title: Adenosine-derived non-phosphate antagonists for P2Y(1) purinoceptors.
abstract: Novel type antagonists for P2Y(1) adenine nucleotide receptors were synthesized by coupling of adenosine 5'-OH group with oligo-aspartate chain via a carbonyl linker. All these conjugates (AdoOC(O)Asp(n), n = 1-4) inhibited the 2MeSADP-stimulated synthesis of inositol phosphates in 1321N1 human astrocytoma cells stably expressing human P2Y(1) receptors. This inhibitory effect followed the rank order AdoOC(O)Asp(2)> AdoOC(O)Asp(3)> AdoOC(O)Asp(1)> AdoOC(O)Asp(4) with antagonistic constant pA(2) = 5.4 for AdoOC(O)Asp(2). Potency of this non-phosphate inhibitor was comparable with the previously known adenosine 3',5'- and 2', 5'-bisphosphates. Chemical and biological stabilities of these novel adenosine derived antagonists of the nucleotide receptor provide perspectives of their pharmacological implication.
authors.affiliation: Institute of Chemical Physics, University of Tartu, Estonia.
authors.forename: K
authors.initials: K
authors.lastname: Sak
authors.forename: A
authors.initials: A
authors.lastname: Uri
authors.forename: E
authors.initials: E
authors.lastname: Enkvist
authors.forename: G
authors.initials: G
authors.lastname: Raidaru
authors.forename: J
authors.initials: J
authors.lastname: Subbi
authors.forename: M
authors.initials: M
authors.lastname: Kelve
authors.forename: J
authors.initials: J
authors.lastname: Järv
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001224:Aspartic Acid / Q000378:metabolism; D001254:Astrocytoma / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010710:Phosphates / Q000032:analysis*; D010716:Phosphatidylinositols / Q000096:biosynthesis / Q000378:metabolism; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C546382:P2RY1 protein, human; D010710:Phosphates; D010716:Phosphatidylinositols; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides; D001224:Aspartic Acid; C002480:methylthio-ADP; C045716:adenosine 2',5'-diphosphate; D000244:Adenosine Diphosphate; C010840:adenosine 3'-phosphate-5'-phosphate; D000241:Adenosine