Research Progress of Opioid Receptor Antagonist Used in Clinic

作者: 王 乔 , 舒 浪 :武汉工程大学化工与制药学院,湖北 武汉; 刘 明 :首都师范大学生命科学学院,北京; 邵开元 , 胡文祥 :北京神剑天军医学科学院,北京;

关键词: 阿片受体一般阿片受体拮抗剂外周阿片受体拮抗剂Opioid Receptor General Opioid Receptor Antagonist Peripheral Opioid Receptor Antagonist


Abstract: Opioid receptor antagonists are a class of specifically drugs for antagonizing the opioid on opioid receptors, thereby reducing or reversing the analgesic activity of narcotic agonists. Antagonists can also eliminate breathing suppression, gastrointestinal disorders and other side effects caused by the use of the agonist. Antagonists are used in clinic as side effects and coma antidote arising from excessive usage of analgesic. This paper summarizes several common clinical types of opioid receptor antagonists and clinical applications. In recent years, antagonists have achieved greater development, but there are still some deficiencies; further research of opioid receptor antagonists is needed to get more competitive, safer and simpler novel μ opioid receptor-specific antagonist, for better use in clinical treatment.

文章引用: 王 乔 , 舒 浪 , 刘 明 , 邵开元 , 胡文祥 (2015) 临床用阿片受体拮抗剂研究进展。 有机化学研究, 3, 9-15. doi: 10.12677/JOCR.2015.31002


[1] Huxtable, R.J. and Schwarz, S.K. (2001) The isolation of morphine. Molecular Interventions, 1, 189-191.

[2] Eddy, N.B. and May, E.L. (1973) The search for a better analgesic. Science, 181, 407-414.

[3] Gates, M. and Tschudi, G. (1956) The synthesis of morphine. Journal of the American Chemical Society, 78, 1380- 1393.

[4] Pert, C.B., Pas-ternak, G.W. and Snyder, S.H. (1973) Opiate agonists and antagonists discriminated by receptor binding in brain. Science, 182, 1359-1361.

[5] Simon, E.J., Hiller, J.M. and Edelman, I. (1973) Stereospecific binding of the potentnarcotic analgesic (3H) etorphine to rat-brain homogenate. Proceedings of the National Academy of Sciences of the United States of America, 70, 1947- 1949.

[6] Terenius, L. (1973) Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacologica et Toxicologica (Copenh), 32, 317-320.

[7] Kieffer, B.L., Befort, K. and Gavériaux-Ruff, C. (1994) The delta-opioid receptor: Isolation of a cDNA by expression cloning and pharmacological characterization. Proceedings of the National Academy of Sciences of the United States of America, 91, 1193.

[8] Evans, C.J., Keith, D.E. and Morrison Jr, H. (1992) Cloning of a delta opioid receptor by functional expression. Science, 258, 1952-1955.

[9] Wang, J.B. and Eppler, C.M. (1993) μ opiate receptor: cDNA cloning and expression. Proceedings of the National Academy of Sciences USA, 90, 10230-10234.

[10] Chen, Y., Mestek, A. and Liu, J. (1993) Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Molecular Pharmacology, 44, 8-12.

[11] Meng, F., Xie, G.X., Thompson, R.C., Mansour, A., Goldstein, A., Watson, S.J. and Akil, H. (1993) Cloning and pharmacological characterization of a rat kappa opioid receptor. Proceedings of the National Academy of Sciences of the United States of America, 90, 9954-9958.

[12] Yasuda, K., Raynor, K., Kong, H., Breder, C.D., Takeda, J., Reisine, T. and Bell, G.I. (1993) Cloning and functional comparison of kappa and delta opioid receptors from mouse brain. Proceedings of the National Academy of Sciences of the United States of America, 90, 6736-6740.

[13] Manglik, A., Kruse, A.C., Kobilka, T.S., Thian, F.S., Mathiesen, J.M., Sunahara, R.K., et al. (2012) Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature, 485, 321-326.

[14] Ewenstein, M.J., Lane, P. and Gardens, K. (1966) Morphine derivative. US Patent No. 3254088.

[15] 郑优丽, 卢美艳, 王星海, 盛韦, 仇缀百 (2008) 纳洛酮的合成工艺改进. 复旦学报(医学版), 6, 888-890.

[16] 刘亚琴, 高永良 (2005) 纳洛酮的研究进展. 中国新药杂志, 4, 403-407.

[17] Blumberg, H., Dayton, H.B. and George, M. (1961) N-allylnoroxymorphone: A potent narcotic antagonist. Federation Proceedings, 20, 311.

[18] 许喜生, 蒋丽萍, 胡永才, 欧阳才生 (2005) 纳洛酮抗烧伤休克治疗体会. 湘南学院学报, 3, 30-31.

