14-Alkoxy- and 14-Acyloxypyridomorphinans: 渭 Agonist/未 Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects

详细信息    查看全文

• 作者：Subramaniam Ananthan ; Surendra K. Saini ; Christina M. Dersch ; Heng Xu ; Nicholas McGlinchey ; Denise Giuvelis ; Edward J. Bilsky ; Richard B. Rothman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8350-8363
• 全文大小：490K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

In the search for opioid ligands with mixed functional activity, a series of 5鈥?(4-chlorophenyl)-4,5伪-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.