Overview of P2Y receptors as therapeutic targets

Abstract

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 ATP, 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 forms of neutropenia and leukemia. Drug Dev.

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…There are several pathological conditions in which the purinergic component of cotransmission is increased (Burnstock, 2002b). The emphasis in this article is on the pathophysiology and therapeutic potential of P2 receptors (see also Burnstock and Williams, 2000;Boeynaems et al, 2001;Yerxa, 2001;Burnstock, 2002a;Jacobson et al, 2002;Ralevic and Burnstock, 2003) and readers are referred to recent reviews about the therapeutic potential of P1 receptors (Fredholm et al, 2002(Fredholm et al, , 2005Okusa, 2002;Pelleg et al, 2002;Dhalla et al, 2003;Ribeiro et al, 2003;Hutchinson and Scammells, 2004;McCallion et al, 2004).…”

Structure and ligand-binding site characteristics of the human P2Y11 nucleotide receptor deduced from computational modelling and mutational analysis

“…processes and involvement in various diseases, varying from cystic fibrosis [14] to platelet secretion and aggregation disorders [15]. Specifically, the hP2Y 11 -R was reported to play roles in the treatment of neutropenia [16], acute myocardial infarcts [17] and in the maturation process of dendritic cells [18].…”

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

“…Inhibition of the P2Y 6 R has also been suggested as a potential therapeutic target for monosodium urate-associated inflammatory diseases, such as tophaceous gout . With these and other recent observations, inhibition of the P2Y 6 R could prove to be a viable therapeutic mechanism in many potential disease areas.…”

“…It is now well-established that signaling by extracellular nucleotides is mediated by two families of receptors: P2Y receptors, which are metabotropic G protein-coupled receptors (GPCRs), and P2X receptors, which are trimeric ion channels . The P2Y receptors (P2YRs) belong to the GPCR superfamily and possess the characteristic molecular topology of an extracellular N-terminus, an intracellular C-terminus, and seven transmembrane-spanning loops . However, in comparison to other GPCR families, P2Y receptors show limited sequence homology, possibly explaining the differences in ligand selectivity and specificity for the relevant G-proteins through which they signal.…”