Xanthine derivatives as antagonists at A₁ and A₂ adenosine receptors

Summary

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 hadK _i-values of 170 μmol/l (A₁) and 93 μmol/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 (K _i 0.2 μmol/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 withK _i-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.