Synthesis and Pharmacological Activity of Morphine Epoxide Derivatives.

麻醉性镇痛药主要用于缓解疼痛，但其使用存在产生身体依赖性和有时心理依赖性的风险。目前还没有完全没有风险的有效治疗严重疼痛的药物。本课题组最近合成了吗啡的7，8-环氧化物。本课题旨在确定麻醉药物7，8-环氧化物的构效关系，分离其药理活性和不良反应（依赖性、耐受性等）。1.合成了去甲吗啡、去甲可待因、N-烯丙基去甲吗啡和N-烯丙基去甲可待因的7，8-环氧化物。它们具有良好的稳定性，可用于药理活性的研究.药理活性用大鼠尾压法测定了这些7，8-环氧化物的镇痛活性。所有测试的化合物剂量依赖性地表现出它们的活性。进一步发现，在吗啡骨架中引入7，8-环氧部分趋向于降低依赖性和耐受性的发展，并且N-烯丙基17，8-环氧化物比母体化合物具有更纯的麻醉拮抗作用。

The narcotic analgesic are employed primarily for the relief of pain, but their use entails the risk of producing physical and sometimes psycological dependence. There are as yet no agents effective against severe pain that are entirely free of the risk. Recently, our group has synthesized 7,8-epoxide of morphine. This compound has almost same analgesic activity compared with morphine, and much less dependence liability.Our Project is to confirm the structure-activity relationship of 7,8-epoxide of narcotic drugs and to separate the pharmacological activity and the adverse reaction ( dependency, tolerance, etc. ). 1. Synthesis7,8-epoxides of normorphine, norcodeine, N-allylnormorphine and N-allyl-norcodeine were synthesized. They have good enough stability to investigate their pharmacological activity.2. Pharmacological activityThe analgesic activity of these 7,8-epoxides was determined by the method of pressure stimuli on the rat tail. All the tested compounds dose-dependently exhibited their activity. Further it was found that the introduction of 7,8-epoxy moiety into morphine skeleton trends toward some decrease in dependency liability and in the development of tolerance, and N-ally17,8-epoxides have more pure narcotic antagonistic action than the parent compounds have.