Organic Chemistry Department, Southern Research Institute, Birmingham, AL 35205, USA.
J Med Chem. 2012 Oct 11;55(19):8350-63. doi: 10.1021/jm300686p. Epub 2012 Sep 27.
In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.
在寻找具有混合功能活性的阿片样物质配体的过程中，合成并评价了一系列在 C-14 位具有烷氧基或酰氧基的 5'-(4-氯苯基)-4,5α-环氧吡啶吗啡烷。在该系列中，配体的亲和力和功能活性受 C-14 位取代基的性质以及 N-17 位取代基的影响。在 N-甲基吡啶吗啡烷的 C-14 位上引入 3-苯丙氧基时，得到双重 MOR 激动剂/DOR 激动剂 17h，而在 N-环丙基甲基吡啶吗啡烷上引入时，得到 MOR 激动剂/DOR 拮抗剂 17d。有趣的是，与 17h 相比，17d 在表达 MOR 和 DOR 的细胞中长时间治疗后不会产生耐受或依赖效应。此外，与吗啡相比，17d 在重复给药时表现出明显降低的镇痛耐受，这支持了这样一种假设，即具有 MOR 激动剂/DOR 拮抗剂功能活性的配体可能成为新型的无耐受、无依赖和相关副作用的镇痛药。
