阿片受体有μ、δ和κ 三种亚型, 传统阿片类药物选择性作用于μ受体，镇痛效果好但有呼吸抑制、依赖性及成瘾性等副作用。阿片受体亚型的激活效应可部分相互抵消，理想镇痛药应具有δ/μ/κ三重激活作用且受体活性δ>μ>κ以最大限度消除副作用。我们的团队及合作者在前期研究中发现结构新颖的噻吩芳基哌嗪类化合物具有δ/μ/κ受体三重激动剂，且镇痛作用强于吗啡，呼吸抑制和依赖性明显减弱，但口服生物利用度不佳，仅能注射给药。以噻吩芳基哌嗪活性骨架为基础，本项目拟研究激动剂与三种受体的作用模式，设计并合成新的具备δ/μ/κ三重激动活性的噻吩芳基哌嗪及哌啶类化合物，同时对其生物利用度进行预测和大鼠体内检测，选择体外活性高而且生物利用度好的候选化合物做大鼠的镇痛评价。以期得到可口服给药的三重激动剂，并为今后确定最佳的δ/μ/κ受体活性比例及研制副作用小的新型镇痛药物提供候选化合物。

There are μ, δ and κ subtypes for opioid receptors. The traditional opioid drugs selectively target the μ receptor，which show good analgesic effect nevertheless with strong side effects such as respiratory depression, dependence and so on. The activation effect of different subtypes of opioid receptor can be partially offset with each other. The ideal analgesic should active all δ, μ, κ receptors and the receptor activity should be δ> μ> κ in order to minimize the side effects. Our team and collaborators have found that thiophenyl aryl piperazine δ/μ/κ receptor triple agonist had analgesic effect stronger than morphine and its respiratory depression as well as dependence were significantly reduced. Although the safety index was significantly higher than morphine and fentanyl, but the oral biology is poor and they are only suitable for injection. Based on structure of thiophenyl aryl piperazine, we would study the interaction mode between the agonist and δ/μ/κ receptor, design and synthesize new thiophenyl aryl piperazine and piperidine drugs with potential δ/μ/κ triplet activity. The bioavailability will be predicated and evaluated before testing the ability of analgesic effect using mouse. It is expected that δ/μ/ Κ triple agonist would lay the foundation for determination of the optimal ratio of δ/μ/ κ receptor activity and the development of new analgesic drugs with low side effects for the future.