Faria R X, Oliveira F H, Salles J P, Oliveira A S, von Ranke N L, Bello M L, Rodrigues C R, Castro H C, Louvis A R, Martins D L, Ferreira V F
Laboratório de Toxoplasmose e outras protozooses, Instituto Oswaldo Cruz, Fiocruz, Brazil.
Laboratório de Toxoplasmose e outras protozooses, Instituto Oswaldo Cruz, Fiocruz, Brazil.
Eur J Med Chem. 2018 Jan 1;143:1361-1372. doi: 10.1016/j.ejmech.2017.10.033. Epub 2017 Oct 23.
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）是一种具有潜在治疗应用价值的ATP门控离子通道。在本研究中，我们制备并筛选了一系列1,4 - 萘醌衍生物，以评估它们对人和小鼠P2X7受体的拮抗作用。我们使用分子建模方法探索了最具活性化合物的构效关系和结合模式。对该系列（八个类似物和两种化合物）的生物学分析显示，它们对人和小鼠P2X7R均具有显著的体外抑制作用。进一步的表征表明，在体内抑制染料摄取、IL - 1β释放和角叉菜胶诱导的爪肿胀方面，AN - 03和AN - 04比BBG和A740003具有更强的效力。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的作用机制。这些结果表明，1,4 - 萘醌，主要是AN - 04，有望成为设计新型P2X7R阻滞剂和抗炎药物的潜在先导化合物。
