Therapeutic potential for P2Y receptor antagonism.

G protein-coupled receptors are the target of more than 30% of all FDA-approved drug therapies. Though the purinergic P2 receptors have been an attractive target for therapeutic intervention with successes such as the P2Y receptor antagonist, clopidogrel, P2Y receptor (P2YR) antagonism remains relatively unexplored as a therapeutic strategy. Due to a lack of selective antagonists to modify P2YR activity, studies using primarily genetic manipulation have revealed roles for P2YR in a multitude of diseases. These include inflammatory and autoimmune diseases, fibrotic diseases, renal diseases, cancer, and pathogenic infections. With the advent of AR-C118925, a selective and potent P2YR antagonist that became commercially available only a few years ago, new opportunities exist to gain a more robust understanding of P2YR function and assess therapeutic effects of P2YR antagonism. This review discusses the characteristics of P2YR that make it unique among P2 receptors, namely its involvement in five distinct signaling pathways including canonical Gα protein signaling. We also discuss the effects of other P2YR antagonists and the pivotal development of AR-C118925. The remainder of this review concerns the mounting evidence implicating P2YRs in disease pathogenesis, focusing on those studies that have evaluated AR-C118925 in pre-clinical disease models.