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合理药物设计促成一种强效且无5-HT(2B)活性的5-HT(2C)激动剂的鉴定。

Rational Drug Design Leading to the Identification of a Potent 5-HT(2C) Agonist Lacking 5-HT(2B) Activity.

作者信息

Chen Gang, Cho Sung Jin, Huang Xi-Ping, Jensen Niels H, Svennebring Andreas, Sassano Maria F, Roth Bryan L, Kozikowski Alan P

机构信息

Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (M/C781), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7230.

出版信息

ACS Med Chem Lett. 2011 Dec 8;2(12):929-932. doi: 10.1021/ml200206z. Epub 2011 Oct 10.

DOI:10.1021/ml200206z
PMID:22778800
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3390974/
Abstract

The 5-HT(2C) receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT(2C) receptor agonists. After expanding our structure-function library, we were able to combine our datasets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT(2B)/5-HT(2C) agonists, which has led to the identification of a highly selective 5-HT(2C) agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC(50) of 55 nM and no detectable agonism at the 5-HT(2B) receptor.

摘要

5-HT(2C)受体是寻求治疗多种人类疾病的新疗法中的一个有吸引力的药物靶点。我们之前开展了一项结构优化工作，已得到了一些强效且具有一定选择性的5-HT(2C)受体激动剂。在扩展我们的结构-功能库之后，我们能够合并我们的数据集，从而设计出选择性和效力得到提高的化合物。我们在此披露我们之前报道的5-HT(2B)/5-HT(2C)激动剂的结构优化情况，这已导致鉴定出一种高选择性5-HT(2C)激动剂，(+)-反式-[2-(2-环丙基甲氧基苯基)环丙基]甲胺盐酸盐，其EC(50)为55 nM，在5-HT(2B)受体上无可检测到的激动作用。

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