Overview of P2Y receptors as therapeutic targets

Currently the only P2Y receptor subtype targeted by drugs in clinical use i s 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 activ e metabolites of thienopyridine antithrombotic agents (ticlopidine, clopido grel) bind covalently to that receptor and inactivate it in an irreversible way. The same receptor is also the target of competitive antagonists deriv ed from ATF: such as AR-C69931MX. Other subtypes also have potential as pha rmacotherapeutic targets. The demonstration that P2Y(1)(-/-) mice have a de fective platelet aggregation and increased resistance to thromboembolism su ggests that P2Y(1) antagonists could constitute a new class of antithrombot ic agents. Activation of the P2Y(2) receptor by aerosolized UTP and derivat ives constitutes one strategy for the symptomatic treatment of cystic fibro sis and other obstructive airway diseases. The study of P2Y(2)(-/-) mice su ggests that P2Y(4) and P2Y(6) receptors might constitute additional targets in that framework. P2Y(6) receptor antagonists might be useful in inflamma tory bowel disease in view of their expression on activated T lymphocytes i nfiltrating the lesions in patients. The P2Y(11) receptor mediates the stim ulatory effect of ATP on the granulocytic differentiation of HL-60 promyelo cytic leukemia cells, suggesting that P2Y(11) agonists might be useful in t he treatment of some farms of neutropenia and leukemia. Drug Dev. Res. 52:1 87-189, 2001. (C) 2001 Wiley-Liss, Inc.