Tools and drugs for uracil nucleotide-activated P2Y receptors.

P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y, P2Y, P2Y, P2Y, P2Y, P2Y, P2Y, and P2Y, which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y (UTP, also ATP and dinucleotides), P2Y (UTP), P2Y (UDP), and P2Y (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2YR agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2YR antagonist is AR-C118925 (10-01). For studies of the P2YR, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) is a selective antagonist. Several potent P2YR agonists have been developed including 5-methoxyuridine 5'-O-((R)α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2YR antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2YR agonist is available, while PPTN (10-14) represents a potent and selective P2YR antagonist. The radioligand [H]UDP can be used to label P2YRs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases.