Development of selective agonists and antagonists of P2Y receptors

Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of many other members of group A G protein-coupled receptors, detailed qualitative and quantitative structure–activity relationships (SARs) were recently constructed for several of the subtypes. Agonists selective for P2Y(1), P2Y(2), and P2Y(6) receptors and nucleotide antagonists selective for P2Y(1) and P2Y(12) receptors are now known. Selective nonnucleotide antagonists were reported for P2Y(1), P2Y(2), P2Y(6), P2Y(11), P2Y(12), and P2Y(13) receptors. At the P2Y(1) and P2Y(12) receptors, nucleotide agonists (5′-diphosphate derivatives) were converted into antagonists of nanomolar affinity by altering the phosphate moieties, with a focus particularly on the ribose conformation and substitution pattern. Nucleotide analogues with conformationally constrained ribose-like rings were introduced as selective receptor probes for P2Y(1) and P2Y(6) receptors. Screening chemically diverse compound libraries has begun to yield new lead compounds for the development of P2Y receptor antagonists, such as competitive P2Y(12) receptor antagonists with antithrombotic activity. Selective agonists for the P2Y(4), P2Y(11), and P2Y(13) receptors and selective antagonists for P2Y(4) and P2Y(14) receptors have not yet been identified. The P2Y(14) receptor appears to be the most restrictive of the class with respect to modification of the nucleobase, ribose, and phosphate moieties. The continuing process of ligand design for the P2Y receptors will aid in the identification of new clinical targets.