Linear and Proximal Benzo-Separated Alkylated Xanthines as Adenosine-Receptor Antagonists

Article abstract of DOI:10.1021/jm00130a004

The linear and proximal benzo-separated derivatives of 8-phenyltheophylline, 1,3-diethyl-8-phenylxanthine, 1,3-dipropylxanthine, 1,3-dibutylxanthine, 3-isobutyl-1-methylxanthine, theophylline, caffeine, and isocaffeine have been synthesized and evaluated for affinity at the A₁ and A₂ adenosine receptors.Although structure-activity relationships in the benzo-separated series differed from the relationships in simple xanthines, the most potent of the benzo-separated xanthines were about equal in affinity to the most potent of the corresponding xanthines.On the basis of the present results and the diverse structures reported in the literature as non-xanthine adenosine antagonists, it appears that the primary requirement for the adenosine-receptor affinity in nonnucelosides is a flat, neutral, fused-ring heterocycle and that once this requirement is met there are numerous potential binding modes.