The P2X4 receptor (P2X4R) is one of seven in the P2X family. This group of ion channels are activated by ATP and allow the flow of Ca2+ and Na2+ into the cell. This receptor has been implicated in neuropathic pain and inflammation, epilepsy, cardiac function, and many other processes. There are limited P2X4 receptor antagonists permitting study of its role in these processes or of the structure-activity relationship (SAR) at the receptor. The antidepressant paroxetine was demonstrated additionally to its SSRI (through serotonin transporter (SERT)) and 5-HT2C activities to inhibit the Ca2+ response in P2X4R expressing cells. However, this and similar antagonists are more potent at other targets and not selective enough for research focused on the P2X4R. Therefore, we believe that paroxetine serves as a perfect template for the development of novel P2X4R antagonists. In a preliminary study, it was demonstrated that the introduction of an additional nitrogen atom, leading to a piperazine ring, resulted in compounds displaying a loss of SERT and serotonin receptor activities but had no detrimental effect on P2X4R activity. We will report the development of novel P2X4R antagonists based on structural modification on a piperazine based scaffold. This route afforded the opportunity for late-stage functionalization of the piperazine-based structure and resulted in the synthesis of four test compounds.

Synthesis of novel P2X4 receptor antagonists

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