P2-Pyrimidinergic Receptors and Their Ligands

Pyrimidine nucleotides, including UTP, UDP and UDP-glucose, are important signaling molecules which activate G protein-coupled membrane receptors of the P2Y family. Four distinct pyrimidine nucleotide-sensitive P2Y receptor subtypes have been cloned, P2Y2, P2Y4, P2Y6 and P2Y14. Pharmacological experiments indicate that further subtypes may exist. P2Y2 and P2Y4 receptors are activated by UTP (the P2Y2 and the rat, but not the human P2Y4 receptor are also activated by ATP), the P2Y6 receptor is activated by UDP, and the P2Y14 receptor by UDPglucose. Derivatives and analogs of the physiological nucleotides UTP, UDP and ATP have been synthesized and evaluated in order to obtain enzymatically stable, subtype-selective agonists. P2Y2 agonists are currently in clinical development for cystic fibrosis and dry eye syndrome. Selective antagonists for pyrimidinergic P2Y receptors are still lacking.