Xanthine derivatives as antagonists at A1 and A2 adenosine receptors.
A variety of alkylxanthines has been comparatively examined as antagonists of A1 adenosine receptors in rat fat cells, rat and bovine cerebral cortex and of A2 adenosine receptors in human platelets. With few exceptions all xanthine derivatives with 7-position substituents such as diprophylline, proxyfylline, pentoxifylline and etofylline were less potent antagonists than xanthine itself which had Ki-values of 170 mumol/l (A1) and 93 mumol/l (A2). Theophylline, caffeine and 3-isobutyl-1-methylxanthine were more potent than xanthine but nearly equipotent antagonists at both receptor subtypes. 8-Phenyl substituents considerably increased the antagonist potency at A1 and A2 receptors. 1,3-Diethyl-8-phenylxanthine was the most potent A2 antagonist (Ki 0.2 mumol/l) in human platelets. At A1 receptors 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX) was the most potent antagonist in all three tissues with Ki-values from 0.3 to 8.6 nmol/l. Several 8-phenylxanthine derivatives were remarkably selective antagonists at A1 receptors. 8-Phenyltheophylline was approximately 700 times more potent as antagonist at A1 receptors (bovine brain) than at A2 receptors (human platelets), and PACPX was even 1,600 times more potent as A1 adenosine receptor antagonist. These compounds offer a possibility for a subtype-selective blockade of adenosine receptors.