Development of selective agonists and antagonists of P2Y receptors

Abstract

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 proteincoupled 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.

Purinergic signalling is required for calcium oscillations in migratory chondrogenic progenitor cells

“…By using various P2 receptor agonists (ATP, ADP, UTP and UDP; see Table 2 and [18]), as well as the non-specific receptor antagonist suramin, our results suggest the function of P2Y1, P2Y2, P2Y4, P2X4, and P2X6 receptor subtypes in CPCs. These results are in a very good correlation with the findings of Zippel and colleagues who implicated the P2 receptor subtypes P2X6, P2Y4, and P2Y14 to be key regulators in MSC commitment [55]; most of these receptors were active also in CPCs.…”

Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y12 Receptor

“…ADP induces the aggregation of human platelets by the activation of G q -coupled P2Y 1 receptors and G i -coupled P2Y 12 receptors (Dorsam and Kunapuli, 2004;Cattaneo, 2007;Gachet, 2008; for an overview of P2Y receptors, see Abbracchio et al, 2006;von Kü gelgen, 2006;Jacobson et al, 2009). The irreversible blockade of the platelet P2Y 12 receptor by active metabolites of thienopyridine antithrombotic drugs such as clopidogrel (Savi et al, 2000) and prasugrel (Sugidachi et al, 2001) has been proven to be useful in pharmacotherapy of thrombotic diseases including heart attack and stroke (Savi and Herbert, 2005;Jakubowski et al, 2007).…”

Altered Gene Expression Pathways in Duchenne Muscular Dystrophy

“…Some of P2Y receptors are activated mainly by nucleoside diphosphates (P2Y 1,6,12 ), while others are activated mainly by nucleoside triphosphates (P2Y 2,4 ). Otherwise, some P2Y receptors are activated by both purine and pyrimidine nucleotides (P2Y 2,4,6 ), and others only by purine nucleotides (P2Y 1, 11, 12 ) (Jacobson et al 2009). Each individual P2Y receptor subtypes can couple to distinct G proteins that are specific for each cell type or tissue.…”