Substituting a methyl group for the ribose moiety of N6-substituted adenosines that are selective agonists at the adenosine A1 receptor creates antagonists that are A1-selective. Inasmuch as 2-phenylethoxyadenosine is a selective agonist for the adenosine A2 receptor, 2-phenylethoxy-9-methyl-adenine (PEMA) was synthesized and tested as a potential adenosine A2 receptor antagonist. In guinea pig hearts, PEMA antagonized with the same potency (pKB approximately 6.1) the A1-mediated negative dromotropic and inotropic actions and the A2-mediated coronary vasoactivity of the nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA). PEMA at concentrations up to 30 microM did not antagonize the NECA-induced relaxations in guinea pig aortic rings. At concentrations exceeding 10 microM, PEMA caused xanthine-insensitive relaxations of both the aorta and the coronary vessels. Pharmacological resultant analysis revealed A2 receptor antagonism by PEMA in the guinea pig aorta (pKB = 5.2). The nonselective adenosine receptor antagonist 8-p-sulfophenyl-theophylline antagonized NECA responses in all four assays with equal potency (pKB approximately 5.7). Thus, PEMA does not discriminate between A2 receptors in the coronary vessels and A1 receptors in the atria of the guinea pig, but it is 10-fold more potent at antagonizing the A2 receptor in coronaries than the A2 receptors in the aorta. The data suggest that the A2 receptors in the coronary vasculature may be of the A2a subtype, whereas those in the aorta may be of the A2b subtype.