Müller C E, Sauer R, Geis U, Frobenius W, Talik P, Pawlowski M
Julius-Maximilians-Universität Würzberg, Institut für Pharmazie und Lebensmittelchemie, Germany.
Arch Pharm (Weinheim). 1997 Jun;330(6):181-9. doi: 10.1002/ardp.19973300606.
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.
在本研究中，我们合成了8-苯乙烯基黄嘌呤的氮杂类似物，其中乙烯基桥被亚胺、酰胺或偶氮官能团取代，以研究A2A选择性黄嘌呤衍生物8-取代基的构效关系。因此，分别将各种8-取代基与茶碱或咖啡因结合，并测定新化合物对腺苷A1和A2a受体的亲和力，并与类似的8-苯乙烯基黄嘌呤衍生物进行比较。8-（苄叉氨基）咖啡因衍生物对A2A-腺苷受体表现出高亲和力和选择性，但在生理pH值的水性缓冲溶液中不稳定。8-（苯基偶氮）咖啡因衍生物在腺苷受体上的活性低于相应的8-苯乙烯基咖啡因衍生物。本系列中最有效的偶氮化合物是8-（间氯苯基偶氮）咖啡因（14b），在A2A-腺苷受体上的Ki值为400 nM，对A1受体的选择性为20倍。由于通过8-未取代的黄嘌呤与苯基重氮盐偶联可轻松合成8-（苯基偶氮）黄嘌呤衍生物，14b可能是开发更有效和选择性的具有偶氮结构的A2A拮抗剂的有趣新先导化合物。
