Structure-activity relationships of 8-styrylxanthines as A2-selective adenosine antagonists.
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 (Ki vs [3H]CGS 21680 was 54 nM) and highly A2-selective (520-fold) adenosine antagonist. 1,3,7-Trimethyl-8-[(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.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
K A
KA
Jacobson
C
C
Gallo-Rodriguez
N
N
Melman
B
B
Fischer
M
M
Maillard
A
A
van Bergen
P J
PJ
van Galen
Y
Y
Karton
D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism; D001665:Binding Sites; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D000959:Antihypertensive Agents; D010627:Phenethylamines; D011983:Receptors, Purinergic; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine