Platelet activation by ADP: the role of ADP antagonists

ADP plays a key role in haemostasis and thrombosis. Despite its early ident ification in 1961 as the first known aggregating agent, the molecular basis of ADP-induced platelet activation is only beginning to be understood. Two purinergic receptors contribute separately to the complex process of ADP-i nduced platelet aggregation: the P2Y(1) metabotropic receptor responsible f or mobilization of ionized calcium from internal stores, which initiates ag gregation, and P2Y receptor coupled to adenylyl cyclase inhibition, which i s essential for the full aggregation response to ADP and stabilization of p latelet aggregates. The latter is the molecular target of the ADP-selective antiaggregating drugs ticlopidine and clopidogrel and the ATP analogues of the AR-C series. In addition, it is probably defective in patients with a bleeding diathesis characterized by selective impairment of platelet respon ses to ADP. Finally, the P2X(1) ionotropic receptor is also present in plat elets, but its role is not yet known. Studies with P2Y(1) knock-out mice as well as the use of selective P2Y(1) antagonists have shown that, in additi on to the P2Y receptor, which is the target of clopidogrel, the P2Y(1) rece ptor is an important potential target for new antithrombotic drugs.