Novel competitive antagonists for P 2 purinoceptors

Abstract

Binding of the radioligand [ 35S]adenosine 5′- O-(2-thiodiphosphate) (ADPβ 35S) to P 2y 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 K i value of 7.3±2.2 μM. The simple benzamide compound XAMR0721 (8-(3,5-dinitrophenylene carbonylimino)-1,3,5- naphthalene trisulfonate, trisodium salt) displays a high affinity for the P 2y purinoceptor ( K i value of 19±6 μM). Similar to suramin, compound XAMR0721 is a competitive antagonist at P 2y 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 μM), compound XAMR0721 is hardly active in this assay (93±1% residual activity at 100 μM). So XAMR0721, the first competitive antagonist for P 2 purinoceptors that is able to discriminate between P 2 purinoceptor affinity and ecto-nucleotidase activity, is an interesting pharmacological tool for the characterization of P 2 purinoceptor mediated effects.