title: Synthesis and P2Y₂ receptor agonist activities of uridine 5'-phosphonate analogues.
abstract: We explored the influence of modifications of uridine 5'-methylenephosphonate on biological activity at the human P2Y(2) receptor. Key steps in the synthesis of a series of 5-substituted uridine 5'-methylenephosphonates were the reaction of a suitably protected uridine 5'-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki-Miyaura coupling. These analogues behaved as selective agonists at the P2Y(2) receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y(2) receptor.
authors.affiliation: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Poecke
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Barrett
authors.forename: T
authors.initials: T
authors.lastname: Santhosh Kumar
authors.forename: Davy
authors.initials: D
authors.lastname: Sinnaeve
authors.forename: José C
authors.initials: JC
authors.lastname: Martins
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: T
authors.initials: T
authors.lastname: Kendall Harden
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058912:Purinergic P2Y Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058473:Receptors, Purinergic P2Y2 / Q000737:chemistry* / Q000378:metabolism; D014500:Uracil Nucleotides / Q000737:chemistry; D014544:Uridine Triphosphate / Q000378:metabolism
chemical_list: D063065:Organophosphonates; D058912:Purinergic P2Y Receptor Agonists; D058473:Receptors, Purinergic P2Y2; D014500:Uracil Nucleotides; D014544:Uridine Triphosphate