Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists.
Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists.
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DOI：
10.1021/jm801272c
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发表时间：
2009-03-12
影响因子：
7.3
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Li G;Aschenbach LC;Chen J;Cassidy MP;Stevens DL;Gabra BH;Selley DE;Dewey WL;Westkaemper RB;Zhang Y
阿片受体选择性拮抗剂是研究阿片受体结构和阿片受体激动剂功能的重要药物探针。迄今为止，还没有一种非肽基、高选择性和可逆的μ阿片受体（莫尔）拮抗剂。在此基础上，设计并合成了一系列新颖的纳洛酮胺衍生物。其中，两个化合物被确定为铅的基础上，在体外和体内试验的结果。它们都显示出对莫尔的高结合亲和力（Ki = 0.37和0.55 nM）。化合物6（NAP）对莫尔的选择性超过δ受体（DOR）的700倍，对κ受体（KOR）的选择性超过150倍。化合物9（NAQ）对莫尔的选择性超过DOR的200倍，对KOR的选择性约为50倍。因此，这两种新的配体将作为进一步开发更有效和选择性的莫尔拮抗剂的先导。
Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible μ opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (Ki = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the δ receptor (DOR) and more than 150-fold selectivity over the κ receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.
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影响因子：
7.3
作者：
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通讯作者：
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作者：
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