The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack ofspecific and subtype-selective antagonists with a “druglike” profile. However, a tyrosine derivative namedKN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplification of KN-62, thepresent study was designed to evaluate the functional antagonistic properties of a novel series of glycinederivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonisticactivity of these glycine derivatives was tested on HEK293 cells transfected with the human P2X7 receptor.The most potent P2X7 receptor antagonist identified in this study (compound 4g) contains an o-fluorinesubstituent on the phenylpiperazine moiety and had an IC50 of 12.1 nM. The biological responses investigatedwere ATP-dependent Ca2+ influx across the plasma membrane and ethidium bromide uptake.
