Benzoyl ATP is an antagonist of rat and human P2Y1 receptors and of platelet aggregation

The effects of 2'- and 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) on intracellular Ca(2+) mobilization and cyclic AMP accumulation were investigated using rat brain capillary endothelial cells which express an endogenous P2Y(1) receptor, human platelets which are known to express a P2Y(1) receptor, and Jurkat cells stably transfected with the human P2Y(1) receptor. In endothelial cells, BzATP was a competitive inhibitor of 2-methylthio ADP (2-MeSADP) and ADP induced [Ca(2+)](i) responses (Ki = 4.7 mu M) and reversed the inhibition by ADP of adenylyl cyclase (Ki = 13 mu M). In human platelets, BzATP inhibited ADP-induced aggregation (Ki = 5 mu M), mobilization of intracellular Ca(2+) stores (Ki = 6.3 mu M), and inhibition of adenylyl cyclase. In P2Y(1)-Jurkat cells, BzATP inhibited ADP and 2-MeSADP-induced [Ca(2+)](i) responses (Ki = 2.5 mu M). It was concluded that BzATP is an antagonist of rat and human P2Y(1) receptors and of platelet aggregation. In contrast to other P2Y(1) receptor antagonists (A2P5P and A3P5P) which inhibit only ADP-induced Ca(2+) mobilization, BzATP inhibits both the Ca(2+)- and the cAMP-dependent intracellular signaling pathways of ADP. These results provide further evidence that P2Y(1) receptors contribute to platelet ADP responses. (C) 1999 Academic Press.