P2X7 receptor (P2X7R) is an ATP-gated ion-channel with potential therapeutic applications. In this study, we prepared and searched a series of 1,4-naphthoquinones derivatives to evaluate their antagonistic effect on both human and murine P2X7 receptors. We explored the structure-activity relationship and binding mode of the most active compounds using a molecular modeling approach. Biological analysis of this series (eight analogues and two compounds) revealed significant in vitro inhibition against both human and murine P2X7R. Further characterization revealed that AN-03 and AN-04 had greater potency than BBG and A740003 in inhibiting dye uptake, IL-1β release, and carrageenan-induced paw edema in vivo. Moreover, we used electrophysiology and molecular docking analysis for characterizing AN-03 and AN-04 action mechanism. These results suggest 1,4-napthoquinones, mainly AN-04, as potential leads to design new P2X7R blockers and anti-inflammatory drugs.

P2X7受体（P2X7R）是具有潜在治疗应用的ATP门控离子通道。在这项研究中，我们准备并搜索了一系列1,4-萘醌衍生物，以评估它们对人和鼠P2X7受体的拮抗作用。我们使用分子建模方法探索了活性最高的化合物的结构-活性关系和结合模式。该系列（八种类似物和两种化合物）的生物学分析表明，其对人和鼠P2X7R均具有显着的体外抑制作用。进一步的特征表明，AN-03和AN-04在体内抑制染料吸收，IL-1β释放和角叉菜胶诱导的足爪水肿方面的功效要比BBG和A740003大。。此外，我们使用电生理学和分子对接分析来表征AN-03和AN-04的作用机理。这些结果表明1,4-萘醌，主要是AN-04，有可能导致设计新的P2X7R阻滞剂和抗炎药。