Molecular pharmacology of P2Y receptor subtypes

Professor Geoffrey Burnstock proposed the concept of purinergic signaling via P1 and P2 receptors. P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular adenine and uracil nucleotides. Eight mammalian P2Y receptor subtypes have been identified. They are divided into two subgroups (P2Y₁, P2Y₂, P2Y₄, P2Y₆, and P2Y₁₁) and (P2Y₁₂, P2Y₁₃, and P2Y₁₄). P2Y receptors are found in almost all cells and mediate responses in physiology and pathophysiology including pain and inflammation. The antagonism of platelet P2Y₁₂ receptors by cangrelor, ticagrelor or active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel reduces the ADP-induced platelet aggregation in patients with thrombotic complications of vascular diseases. The nucleotide agonist diquafosol acting at P2Y₂ receptors is used for the treatment of the dry eye syndrome. Structural information obtained by crystallography of the human P2Y₁ and P2Y₁₂ receptor proteins, site-directed mutagenesis and molecular modeling will facilitate the rational design of novel selective drugs.