Pharmacology of P2Y receptors

Abstract

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes divided into two subgroups (P2Y₁, P2Y₂, P2Y₄, P2Y₆, and P2Y₁₁) and (P2Y₁₂, P2Y₁₃, and P2Y₁₄). The P2Y receptors are expressed in various cell types and play important roles in physiology and pathophysiology including inflammatory responses and neuropathic pain. The antagonism of P2Y₁₂ receptors is used in pharmacotherapy for the prevention and therapy of cardiovascular events. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel inhibit platelet P2Y₁₂ receptors and reduce thereby platelet aggregation. The P2Y₂ receptor agonist diquafosol is used for the treatment of the dry eye syndrome. The P2Y receptor subtypes differ in their amino acid sequences, their pharmacological profiles and their signaling transduction pathways. Recently, selective receptor ligands have been developed for all subtypes. The published crystal structures of the human P2Y₁ and P2Y₁₂ receptors as well as receptor models will facilitate the development of novel drugs for pharmacotherapy.

Keywords: Adenine nucleotides; Crystal structure; P2Y receptors; Receptor ligands; Uracil nucleotides.