Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.
Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.
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2-苯基丙烷基甲胺作为选择性5-羟色胺2C受体激动剂的优化及其作为潜在抗精神病药的评估。
DOI：
10.1021/jm5019274
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发表时间：
2015-02-26
影响因子：
7.3
通讯作者：
Kozikowski AP
中科院分区：
文献类型：
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作者：
Cheng J;Giguère PM;Onajole OK;Lv W;Gaisin A;Gunosewoyo H;Schmerberg CM;Pogorelov VM;Rodriguiz RM;Vistoli G;Wetsel WC;Roth BL;Kozikowski AP
本文描述了一系列新的化合物的发现，这些化合物是有效的、选择性的5-HT 2C受体激动剂，因为我们继续努力优化2-苯基环丙基甲胺支架。修饰集中在芳环上存在的烷氧基取代基上，导致鉴定出对5-HT 2C受体具有更好效力和对5-HT 2A和5-HT 2B受体具有优异选择性的改进配体。ADMET研究结合使用安非他明诱导的多动症模型的行为测试，确定了四种具有药物样特征并具有抗精神病特性的化合物。化合物（+）-16 b对5-HT 2C的EC 50为4.2 nM，对5-HT 2B无活性，对5-HT 2A的选择性为89倍，是迄今报道的最有效和选择性的5-HT 2C激动剂之一。还在建模研究中研究了该系列化合物与5-HT 2C受体的可能结合模式，使用结合β2-肾上腺素能受体和5-HT 2B受体结构的优化模型。
The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.