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

Kenneth A. Jacobson, Carola Gallo-Rodriguez, Neli Melman, Bilha Fischer, Michel Maillard, Andrew van Bergen, Philip J.M. van Galen, Yishai Karton

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153 Scopus citations


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 (Ki 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 (Ki = 24 nM) and very A2-selective (110-fold) adenosine antagonist.

Original languageEnglish
Pages (from-to)1333-1342
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number10
StatePublished - 14 May 1993
Externally publishedYes


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