The P2X7 receptor (P2X7R) is an ion channel which is activated by interactions with the extracellular ATP molecules. The molecular complex P2X7R/ATP induces conformational changes in the protein subunits, opening a pore in the ion channel macromolecular structure. Currently, the P2X7R has been studied as a potential therapeutic target of anti-inflammatory drugs. Based on this, a series of eight boronic acids (NO) analogs were evaluated on the biologic effect of this pharmacophoric group on the human and murine P2X7R. The boronic acids derivatives NO-01 and NO-12 inhibited in vitro human and murine P2X7R function. These analogs compounds showed effect better than compound BBG and similar to inhibitor A740003 for inhibiting dye uptake, in vitro IL-1β release and ATP-induced paw edema in vivo. In both, in vitro and in vivo assays the compound NO-01 showed to be the hit compound in the present series of the arylboronic acids analogs. The molecular docking suggests that the NO derivatives bind into the upper body domain of the P2X7 pore and that the main intermolecular interaction with the two most active NO derivatives occur with the residues Phe 95, 103 and 293 by hydrophobic interactions and with Leu97, Gln98 and Ser101 by hydrogen bonds.. These results indicate that the boronic acid derivative NO-01 shows the lead compound characteristics to be used as a scaffold structure to the development of new P2X7R inhibitors with anti-inflammatory action.

中文翻译：

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芳基硼酸抑制P2X7受体功能和急性炎症反应。

P2X7受体（P2X7R）是通过与细胞外ATP分子相互作用而激活的离子通道。分子复合物P2X7R / ATP诱导蛋白质亚基的构象变化，在离子通道大分子结构中打开一个孔。当前，已经研究了P2X7R作为抗炎药的潜在治疗靶标。在此基础上，评估了一系列八个硼酸（NO）类似物对该药效基团对人和鼠P2X7R的生物学作用。硼酸衍生物NO-01和NO-12抑制体外人和鼠P2X7R功能。这些类似物化合物在抑制染料吸收，体外IL-1β释放和体内ATP诱导的爪水肿方面表现出比化合物BBG更好的效果，并且与抑制剂A740003相似。同时，在体外和体内试验中，化合物NO-01被证明是本系列芳基硼酸类似物中的命中化合物。分子对接表明，NO衍生物结合到P2X7孔的上半区域中，并且与两个最活跃的NO衍生物的主要分子间相互作用发生在残基Phe 95、103和293之间，它们之间是通过疏水作用发生的，并且与Leu97，Gln98和这些结果表明，硼酸衍生物NO-01显示出先导化合物的特征，可被用作支架结构，以开发具有抗炎作用的新型P2X7R抑制剂。