Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
J Med Chem. 2015 Feb 26;58(4):1992-2002. doi: 10.1021/jm5019274. Epub 2015 Feb 10.
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.
本文描述了我们在努力优化 2-苯基环丙基甲胺骨架时发现的一系列新的强效、选择性 5-HT2C 受体激动剂。对芳环上存在的烷氧基取代基的修饰导致了具有更高 5-HT2C 受体活性和对 5-HT2A 和 5-HT2B 受体更好选择性的改进配体的鉴定。ADMET 研究结合使用安非他命诱导的过度活动模型的行为测试，确定了四个具有类药性特征和抗精神病特性的化合物。化合物 (+)-16b 在 5-HT2C 上的 EC50 为 4.2 nM，对 5-HT2B 没有活性，对 5-HT2A 的选择性为 89 倍，是迄今为止报道的最有效和选择性最高的 5-HT2C 激动剂之一。在一项使用优化模型（包含β2-肾上腺素能受体和 5-HT2B 受体的结构）的建模研究中，还研究了这一系列化合物与 5-HT2C 受体的可能结合模式。
