Adenosine antagonism by purines,pteridines and benzopteridines in human fibroblasts

Theophylline (K_i 5 μM) is a competitive inhibitor of the increase in cyclic AMP caused by adenosine in the VA13 fibroblast line. More than 100 purine bases and structurally related heterocycles were tested as adenosine antagonists. Three families of adenosine antagonists were found: xanthines, benzo[g]pteridines and 9-substituted adenines. For the xanthines, the optimal group at the 1-position was butyl (5-fold improvement versus methyl), at the 7-position was 2-chloroethyl (5-fold improvement versus hydrogen) and at the 8-position was p-bromophenyl (100-fold improvement versus hydrogen). The receptors appeared to have butyl- and phenyl-sized “pockets” at the 1- and 8-positions, respectively, since compounds with larger groups had greatly reduced activity.