2-PHENYLETHOXY-9-METHYLADENINE - AN ADENOSINE RECEPTOR ANTAGONIST THAT DISCRIMINATES BETWEEN A2 ADENOSINE RECEPTORS IN THE AORTA AND THE CORONARY VESSELS FROM THE GUINEA-PIG

Substituting a methyl group for the ribose moiety of N6-substituted ad enosines that are selective agonists at the adenosine A1 receptor crea tes antagonists that are Al-selective. Inasmuch as 2-phenylethoxyadeno sine is a selective agonist for the adenosine A2 receptor, 2-phenyleth oxy-9-methyl-adenine (PEMA) was synthesized and tested as a potential adenosine A2 receptor antagonist. In guinea pig hearts, PEMA antagoniz ed with the same potency (pK(B) approximately 6.1) the A1-mediated neg ative dromotropic and inotropic actions and the A2-mediated coronary v asoactivity of the nonselective adenosine receptor agonist 5'-N-ethylc arboxamidoadenosine (NECA). PEMA at concentrations up to 30 muM did no t antagonize the NECA-induced relaxations in guinea pig aortic rings. At concentrations exceeding 10 muM, PEMA caused xanthine-insensitive r elaxations Of both the aorta and the coronary vessels. Pharmacological resultant analysis revealed A2 receptor antagonism by PEMA in the gui nea pig aorta (pK(B) = 5.2). The nonselective adenosine receptor antag onist 8-p-sulfophenyl-theophylline antagonized NECA responses in all f our assays with equal potency (pK(B) approximately 5.7). Thus, PEMA do es not discriminate between A2 receptors in the coronary vessels and A 1 receptors in the atria of the guinea pig, but it is 10-fold more pot ent at antagonizing the A2 receptor in coronaries than the A2 receptor s 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.