CGS 15943A is a potent adenosine receptor antagonist with a novel nonxanthine heterocyclic ring structure. In vitro, CGS 15943A competitively inhibited the 2-chloroadenosine-induced A2 receptor-mediated relaxation of dog coronary artery strips contracted with KCl (25 mM). Similarly, CGS 15943A blocked 2-chloroadenosine- and N-ethylcarboxamideadenosine-induced A2 receptor-mediated relaxation of histamine-contracted guinea pig tracheal strips. Schild analysis of these results yielded pA2 values of 10.8 and 10.1 for the coronary arteries and the tracheal smooth muscle strips, respectively. In comparison, 8-phenyltheophylline blocked 2-chloroadenosine-induced tracheal response with a pA2 value of 7.0. CGS 15943A was devoid of intrinsic activity, and did not affect either histamine- or KCl-induced contractions of the smooth muscle strips. In the electrically stimulated guinea pig left atrial preparation, CGS 15943A antagonized the A1 receptor-mediated negative inotropic effects of R-phenylisopropyladenosine with a pA2 value of 7.4. In vivo, i.v. administration of CGS 15943A blocked the vasodepressor response to 2-chloradenosine in anesthetized normotensive rats with an ID50 of 0.024 mg/kg. In addition, p.o. administration of CGS 15943A (4.0 mg/kg) to conscious rats inhibited 2-chloroadenosine-induced decreases in diastolic blood pressure; maximal effects were observed 30 min after dosing, with a T1/2 of approximately 103 min. Therefore suggesting that CGS 15943A is an orally active antagonist of adenosine receptors. These results indicate that CGS 15943A antagonized both A1 and A2 receptor-mediated responses with a greater affinity toward the A2 than the A1 receptor subtype.