内源性大麻素水解酶NAAA是一种极具吸引力的新型药物开发靶标，通过抑制NAAA活性可以阻止内源性活性小分子PEA灭活，激活核受体PPAR-α等产生强效的抗神经痛作用。然而现有的NAAA抑制剂存在活性低、体内稳定性差等缺点，无法应用于整体动物，对全面了解NAAA-PEA途径在体内的作用机制亦缺乏帮助。课题组在前期研究中发现，一类氨基甲酰尿嘧啶类化合物对NAAA具有良好的抑制活性，且体内稳定性高。由此，本项目在初步构效总结基础上，拟对该类结构的氢键受体、疏水片段以及各基团链接方式进行改造，以蛋白、细胞、整体动物等模型对其活性进行立体评价，结合计算机辅助分子对接实验设计结构优化方案，合成筛选出高效、低毒、特异性强的新型抗神经痛类先导化合物，为深入研究NAAA-PEA途径在病理生理过程中的作用机制提供有效的科学工具，为开发具有自主知识产权的新药提供扎实的理论基础。

N-acylethanolamine-hydrolyzing acid amidase (NAAA) is an attractive new drug target involved in biological deactivation of N-palmitoylethanolamide (PEA), which exerts analgesic effects through the activation of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-α). However, the NAAA inhibitors reported showed low-activity and poor- stability in vivo, which couldn't be applied to the whole animals. A comprehensive understanding of the NAAA-PEA pathway mechanism in vivo is not clearly. To develop selective and potent NAAA inhibitors, we designed and synthesized a series of derivatives of carbamoyl uracil, which showed high inhibition on NAAA activity. Structure-activity relationship (SAR) studies resulted in the structural modification of hydrogen bond acceptor, hydrophobic fragment and connection chain. The selective and potent NAAA inhibitors would be designed and synthesized by activity screening models of protein, cell and whole animals. Computer-aided molecular docking experiments would be used in this project. The carbamoyl uracil compounds may be promising analgesic agents, which could provide effective scientific tools for the mechanism research of NAAA-PEA pathway.