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A Langendorff guines pig heart preparation served for the assay of agonist potency of a series of 26 2-aralkoxyadenosines at the A1 and A2 receptors of, respectively, the atrioventricular node (conduction block) and coronary arteries (vasodilation).All of the analogues are weak agonists at the A1 receptor, requiring concentrations >9 muM to cause second degree heart block.At the A2 receptor 2-phenethoxyadenosine is the most potent of the 2-phenylalkyladenosines.The activity of ring-substituted (F, Cl, CH3, and OCH3) 2-phenethoxyadenosines increases ortho < meta < para.The EC50s of coronary vasoactivity of several para-substituted analogues are in the subnanomolar range.The most potent analogue, 2-<2-(4-methylphenyl)ethoxy>adenosine 19, has an EC50 for coronary vasodilation of 190 pM and an A1/A2 selectivity ratio of 44000.Aryl groups such as thienyl, indoloyl, or naphthyl also support A2 agonist activity.Although 2-oxoadenosine is 3 times more vasoactive than 2-aminoadenosine, the activites of the phenyl derivatives are markedly different; 2-phenoxyadenosine is 23 times weaker than 2-(phenylamino)adenosine (CV-1808).
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