Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan analogues as opioid receptor ligands.
Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan analogues as opioid receptor ligands.
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DOI：
10.1016/j.bmc.2015.02.055
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发表时间：
2015-04-15
影响因子：
3.5
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Yuan Y;Zaidi SA;Stevens DL;Scoggins KL;Mosier PD;Kellogg GE;Dewey WL;Selley DE;Zhang Y
合成了一系列 17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6α-(异喹啉-3'-甲酰胺基)吗啡喃 (NAQ) 类似物并进行药理学表征，以研究它们在 mu 阿片受体 (MOR) 上的结构-活性关系。竞争结合测定表明，双原子间隔基和芳香族侧链对于 MOR 选择性是最佳的。同时，异喹啉环1'-和/或4'-位的取代保留或改善了对κ阿片受体的MOR选择性，同时仍具有比δ阿片受体高20倍的MOR选择性。相反，异喹啉环 6'-和/或 7'-位的取代降低了 MOR 选择性以及 MOR 功效。在这一系列配体中，化合物11在温水尾浸试验中用吗啡激发时充当拮抗剂，并且与吗啡丸状小鼠中的纳曲酮相比产生较不显着的戒断症状。化合物11还拮抗DAMGO诱导的细胞内Ca2+增加。对三种阿片受体中的 11 种阿片受体的分子动力学模拟研究表明，6'-硝基基团的方向在受体的不同“地址”域中存在显着差异，并且在观察到的结合亲和力和选择性中发挥着至关重要的作用。总的来说，当前的研究结果为基于 NAQ 的 MOR 选择性配体的未来开发提供了宝贵的见解。
A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′-and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6’-nitro group varied significantly in the different “address” domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.
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影响因子：
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