STRUCTURE-ACTIVITY-RELATIONSHIPS OF 8-STYRYLXANTHINES AS A(2)-SELECTIVE ADENOSINE ANTAGONISTS

A series of substituted 8-styryl derivatives of 1,3,7-alkylxanthines w as synthesized as potential A2-selective adenosine receptor antagonist s, and the potency at rat brain A1- and A2-receptors was studied in ra dioligand 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 vers us A1 receptors than the corresponding 7-H analogues. 1,3-Dimethylxant hine derivatives tended to be more selective for A2-receptors than the corresponding 1,3-diallyl, diethyl, or dipropyl derivatives. Substitu tions of the phenyl ring at the 3-(monosubstituted) and 3,5-(disubstit uted) positions were favored. 1,3,7-Trimethyl-8-(3-chlorostyryl)xanthi ne was a moderately potent (K(i) vs [H-3]CGS 21680 was 54 nM) and high ly A2-selective (520-fold) adenosine antagonist. 8-[3-[(3-carboxy-1-ox opropyl)amino]styryl]xanthine was highly A2-selective (250-fold) and o f enhanced water solubility (max 19 mM). -Dipropyl-7-methyl-8-(3,5-dim ethoxystyryl)xanthine was a potent (K(i) = 24 nM) and very A2-selectiv e (110-fold) adenosine antagonist.