Effect of trifluoromethyl and other substituents on activity of xanthines at adenosine receptors.
An aryl p-(trifluoromethyl) substituent increases the affinity of 1,3-disubstituted 8-phenylxanthines at A2a-adenosine receptors, while having little effect on affinity at A1-adenosine receptors. In contrast, an aryl p-(trifluoromethyl) substituent has little effect on affinity of 3,7-disubstituted and 1,3,7-trisubstituted 8-phenylxanthines. An aryl p-sulfo substituent reduces affinity of all 8-phenylxanthines at A1- and A2a-adenosine receptors. An 8-(trifluoromethyl) substituent markedly reduces affinity of 1,3-dialkylxanthines at both A1- and A2a-adenosine receptors. In contrast, 8-(trifluoromethyl)caffeine retains affinity for A2a-adenosine receptors, but does lose affinity for A1-adenosine receptors. 8-Bromo-, 8-acryl-, and 8-pent-1-enylcaffeines are also selective for A2-adenosine receptors, while 8-cyclobutylcaffeine is nonselective. 8-[trans-2-(tert-butyloxycarbonyl)vinylcaffeine is 20-fold selective for Aza vs A1 receptors.
Jacobson
K A
KA
Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
Shi
D
D
Gallo-Rodriguez
C
C
Manning
M
M
Müller
C
C
Daly
J W
JW
Neumeyer
J L
JL
Kiriasis
L
L
Pfleiderer
W
W
D000215:Acylation; D000478:Alkylation; D000818:Animals; D001921:Brain / Q000378:metabolism; D002110:Caffeine / Q000031:analogs & derivatives; D002462:Cell Membrane / Q000378:metabolism; D003500:Cyclization; D015394:Molecular Structure; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014269:Trifluoroacetic Acid; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D002110:Caffeine; D014269:Trifluoroacetic Acid