高效、低副作用的镇痛新药研发一直备受关注，近年来发现大麻对部分慢性痛的疗效优于吗啡且依赖性相对低，已成为镇痛新药研究中的“热点”。然而，传统大麻药物因神经精神类副作用而限制了其临床应用范围，因此急需解决此难题。我们前期文章报道：大麻与神经肽FF相关肽的联合使用能降低大麻有效镇痛剂量，且无镇痛耐受出现，减轻了便秘副作用，并发现大麻肽VD-Hpα可作为新型大麻镇痛新药研究的模板分子。近期预实验发现，基于大麻肽和神经肽FF相关肽化学构建的大麻/神经肽FF受体的多靶点分子可介导无耐受镇痛作用。本项目将利用“分子嵌合”策略，基于内源性神经肽构建一系列大麻/神经肽FF受体的多靶点分子，筛选出无耐受镇痛作用的高效分子，并全面评价其镇痛药效和大麻样副作用，以期获得高效、低副作用镇痛新药的先导化合物，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、药理学和神经科学为一体的多学科交叉研究。

The novel analgesic drugs with fewer side effects are gaining increasing recognition as a widespread and costly medical research. In contrast to morphine, cannabinoids could produce more efficient treatment in the chronic, persistent pain and limited physical dependence. Therefore, cannabinoids have become a "hot spot" of analgesics studies. However, the clinical usage of the classical cannabinoid drugs is limited because of their neuropsychological side effects. Our previous papers reported that the antinociception of combination of cannabinoids and neuropeptide FF related peptides was more potent than that of cannabinoid agonist given alone, and the combination treatment produced nontolerance-forming antinociception and weaker inhibition of gastrointestinal transit. Meanwhile, our recent results have shown that VD-Hpαcan be used as the chemical template for the research of novel cannabinoid analgesics. Recently, our preliminary tests demonstrated that the multi-target compounds towards cannabinoid/neuropeptide FF receptors basing on cannabinoid peptides and neuropeptide FF related peptides could induce nontolerance-forming analgesic effects. In the present studies, by using the "chimeric molecular" strategy, a series of multi-target compounds towards cannabinoid/neuropeptide FF receptors basing on endogenous peptides are designed and synthesized. Sequentially, the potent multi-target ligands targeting both opioid and NPFF receptors which can induce nontolerance-forming analgesia are selected. Finally, the pharmacological functions and the side effects of these potent ligands are also evaluated. These studies are expected that in future these ligands may be developed as the lead compounds of clinic pain relievers with limited 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 and neuroscience.