STEREOSPECIFIC SYNTHESIS OF 6-BETA-HYDROXY METABOLITES OF NALTREXONE AND NALOXONE
STEREOSPECIFIC SYNTHESIS OF 6-BETA-HYDROXY METABOLITES OF NALTREXONE AND NALOXONE
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DOI：
10.1021/jm00239a010
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发表时间：
1975-01-01
影响因子：
7.3
通讯作者：
BLUMBERG, H
中科院分区：
文献类型：
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作者：
CHATTERJIE, N;INTURRISI, CE;BLUMBERG, H
在水性碱性介质中，用甲脒亚磺酸将麻醉拮抗剂纳曲酮(1a)和纳洛酮(2a)分别立体定向地还原为相应的6J-羟基差向异构体1b和2b。获得的反应产物没有检测到数量的6a差向异构体1c和2c。产物1b和2b的产率分别为88.5%和40%，并通过光谱方法进行了表征。与1a和2a相比，立体特异性还原产物1b和2b及其6a差向异构体1c和2c在小鼠中作为麻醉拮抗剂的效力均显着降低。只有 lc 和 2c 也具有抗伤害活性。麻醉拮抗剂如纳曲酮 (la) 和纳洛酮 (2a) 阻断麻醉剂产生欣快感和产生依赖性作用的能力构成了使用这些药物治疗阿片依赖的药理学基础。与纳洛酮相比，纳曲酮在实验室啮齿动物1·2 和人类中被发现更有效且拮抗作用持续时间更长。 3 此外，纳曲酮对于人体来说是一种有效的拮抗剂，口服剂量为 30-50 毫克/天，而纳洛酮的等效口服剂量要大得多（高达 3000 毫克/天）。 3, 4 纳洛酮在人体中的主要代谢物是 3-葡萄糖-
The narcotic antagonists naltrexone (la) and naloxone (2a) were stereospecifically reduced to the corresponding 6J-hydroxy epimers lb and 2b, respectively, with formamidinesulfinic acid in an aqueous alkaline medium. The reaction products were obtained with no detectable quantity of the 6a epimers lc and 2c. The products lb and 2b were formed in yields of 88.5 and 40%, respectively, and characterized by spectral methods. Compared to la and 2a, the stereospecific reduction products lb and 2b and their 6a epimers lc and 2c are all significantly less potent as narcotic antagonists in mice. Only lc and 2c alsopossess antinociceptive activity.The ability of narcotic antagonists such as naltrexone (la) and naloxone (2a) to block the euphorigenic and dependence producing effectsof narcotics forms the pharma-cologic basis for the use of these drugs in the treatment of opiate dependence. Compared to naloxone, naltrexone has been found to be more potent and to have a longer duration of antagonist action in laboratory rodents1· 2 and man. 3 In addition, naltrexone is an effective antagonist in man at oral doses of 30-50 mg/day, while an equieffective oral dose of naloxone would be much larger (up to3000 mg/day). 3, 4 In man the major metabolite of naloxone is the 3-glucu-