Synthetic 1,4-Naphthoquinones inhibit P2X7 receptors in murine neuroblastoma cells.

ABSTRACT

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 Ca2+ 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.