title: Agonists and antagonists for P2 receptors.
abstract: Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X(2/3)/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X(2/3)/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformationally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4nM at the P2Y1 receptor, with >10000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Bhalchandra V
authors.initials: BV
authors.lastname: Joshi
authors.forename: Pedro
authors.initials: P
authors.lastname: Besada
authors.forename: Dae Hong
authors.initials: DH
authors.lastname: Shin
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Ivanov
authors.forename: Liaman
authors.initials: L
authors.lastname: Mamedova
mesh_terms: D000818:Animals; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism
chemical_list: D008024:Ligands; D009711:Nucleotides; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2