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首页> 外文期刊>Bioorganic and medicinal chemistry >Binding mode characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: Application of the 'message-address' concept in development of mu opioid receptor selective antagonists
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Binding mode characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: Application of the 'message-address' concept in development of mu opioid receptor selective antagonists

机译：通过停泊在阿片样物质受体晶体结构和定点诱变研究中的6α-和6β-N-杂环取代的纳曲胺衍生物的结合模式表征：“消息地址”概念在开发阿片类阿片受体选择性拮抗剂中的应用

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Highly selective opioid receptor antagonists are essential pharmacological probes in opioid receptor structural characterization and opioid agonist functional studies. Currently, there is no highly selective, nonpeptidyl and reversible mu opioid receptor antagonist available. Among a series of naltrexamine derivatives that have been designed and synthesized, two compounds, NAP and NAQ, were previously identified as novel leads for this purpose based on their in vitro and in vivo pharmacological profiles. Both compounds displayed high binding affinity and selectivity to the mu opioid receptor. To further study the interaction of these two ligands with the three opioid receptors, the recently released opioid receptor crystal structures were employed in docking studies to further test our original hypothesis that the ligands recognize a unique 'address' domain in the mu opioid receptor involving Trp318 that facilitates their selectivity. These modeling results were supported by site-directed mutagenesis studies on the mu opioid receptor, where the mutants Y210A and W318A confirmed the role of the latter in binding. Such work not only enriched the 'message-address' concept, also facilitated our next generation ligand design and development.
机译：高选择性阿片受体拮抗剂是阿片受体结构表征和阿片激动剂功能研究中必不可少的药理探针。当前，没有高选择性的非肽基和可逆的μ阿片样物质受体拮抗剂。在已设计和合成的一系列纳曲胺衍生物中，基于它们的体内和体外药理学特征，两种化合物NAP和NAQ先前已被确定为此目的的新型药物。两种化合物均显示出对μ阿片样物质受体的高结合亲和力和选择性。为了进一步研究这两个配体与三个阿片受体的相互作用，最近对接的阿片受体晶体结构被用于对接研究中，以进一步检验我们的原始假设，即配体识别涉及Trp318的μ阿片受体中的独特“地址”结构域有助于它们的选择性。这些建模结果得到了对阿片类阿片受体的定点诱变研究的支持，突变体Y210A和W318A证实了后者在结合中的作用。这些工作不仅丰富了“消息地址”的概念，还促进了我们下一代配体的设计和开发。

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