Structure-Activity Relationships of 8-Styrylxanthines as A₂-Selective Adenosine Antagonists

A series of substituted 8-styryl derivatives of 1,3,7-alkybxanthines was synthesized as potential A₂-selective adenosine receptor antagonists, and the potency at rat brain A₁- and A₂-receptors was studied in radioligand binding experiments. At the xanthine 7-position, only small hydrophobic substituents were tolerated in receptor binding. 7-Methyl analogues were roughly 1 order of magnitude more selective for A₂ versus A₁ receptors than the corresponding 7-H analogues. 1,3-Dimethylxanthine derivatives tended to be more selective for A₂-receptors than the corresponding 1,3-diallyl, diethyl, or dipropyl derivatives. Substitutions of the phenyl ring at the 3-(monosubstituted) and 3,5-(disubstituted) positions were favored. 1,3,7-Trimethyl-8-(3-chlorostyryl)xanthine was a moderately potent (K_i vs [³H]CGS 21680 was 54 nM) and highly A₂-selective (520-fold) adenosine antagonist. 1,3,7-Trimethyl-8-[3-[(3-carboxy-1-oxopropyl)amino]styryl]xanthine was highly A₂-selective (250-fold) and of enhanced water solubility (max 19 mM). 1,3-Dipropyl-7-methyl-8-(3,5-dimethoxystyryl)xanthine was a potent (K_i = 24 nM) and very A₂-selective (110-fold) adenosine antagonist.