Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands
Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands
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DOI：
10.1016/j.bmcl.2013.12.021
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发表时间：
2014-01-15
影响因子：
2.7
通讯作者：
Mosberg, Henry I.
中科院分区：
文献类型：
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作者：
Bender, Aaron M.;Clark, Mary J.;Mosberg, Henry I.
在这封信中，我们描述了一系列基于四氢喹啉1的4-取代哌啶和哌嗪化合物，四氢喹啉1是一种对u阿片受体(MOR)和增量阿片受体(DOR)显示出平衡的低纳摩尔结合亲和力的化合物。我们已经证明，通过改变该位置侧链的长度和柔性轮廓，两个受体的结合亲和力都得到了显著的提高。此外，这里描述的几个化合物在MOR中表现出良好的效果，同时表现出DOR拮抗作用。MOR激动剂/DOR拮抗剂在减少选择性MOR激动剂表现出的负面副作用方面表现出了希望，即发展依赖性和耐受性。(C)2013爱思唯尔有限公司。保留所有权利。
In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance. (C) 2013 Elsevier Ltd. All rights reserved.