Overview of P2Y receptors as therapeutic targets

Currently the only P2Y receptor subtype targeted by drugs in clinical use is the P2T(AC) (or P2Y(12)) receptor, which has been recently cloned and is only distantly related to other P2Y subtypes. It is believed that the active metabolites of thienopyridine antithrombotic agents (ticlopidine, clopidogrel) bind covalently to that receptor and inactivate it in an irreversible way. The same receptor is also the target of competitive antagonists derived from ATF: such as AR-C69931MX. Other subtypes also have potential as pharmacotherapeutic targets. The demonstration that P2Y(1)(-/-) mice have a defective platelet aggregation and increased resistance to thromboembolism suggests that P2Y(1) antagonists could constitute a new class of antithrombotic agents. Activation of the P2Y(2) receptor by aerosolized UTP and derivatives constitutes one strategy for the symptomatic treatment of cystic fibrosis and other obstructive airway diseases. The study of P2Y(2)(-/-) mice suggests that P2Y(4) and P2Y(6) receptors might constitute additional targets in that framework. P2Y(6) receptor antagonists might be useful in inflammatory bowel disease in view of their expression on activated T lymphocytes infiltrating the lesions in patients. The P2Y(11) receptor mediates the stimulatory effect of ATP on the granulocytic differentiation of HL-60 promyelocytic leukemia cells, suggesting that P2Y(11) agonists might be useful in the treatment of some farms of neutropenia and leukemia. Drug Dev. Res. 52:187-189, 2001. (C) 2001 Wiley-Liss, Inc.