Yuan Yunyun, Zaidi Saheem A, Stevens David L, Scoggins Krista L, Mosier Philip D, Kellogg Glen E, Dewey William L, Selley Dana E, Zhang Yan
Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
Bioorg Med Chem. 2015 Apr 15;23(8):1701-15. doi: 10.1016/j.bmc.2015.02.055. Epub 2015 Mar 6.
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 Ca(2+) 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，并对其进行了药理学表征，以研究它们在μ阿片受体(MOR)上的构效关系。竞争结合试验表明，两原子间隔基和芳香侧链对MOR选择性最为理想。同时，异喹啉环1'-和/或4'-位的取代基保持或提高了对κ阿片受体的MOR选择性，同时对δ阿片受体仍具有20倍以上的MOR选择性。相比之下，异喹啉环6'-和/或7'-位的取代降低了MOR选择性以及MOR效能。在这一系列配体中，化合物11在温水甩尾试验中与吗啡同时给药时表现为拮抗剂，与纳曲酮相比，在植入吗啡的小鼠中产生的戒断症状不那么明显。化合物11还拮抗了DAMGO诱导的细胞内Ca(2+)增加。对11在三种阿片受体中的分子动力学模拟研究表明，6'-硝基的取向在受体的不同“结合位点”结构域中存在显著差异，并且在观察到的结合亲和力和选择性中起关键作用。总的来说，目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有价值的见解。
