Laboratory of Studies in Experimental Pharmacology, Biomedical Science Institute, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Niterói, RJ, 24020-150, Brazil.
J Bioenerg Biomembr. 2022 Dec;54(5-6):227-239. doi: 10.1007/s10863-022-09947-2. Epub 2022 Sep 7.
The P2X7 receptor (P2X7R) is an ion channel that promotes the passage of ions through the membrane through brief stimulation once activated by ATP, its endogenous opener. However, prolonged stimulation with ATP, which occurs in pathological processes, opens a nonselective pore in the plasma membrane, allowing the passage of large molecules and leading to cytokine release or even cell death. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Considering the booming of biomass upgrading reactions in recent years and the continued efforts to synthesize biologically active molecules containing the 1,2,3-triazole ring, in the present work, we aimed to investigate whether triazole-linked menadione-furan derivatives could present P2X7R inhibitory activity. The novel compounds were tested for their inhibitory activity on ATP-induced dye uptake in peritoneal macrophages. Some have shown promising results, having displayed IC values lower than that of the P2X7R inhibitor BBG. Molecular docking studies also indicated that the active compounds bind to an allosteric site on P2X7R, presenting potential P2X7R inhibition.
P2X7 受体（P2X7R）是一种离子通道，一旦被其内源性激动剂 ATP 短暂刺激激活，就会促进离子通过细胞膜。然而，在病理过程中，ATP 的长时间刺激会在质膜上打开一个非选择性孔，允许大分子通过，从而导致细胞因子释放甚至细胞死亡。从这个意义上说，近年来，寻找这种受体的新抑制剂引起了极大的关注。考虑到近年来生物质升级反应的蓬勃发展以及合成含有 1,2,3-三唑环的生物活性分子的持续努力，在本工作中，我们旨在研究三唑连接的甲萘醌-呋喃衍生物是否具有 P2X7R 抑制活性。新型化合物被测试了它们对 ATP 诱导的腹腔巨噬细胞染料摄取的抑制活性。一些化合物表现出了有希望的结果，其 IC 值低于 P2X7R 抑制剂 BBG。分子对接研究还表明，活性化合物结合到 P2X7R 的别构位点上，具有潜在的 P2X7R 抑制作用。
