Aza-analogs of 8-styrylxanthines as A2A-adenosine receptor antagonists.
In the present study we synthesized aza-analogs of 8-styrylxanthines, in which the ethenyl bridge is replaced by an imine, amide, or azo function, in order to investigate structure-activity relationships of the 8-substituent of A2A-selective xanthine derivatives. Thus, various 8-substituents were combined with theophylline or caffeine, respectively, and affinities of the novel compounds for adenosine A1- and A2a-receptors were determined and compared with those of analogous 8-styrylxanthine derivatives. 8-(Benzylideneamino)caffeine derivatives exhibited high affinity and selectivity for A2A-adenosine receptors, but were unstable in aqueous buffer solution at physiological pH values. 8-(Phenylazo)caffeine derivatives were less potent than corresponding 8-styrylcaffeine derivatives at adenosine receptors. The most potent azo compound of the present series was 8-(m-chlorophenylazo)caffeine (14b) exhibiting a Ki value of 400 nM at A2A-adenosine receptors and 20-fold selectivity versus A1-receptors. Due to the facile synthetic access to 8-(phenylazo)xanthine derivatives, which are obtained by coupling of 8-unsubstituted xanthines with phenyldiazonium salts, 14b may be an interesting new lead compound for the development of more potent and selective A2A-antagonists with azo structure.
Müller
C E
CE
Julius-Maximilians-Universität Würzberg, Institut für Pharmazie und Lebensmittelchemie, Germany.
Sauer
R
R
Geis
U
U
Frobenius
W
W
Talik
P
P
Pawlowski
M
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001372:Aza Compounds; D058915:Purinergic P1 Receptor Antagonists; D013343:Styrenes; D014970:Xanthines; C027513:N(6)-cyclohexyladenosine; D000241:Adenosine