NOVEL COMPETITIVE ANTAGONISTS FOR P-2 PURINOCEPTORS

Binding of the radioligand [S-35]adenosine 5'-O-(2-thiodiphosphate) (A DP beta(35)S) to P-2y purinoceptors on turkey erythrocyte membranes wa s used to determine the affinity of suramin and various suramin congen ers 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 mu M. The simple benzamide compound XAMR0721 (8-(3,5-dinitrophenylene carbonyli mino)-1,3,5-naphthalene trisulfonate, trisodium salt) displays a high affinity for the P-2y purinoceptor (K-i value of 19 +/- 6 mu M), Simil ar to suramin, compound XAMR0721 is a competitive antagonist at P-2y p urinoceptors. In contrast to suramin, which is a potent inhibitor of t he ecto-nucleotidase activity in human blood cells (44 +/- 2% residual activity at 100 mu M), compound XAMR0721 is hardly active in this ass ay (93 +/- 1% residual activity at 100 mu M). So XAMR0721, the first c ompetitive antagonist for P-2 purinoceptors that is able to discrimina te between P-2 purinoceptor affinity and ecto-nucleotidase activity, i s an interesting pharmacological tool for the characterization of P-2 purinoceptor mediated effects.