Synthesis and structure-activity relationships of a series of pyrrole cannabinoid receptor agonists
Synthesis and structure-activity relationships of a series of pyrrole cannabinoid receptor agonists
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DOI：
10.1016/s0968-0896(03)00413-9
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Piomelli, D
中科院分区：
文献类型：
--
作者：
Tarzia, G;Duranti, A;Piomelli, D
我们设计合成了一系列吡咯类化合物，旨在研究非经典激动剂与CB1和CB2受体结合的构效关系(SAR)。两种含吡咯的大麻素激动剂JWH-007和JWH-161的叠加使我们能够确定吡咯核的第1、3和4位位置有待进一步研究。我们制备了1-烷基-2，5-二甲基-3，4-取代吡咯10a-e，11a-d，17，21，25和四氢吲哚15，并评价了它们与大麻素受体结合和激活的能力。在这组化合物中值得注意的是4-溴吡咯11a，它对CB1和CB2受体的亲和力与Win-55,212-2等特性良好的杂环大麻仿制药的亲和力相当；酰胺25，虽然对大麻受体有中等亲和力，但表明3-萘基，通常存在于吲哚和吡咯大麻仿制药中，可以被替代部分取代；以及化合物10d，11d，显示CB1部分激动剂性质。(C)2003爱思唯尔有限公司。保留所有权利。
We designed and synthesized a series of pyrrole derivatives with the aim of investigating the structure-activity relationship (SAR) for the binding of non-classical agonists to CB1 and CB2 cannabinoid receptors. Superposition of two pyrrole-containing cannabinoid agonists, JWH-007 and JWH-161, allowed us to identify positions 1, 3 and 4 of the pyrrole nucleus as amenable to additional investigation. We prepared the 1-alkyl-2,5-dimethyl-3,4-substituted pyrroles 10a-e, 11a-d, 17, 21, 25 and the tetrahydroindole 15, and evaluated their ability to bind to and activate cannabinoid receptors. Noteworthy in this set of compounds are the 4-bromopyrrole 11a, which has an affinity for CB1 and CB2 receptors comparable to that of well-characterized heterocyclic cannabimimetics such as Win-55,212-2; the amide 25, which, although possessing a moderate affinity for cannabinoid receptors, demonstrates that the 3-naphthoyl group, commonly present in indole and pyrrole cannabimimetics, can be substituted by alternative moieties; and compounds 10d, 11d, showing CB1 partial agonist properties. (C) 2003 Elsevier Ltd. All rights reserved.