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

• Published in: Journal of medicinal chemistry Vol. 36; no. 10; pp. 1333 - 1342
• Main Authors: JACOBSON, KA, GALLORODRIGUEZ, C, MELMAN, N, FISCHER, B, MAILLARD, M, VANBERGEN, A, VANGALEN, PJM, KARTON, Y
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 14.05.1993
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; SUBSTITUTION; POTENT; AFFINITY; ANALOGS; SPECIES-DIFFERENCES; RAT-BRAIN; INHIBITORS; BINDING-SITES; AGONISTS; A1-ADENOSINE RECEPTORS
• ISSN: 0022-2623
• DOI: 10.1021/jm00062a005

A series of substituted 8-styryl derivatives of 1,3,7-alkylxanthines 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 [H-3]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.