Therapeutic potential for P2Y₂ 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 P2Y₁₂ receptor antagonist, clopidogrel, P2Y₂ receptor (P2Y₂R) antagonism remains relatively unexplored as a therapeutic strategy. Due to a lack of selective antagonists to modify P2Y₂R activity, studies using primarily genetic manipulation have revealed roles for P2Y₂R 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 P2Y₂R antagonist that became commercially available only a few years ago, new opportunities exist to gain a more robust understanding of P2Y₂R function and assess therapeutic effects of P2Y₂R antagonism. This review discusses the characteristics of P2Y₂R that make it unique among P2 receptors, namely its involvement in five distinct signaling pathways including canonical Gα_q protein signaling. We also discuss the effects of other P2Y₂R antagonists and the pivotal development of AR-C118925. The remainder of this review concerns the mounting evidence implicating P2Y₂Rs in disease pathogenesis, focusing on those studies that have evaluated AR-C118925 in pre-clinical disease models.