吗啡等阿片类镇痛药虽然已被广泛应用于临床，但其耐受、成瘾、便秘和呼吸抑制等副作用限制了其应用范围。近年来发现阿片类双功能分子可介导无耐受的镇痛活性，因此在高效、低副作用的镇痛药物研发中备受关注，但双功能配体的化学构建及其无耐受镇痛的作用机制仍不清楚。本项目首次引入了具有阿片调节功能的神经肽FF（NPFF）系统，拟结合最新的神经肽构效关系研究进展，设计和合成两类全新的阿片/NPFF受体双功能肽类配体，即嵌合型和二价型的双功能分子，并化学筛选出无耐受镇痛活性的高效配体。进一步，全面地评价高效配体在各种慢性痛模型中的药理学功能及其阿片样副作用。同时，以高效的双功能配体为药理学工具，从分子、细胞和整体动物等水平来探讨其无耐受镇痛作用的机制，以期获得高效且低副作用镇痛药的先导化合物，并为临床疼痛治疗提供新策略和新思路。这是一项集药物化学、多肽化学、药理学、神经科学和生物学为一体的多学科交叉研究。

The opioid drugs including morphine are currently used to alleviate pain in patients despite the fact that these drugs elicit strong side effects, such as constipation, respiratory depression, development of tolerance and addiction. The recent studies have shown that the bifunctional ligands could induce nontolerance-forming analgesic effects. However, the strategies for design of these ligands are fewer reported. Moreover, the detailed mechanisms underlying their pain regulation are still not clear. In the present studies, the opioid-modulating peptide, neuroeptide FF (NPFF) is firstly introduced to the design of opioid bifunctional molecules, and two types of novel peptide ligands for opioid and NPFF receptors, including the chimeric and bivalent peptide ligands, are designed and synthesized. Followingly, the potent bifunctional ligands targeting both opioid and NPFF receptors are selected. Additionally, the side effects and the pharmacological functions of these potent ligands are also evaluated in chronic pain conditions. Finally, these bifunctional ligands are used as the pharmacological tools to investigate the mechanisms of their nontolerance-forming analgesia. These studies are expected that in future these ligands may be developed as the lead compounds of clinic pain relievers with fewer side effects. It might be helpful to pave the way for a new strategy for pain management. The present project is an interdisciplinary research in medicinal chemistry, peptide chemistry, pharmacology, neuroscience and biology.