发现蛋白别构调节剂药物为近年来新药创制的重大突破。钩吻素子具有显著抗神经病理性痛(NP)作用，成药特征良好，其作用机制亟待深入研究。TSPO蛋白可成为治疗NP的重要靶点。我们前期工作提示，钩吻素子可能是TSPO正性别构调节剂，但有待确证。鉴此，本项目拟采用药理学、化学生物学技术手段，首先在分子水平从增强TSPO正位配体亲和力角度，探讨钩吻素子对TSPO的别构调节；进而在细胞模型上，论证钩吻素子可否增强TSPO正位配体功能的效价或效能；最后在大鼠NP模型上，分析钩吻素子可否增强TSPO激动剂的镇痛效应，从多个角度较为全面阐释钩吻素子对TSPO的别构调节作用，确证其为TSPO正性别构调节剂。本研究将为创制新药钩吻素子奠定理论基础，为开发新型TSPO别构调节剂药物提供科学依据，并为防治NP新药研发提供新的药物作用方式。

The discovery of allosteric modulator drugs of proteins is an important breakthrough in the field of new medicine development. Koumine, a new drug candidate, possesses the significant antagonistic effect on neuropathic pain, but its deep understanding of mechanisms is to be undertaken urgently. The 18 kDa translocator protein (TSPO) may become a new important therapeutic target on neuropathic pain. Our preliminary study has demonstrated that koumine may be a positive allosteric modulator of protein TSPO, which needs further confirmation. Based on this finding, the present project is going to confirm that koumine is a positive allosteric modulator of TSPO by using approaches about pharmacology and chemical biology. Firstly, we are going to explore how koumine enhances the affinity of TSPO interacting with its orthosteric ligands including TSPO endogenous ligands. Subsequently, we will investigate whether koumine could promotes the efficacy or potency of function of TSPO orthosteric ligands in cell models. In expect of confirming that koumine is a positive allosteric modulator of protein TSPO, finally, we are plan to study the cooperative effects of koumine and TSPO agonists on neuropathic pain in models of rats. This project is undertaken to establish foundation for proposing the new efficiency of koumine against neuropathic pain, and provide a scientific basis for developing new allosteric modulator drugs of TSPO. It will also provide the new mode of drug action for the development of new therapeutic drugs against neuropathic pain.