[19] 林时辉, 刘琼 (2010) 纳洛酮联合醒脑静抢救急性重度酒精中毒研究. 重庆医科大学学报, 7, 1077-1080.

[20] 许玉霞 (2001) 纳洛酮治疗重症镇静催眠药中毒30例. 山东医药, 16, F004.

[21] 孙彦辉, 蒙和, 张亚卓, 李庆国, 孙梅珍, 王红云, 何乐 (2004) 盐酸纳洛酮治疗大鼠急性颅脑损伤的药效学观察. 中华神经外科杂志, 2, 167-169.

[22] Goodman, A.J., Bourdonnec, B.L. and Dolle, R.E. (2007) Mu opioid receptor antagonists: Recent developments. ChemMedChem, 2, 1552-1570.

[23] 杜玍妮, 高永良, 吴祥根 (2006) 纳美芬的研究进展. 中国医院药学杂志, 9, 1141-1143.

[24] 任爱国 (1996) 纳美芬的药理作用及临床应用概况. 解放军医学情报, 2, 66-68.

[25] Glass, P.S., Jhaveri, R.M. and Smith, L.R. (1994) Comparison of potency and duration of action of nalmefene and naloxone. Anesthesia & Analgesia, 78, 536-541.

[26] 朱海兵, 温预关, 黄河清 (2008) 盐酸纳美芬的药理作用及临床应用. 广州医药, 4, 1-4.

[27] Vallejo, R., de Leon-Casasola, O. and Benyamin, R. (2004) Opioid therapy and immunosuppression: A review. American Journal of Therapeutics, 11, 354-365.

[28] Linn, A.J. and Steinbrook, R.A. (2007) Peripherally restricted μ-opioid receptor antagonists: A review. Techniques in Regional Anesthesia and Pain Management, 11, 27-32.

[29] Yuan, C.S., Foss, J.F., O’Connor, M., Toledano, A., Roizen, M.F. and Moss, J. (1996) Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: A double-blind randomized placebo- controlled trial. Clinical Pharmacology & Therapeutics, 59, 469-475.

[30] Rauck, R.L. (2013) Treatment of opioid-induced constipation: Focus on the peripheral μ-opioid receptor antagonist methylnaltrexone. Drugs, 73, 1297-1306.

[31] Portenoy, R.K., Thomas, J., Moehl-Boatwright, M.L., Tran, D., Galasso, F.L., Stambler, N., et al. (2008) Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: A double-blind, randomized, parallel group, dose-ranging study. Journal of Pain and Symptom Management, 35, 458-468.

[32] Brown, D.R. and Goldberg, L.I. (1985) The use of quaternary narcotic antagonists in opiate research. Neuropharmacology, 24, 181-191.

[33] DeHaven-Hudkins, D.L., DeHaven, R.N., Little, P.J. and Techner, L.M. (2008) The involvement of the μ-opioid receptor in gastrointestinal pathophysiology: Therapeutic opportunities for antagonism at this receptor. Pharmacology & Therapeutics, 117, 162-187.

[34] Thomas, J., Karver, S., Cooney, G.A., Chamberlain, B.H., Watt, C.K., Slatkin, N.E., et al. (2008) Methylnaltrexone for opioid-induced constipation in advanced illness. New England Journal of Medicine, 358, 2332-2343.

[35] 胡文祥, 刘明 (2014) 阿片受体分子药学. 化学工业出版社, 北京.

[36] Yuan, C.S., Foss, J.F., O’Connor, M., et al. (2000) Effects of enteric-coated methylnaltrexone in preventing opioid- induced delay in oral-cecal transit time. Clinical Pharmacology & Therapeutics, 67, 398-404.

[37] 杨学林 (2008) 爱维莫潘. 中国药物化学杂志, 6, 479-480.

[38] 岳向阳, 史爱欣, 傅得兴, 王唯红, 胡欣 (2009) 爱维莫潘的药理与临床评价. 中国新药杂志, 19, 1819-1822.

[39] Paulson, D.M., Kennedy, D.T., Donovick, R.A., Carpenter, R.L., Cherubini, M., Techner, L., et al. (2005) Alvimopan: An oral, peripherally acting, μ-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction—A 21-day treatment-randomized clinical trial. The Journal of Pain, 6, 184-192.

[40] Rosow, C.E., Gomery, P., Chen, T.Y., Stefanovich, P., Stambler, N. and Israel, R. (2007) Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone. Clinical Pharmacology & Therapeutics, 82, 48- 53.

[41] Taylor, R., Pergolizzi, J.V., Porreca, F. and Raffa, R.B. (2013) Opioid antagonists for pain. Expert Opinion on Investigational Drugs, 22, 517-525.

[42] Yuan, C.S. and Israel, R.J. (2006) Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects. Expert Opinion on Investigational Drugs, 15, 541-552.

[43] Schmidt, W.K. (2001) Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. The American Journal of Surgery, 182, S27-S38.