P-2 RECEPTOR - SUBCLASSIFICATION AND STRUCTURE-ACTIVITY-RELATIONSHIPS

Structure-activity relationships (SAR) at P2 receptors that support their subclassification into at least five nucleotide receptor subtypes, P2Z, P2T, P2Y, P2U, and P2X, are reviewed. The P2Z receptor is the most sensitive to alterations to ATP. The adenine base, D-ribose sugar, and 5'-triphosphate chain are absolute requirements, but substitutions are tolerated at the C-2 position and replacement by sulphur of an ionized phosphate oxygen leads to enhanced potency. The P2T receptor, where ADP is the only endogenous agonist, has an absolute requirement for the adenine base, D-ribose sugar, and a 5'-diphosphate chain. C-2 substitution and replacement by sulphur of an ionized oxygen is tolerated. Many analogs of AMP and of ATP are antagonists. The P2Y receptor requires an adenine base, D-ribose, and a 5'-polyphosphate for maximal potency only. C-2 substitution, and replacement of an ionized oxygen by sulphur, can enhance potency. Methylene-phosphonate potencies depend on the position of the methylene group. ADP-beta-F is a specific agonist. The P2X receptor is least sensitive to alterations to ATP. There is no requirement for an adenine base, D-ribose sugar, or triphosphate chain. Methylenephosphonates and some phosphorothioates have enhanced potencies. L-AMP-PCP is a specific agonist. Evidence from SAR for a P2U subtype is reviewed. SAR studies are complicated by the presence of ectonucleotidases. The overall subclassification of P2 receptors is inadequate and awaits the availability of selective competitive antagonists.