NAAA是一种选择性作用于外周神经系统的新型镇痛类药物靶标，极具关注力。然而现有的NAAA抑制剂存在活性低、体内稳定性差等缺点，无法应用于系统给药，对全面了解NAAA-PEA途径的镇痛机制亦缺乏帮助。在前期研究中，我们发现以噁唑烷酮为亲水性头部的一类化学结构对NAAA抑制活性高、选择性好且在生物环境中稳定。更多构效研究表明，噁唑烷酮2位增加亲水性取代基团、调整疏水区相对空间位置、提高连接桥刚性可大幅度提高其活性及选择性。本项目拟采用合成生物学手段建立高通量体外筛选模型、化学空间分析法构建药效团及其连接方式、片段药物设计法理性设计匹配性能良好的疏水区，以蛋白、细胞、整体动物多层次药效及副作用评价筛选体系结合柔性分子模拟对接实验总结构效关系，对噁唑烷酮酰亚胺结构进行进一步优化，发现新型抗神经性疼痛活性强、稳定性好，且克服中枢依赖性的先导化合物。

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 molecular mechanism undergone the interaction between NAAA inhibitors and NAAA target are still unclear as current classic NAAA inhibitors showed low-activity and instability in vivo, which limited their medical applications. Therefore, it is important to develop the new compounds targeted human NAAA protein and evaluate their pharmacologic properties. We reported that oxazolidinone derivative, showed a significant inhibition on NAAA in vivo as well as in vitro. Base on our previous data, we will design and synthesize a series of oxazolidinone derivatives according structure-activity relationship (SAR) studies, in which interpret the structural modifications of hydrogen bond acceptor, hydrophobic fragment and carbon chain of oxazolidinone compound. Assistant by computer-aided molecular docking methodology, we will obtain the selective, potent NAAA inhibitors that will be evaluated their pharmacology properties by using enzymatic screening, cell-base activity screening, and in vivo pain/inflammation animal models. This project crosses the multiple disciplines including computational chemistry, synthetic chemistry, molecular biology, and pharmacology. The aim of project is going to develop the promising analgesic drug targeted human NAAA and provide effective tools for drug discovery platform.