominent central serotonin receptor subtype, is widely distributed throughout the central nervous system (CNS) and is thought to play a role in regulating a wide variety of behavioral processes, such as mood, appetite, and sexual behavior.[1–4] The 5-HT2A receptor mediates the hallucinogenic activity of drugs, such as lysergic acid diethylamide (LSD), and is a major target for treating schizophrenia, insomnia and other disorders.[5–8] The 5-HT2B receptor mediates the potentially lethal valvulopathic side effects of several compounds that were used as prescription drugs.[9, 10]5-HT2C agonists have demonstrated efficacy in preclinical models of depression, obesity, addiction, and psychosis.[11–13] Thus, targeting the 5-HT2C receptor appears to offer a promising means for developing novel therapeutics for the treatment of CNS-related disorders. However, as this receptor is homologous to the two other family members, 5-HT2A and 5-HT2B,[14] it is essential that 5-HT2C agonists being developed for clinical use show little, if any, activity at these subtypes.[15] To date, several 5-HT2C agonists have shown efficacy in preclinical animal models (2–8),[16–18] and are currently undergoing human trials.[16] In particular, one of the most advanced 5-HT2C ligands is lorcaserin (2), which is being developed by Arena Pharmaceuticals and which has been demonstrated in two phase III trials to be an orally active, antiobesity medication.[19] Based upon the identification of tranylcypromine as the initial hit from an HTS campaign employing a library of FDA-approved drugs, we undertook a structural optimization campaign that led to a potent, but moderately selective, agonist (8) with 120-and 14-fold selectivity over 5-HT2A and 5-HT2B, respectively (EC50= 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). Compound 8 (10–-60 mg kgĀ1) was also demonstrated to exhibit moderate antidepressant-like effects in a commonly used behavioral assay.[18] However, because compound 8 fails to exhibit sufficient selectivity over the 5-HT2B receptor, further optimization was re-