G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia.
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia.
Bioorg Med Chem. 2021 Feb 1;31:115975. doi: 10.1016/j.bmc.2020.115975. Epub 2020 Dec 29.
The P2X7 receptor (P2X7R) is an ATP-gated ion channel and potential therapeutic target for new drug development. In this study, we synthesized a series of new 1,4-naphthoquinone (1,4-NQ) derivatives and investigated their antagonistic effects against mouse P2X7R. We explored the ability of the tested substances to block ATP-induced Ca influx into mouse Neuro-2a cells and selected the four most effective substances: the 1,4-naphthoquinone thioglucosides U-548 and U-557 and their tetracyclic conjugates U-286 and U-556. Biological analysis of these compounds revealed significant in vitro inhibition of murine P2X7R. This inhibition resulted in marked blockade of ethidium bromide (EtBr) and YO-PRO-1 fluorescent dye uptake, pronounced decreases in ROS and NO production and protection of neuronal cell viability against the toxic action of high ATP concentrations. In silico analysis indicated favorable molecular docking results of these 1,4-NQs, pointing to their potential to bind in an allosteric site located in the extracellular region of P2X7R. These findings suggest compounds U-286, U-548, U-556 and U-557 as potential scaffolds for the design of new P2X7R blockers and drugs effective against neuropathic pain and neurodegenerative diseases.
P2X7 受体（P2X7R）是一种 ATP 门控离子通道，也是开发新药的潜在治疗靶点。在这项研究中，我们合成了一系列新的 1,4-萘醌（1,4-NQ）衍生物，并研究了它们对小鼠 P2X7R 的拮抗作用。我们探索了测试物质阻断 ATP 诱导的 Ca 内流进入小鼠 Neuro-2a 细胞的能力，并选择了四种最有效的物质：1,4-萘醌硫葡萄糖苷 U-548 和 U-557 及其四环共轭物 U-286 和 U-556。这些化合物的生物学分析显示出对小鼠 P2X7R 的显著体外抑制作用。这种抑制作用导致溴化乙锭（EtBr）和 YO-PRO-1 荧光染料摄取明显受阻，ROS 和 NO 产生显著减少，以及神经元细胞活力免受高 ATP 浓度的毒性作用的保护。计算机分析表明，这些 1,4-NQ 具有有利的分子对接结果，表明它们有可能结合位于 P2X7R 细胞外区域的变构位点。这些发现表明化合物 U-286、U-548、U-556 和 U-557 可能作为设计新的 P2X7R 阻滞剂和治疗神经病理性疼痛和神经退行性疾病的有效药物的潜在支架。
