THE NONXANTHINE HETEROCYCLIC COMPOUND SCH-58261 IS A NEW POTENT AND SELECTIVE A(2A) ADENOSINE RECEPTOR ANTAGONIST

We have characterized the in vitro pharmacological profile of the new potent and selective A(2a), adenosine receptor antagonist SCH 58261 py razolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine). In binding studies on rat and bovine brain tissues, SCH 58261 showed affinity in the low na nomolar range at A(2a), adenosine striatal receptors and good A(2a) ad enosine vs. A(1) adenosine selectivity (about 50- to 100-fold in rat a nd bovine brain, respectively). SCH 58261 did not show affinity for ei ther the A(3) adenosine receptor or other receptors at concentrations up to 1 mu M. Saturation experiments on rat A(1) and A(2a) adenosine r eceptors indicated the competitive nature of the antagonism. SCH 58261 antagonized competitively the effects induced by the A(2a) adenosine- selective agonist CGS 21680 l)-phenethylamino]-5'-N-ethylcarboxamidoad enosine} in two functional assays, such as inhibition of rabbit platel et aggregation and porcine coronary artery relaxation. Specifically, t he compound showed pA(2) values of 7.9 and 9.5, respectively. SCH 5826 1 (300 nM) failed to antagonize 5'-N-ethylcarboxamidoadenosine-induced vasorelaxation in the isolated guinea pig aorta, a response mediated by A(2b) adenosine receptors. Likewise, at the same concentration, the compound weakly inhibited the A(1) adenosine-mediated negative chrono tropic effect induced by 2-chloro-N-6-cyclopentyladenosine in the isol ated rat atria. These data show that SCH 58261 is a potent and selecti ve non-xanthine A(2a), adenosine antagonist which has competitive prop erties in biological responses mediated by this receptor subtype. The compound is of interest for investigating the biological role of A(2a) adenosine receptors and deserves further attention to clarify the the rapeutic potential of A(2a) antagonists.