title: Novel competitive antagonists for P2 purinoceptors.
abstract: Binding of the radioligand [35S]adenosine 5'-O-(2-thiodiphosphate) (ADP beta 35S) to P2 gamma purinoceptors on turkey erythrocyte membranes was used to determine the affinity of suramin and various suramin congeners belonging to different structure classes (large urea, small urea, dibenzamides and benzamides) for these receptors. Suramin was shown to be a competitive antagonist with a Ki value of 7.3 +/- 2.2 microM. The simple benzamide compound XAMR0721 (8-(3,5-dinitrophenylene carbonylimino)-1,3,5-naphthalene trisulfonate, trisodium salt) displays a high affinity for the P2 gamma purinoceptor (Ki value of 19 +/- 6 microM). Similar to suramin, compound XAMR0721 is a competitive antagonist at P2 gamma purinoceptors. In contrast to suramin, which is a potent inhibitor of the ecto-nucleotidase activity in human blood cells (44 +/- 2% residual activity at 100 microM), compound XAMR0721 is hardly active in this assay (93 +/- 1% residual activity at 100 microM). So XAMR0721, the first competitive antagonist for P2 purinoceptors that is able to discriminate between P2 purinoceptor affinity and ecto-nucleotidase activity, is an interesting pharmacological tool for the characterization of P2 purinoceptor mediated effects.
authors.affiliation: Center for Bio-Pharmaceutical Sciences, Division of Medicinal Chemistry, Leiden, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: van Rhee
authors.forename: M P
authors.initials: MP
authors.lastname: van der Heijden
authors.forename: M W
authors.initials: MW
authors.lastname: Beukers
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: W
authors.initials: W
authors.lastname: Soudijn
authors.forename: P
authors.initials: P
authors.lastname: Nickel
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009708:Nucleotidases / Q000037:antagonists & inhibitors / Q000097:blood; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013498:Suramin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D014422:Turkeys; D014508:Urea / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D013498:Suramin; D014508:Urea; D009708:Nucleotidases; C030287:nucleotidase