Piperazine-based P2X4 receptor antagonists.

ABSTRACT: The P2X4 receptor (P2X4R), a ligand-gated ion channel activated by ATP, plays a critical role in neuroinflammation, chronic pain, and cancer progression, making it a promising therapeutic target. In this study, we explored the design and synthesis of piperazine-based P2X4R antagonists, building on the structural framework of paroxetine. A series of over 35 compounds were synthesized to investigate structure-activity relationships (SARs) in a Ca²⁺-flux assay for P2X4R antagonistic activity. Several compounds outperformed paroxetine in terms of antagonistic P2X4R potency. Further studies on absorption, distribution, metabolism, excretion properties revealed that increased lipophilicity often correlated with high plasma protein binding and decreased metabolic stability, particularly in compou

SUBMITTER: Erlitz KS 

PROVIDER: S-EPMC11686045 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature