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.

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 阿片类药物中的构效关系受体（MOR）。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Ca ²⁺增加。对三种阿片受体中的11 个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”域中显着变化，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。