Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes
Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes
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DOI：
10.1016/j.bmc.2010.05.017
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发表时间：
2010-07-01
影响因子：
3.5
通讯作者：
Schetz, John A.
中科院分区：
文献类型：
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作者：
Cummings, David F.;Canseco, Diana C.;Schetz, John A.
开发区分临床上相关的5-HT2A和5-HT2C 5-HT2C受体亚型的配体一直是具有挑战性的，因为它们的序列具有很高的同源性。以往的研究表明，一种从海绵中分离出来的天然产物对5-HT2C的选择性高于5-HT2A受体亚型。我们的目标是探索基于海藻毒素天然产物药效团的衍生物的5-HT2A/2C受体结构与亲和力的关系。合成、纯化并测定了20个海绵体蛋白衍生物与克隆的人5-羟色胺5-羟色胺受体亚型5-HT1A、5-HT2A和5-HT2C的亲和力。该系列中的四个化合物对5-HT2A或5-HT2C受体有30倍的选择性。化合物(E)-5-((5，6-二氯-1H-吲哚-3-基)methylene)-2-imino-1，3-dimethylimidazolidin-4-one(UNT-TWU-22，16)对5-HT2C受体亚型的选择性约为2100倍：对5-HT2C受体亚型的亲和力为46 nM，对5-HT1A或5-HT2A受体亚型的亲和力为零。控制5-HT2A或5-HT2C受体亚型选择性的两个最重要的因素是咪唑烷酮环上的R1、R3-烷基化反应和Aplysinopsin药效团吲哚环上卤素的类型和数量。(C)2010爱思唯尔有限公司。保留所有权利。
Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl) methylene)-2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1,R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore. (C) 2010 Elsevier Ltd. All rights reserved.