Structure-activity relationships for 1-alkyl-3-(l-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors:: steric and electronic effects of naphthoyl substituents.: New highly selective CB2 receptor agonists
Structure-activity relationships for 1-alkyl-3-(l-naphthoyl)indoles at the cannabinoid CB1 and CB2 receptors:: steric and electronic effects of naphthoyl substituents.: New highly selective CB2 receptor agonists
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DOI：
10.1016/j.bmc.2004.09.050
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发表时间：
2005-01-03
影响因子：
3.5
通讯作者：
Martin, BR
中科院分区：
文献类型：
--
作者：
Huffman, JW;Zengin, G;Martin, BR
为了改善基于吲哚的CB 2大麻素受体配体，并为CB 1和CB 2受体开发SAR，制备了47种吲哚衍生物，并测定了它们的CB 1和CB 2受体亲和力。吲哚衍生物包括具有和不具有2-甲基取代基的1-丙基-和1-戊基-3-（1-萘甲酰基）吲哚。萘甲酰基取代基包括4-和7-烷基以及2-、4-、6-、7-甲氧基和4-乙氧基。这些取代基对受体亲和力的影响进行了讨论，并提出了构效关系。在这项工作的过程中，鉴定了三种新的高选择性CB 2受体激动剂，1-丙基-3-（4-甲基-1-萘甲酰基）吲哚（JWH-120）、1-丙基-2-甲基-3-（6-甲氧基-1-萘甲酰基）吲哚（JWH-151）和1-戊基-3-（2-甲氧基-1-萘甲酰基）吲哚（JWH-267）。GTP γ S测定表明JWH-151是CB 2的完全激动剂，而JWH-120和JWH-267是部分激动剂。对一组3-（4-丙基-1-萘甲酰基）吲哚、一组3-（6-甲氧基-1-萘甲酰基）吲哚和一对N-戊基-3-（2-甲氧基-1-萘甲酰基）吲哚进行了分子模拟和受体对接研究。对接的研究表明，这些化合物的CB 1受体的亲和力是一致的，其芳香堆积相互作用的CB 1受体的芳香族微域。(C)2004爱思唯尔有限公司保留所有权利。
In an effort to improve indole-based CB2 cannabinoid receptor ligands and also to develop SAR for both the CB1 and CB2 receptors, 47 indole derivatives were prepared and their CB1 and CB2 receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB2 receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPgammaS assays indicated that JWH-151 is a full agonist at CB2, while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB1 receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB1 receptor. (C) 2004 Elsevier Ltd. All rights reserved.