A panel of 18 protein tyrosine kinase antagonists were tested for their inhibitory effect on human P2X(7) receptor-mediated Rb-86(+) (K+) efflux. The most potent compound (compound P), a phthalazinamine derivative and an inhibitor of vascular endothelial growth factor receptor kinase, blocked ATP-induced Rb-86(+)-efflux in human B-lymphocytes and erythrocytes by 76% and 66%, respectively. This inhibition was dose-dependent in both cell types with an IC50 of similar to 5 mu M. Kinetic analysis showed compound P was a non-competitive inhibitor of P2X(7). This compound also inhibited ATP-induced ethidium(+) influx into B-lymphocytes and P2X(7)-transfected-HEK-293 cells, as well as ATP-induced Rb-86(+)-efflux from canine erythrocytes. Externally, but not internally, applied compound P impaired ATP-induced inward currents in P2X(7)-transfected-HEK-293 cells. This study demonstrates that a novel protein tyrosine kinase antagonist directly impairs native and recombinant human P2X(7) receptors. The data suggests that antagonists which target ATP-binding sites of kinases may potentially block the P2X(7) receptor. (c) 2007 Elsevier Inc. All rights reserved.