Franchetti P, Messini L, Cappellacci L, Grifantini M, Lucacchini A, Martini C, Senatore G
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
J Med Chem. 1994 Sep 2;37(18):2970-5. doi: 10.1021/jm00044a018.
A series of 1,3-dimethyl- and 1,3-dipropyl-8-azaxanthines, substituted at the N8 or N7 position with substituents which usually increase the affinity of the xanthines for the adenosine receptors, was synthesized and studied in radioligand binding experiments. The substitution of CH with N at the 8-position of both theophylline and caffeine dramatically reduced the affinity, as demonstrated by the fact that 8-azatheophylline and 8-azacaffeine were inert. The introduction of a methyl group at 8-position of 8-azatheophylline restored the antagonistic activity at A2 receptors, while a 8-cycloalkyl substituent increased the affinity for both receptor subtypes. A more favorable effect on affinity was produced by the substitution of the 7-methyl group in 8-azacaffeine with cycloalkyl groups. 7-Cyclopentyl-1,3-dimethyl-8-azaxanthine was 3 times more potent than caffeine at A1 receptors and 6 times less active at A2 receptors. On the contrary, the 7-cyclohexyl-1,3-dimethyl-8-azaxanthine was more potent than caffeine at A2 receptors. The substitution of 1- and 3-methyl groups with propyl in both 7- and 8-substituted 8-azatheophylline increased remarkably the affinity for A1 receptors. The 7-cyclopentyl-1,3-dipropyl-8-azaxanthine appears to be one of the most potent and selective among 7-alkyl-substituted xanthines at A1 receptors so far known. Because the 8-aza analogues of 8-substituted 1,3-dialkylxanthine were in any case less active than the corresponding xanthine derivatives, it was confirmed that the hydrogen atom at the 7-position of xanthines plays an important role in the binding to adenosine receptors.
合成了一系列1,3 - 二甲基和1,3 - 二丙基 - 8 - 氮杂黄嘌呤，它们在N8或N7位被通常会增加黄嘌呤对腺苷受体亲和力的取代基所取代，并在放射性配体结合实验中进行了研究。如8 - 氮杂茶碱和8 - 氮杂咖啡因呈惰性这一事实所示，在茶碱和咖啡因的8位用氮取代碳显著降低了亲和力。在8 - 氮杂茶碱的8位引入甲基恢复了对A2受体的拮抗活性，而8 - 环烷基取代基增加了对两种受体亚型的亲和力。用环烷基取代8 - 氮杂咖啡因中的7 - 甲基对亲和力产生了更有利的影响。7 - 环戊基 - 1,3 -二甲基 - 8 - 氮杂黄嘌呤在A1受体上的效力比咖啡因高3倍，在A2受体上的活性比咖啡因低6倍。相反，7 - 环己基 - 1,3 -二甲基 - 8 - 氮杂黄嘌呤在A2受体上比咖啡因更有效。在7 - 和8 - 取代的8 - 氮杂茶碱中，用丙基取代1 - 和3 - 甲基显著增加了对A1受体的亲和力。7 - 环戊基 - 1,3 -二丙基 - 8 - 氮杂黄嘌呤似乎是迄今为止已知的7 - 烷基取代黄嘌呤中对A1受体最有效和最具选择性的之一。由于8 - 取代的1,3 - 二烷基黄嘌呤的8 - 氮杂类似物在任何情况下都比相应的黄嘌呤衍生物活性低，因此证实了黄嘌呤7位的氢原子在与腺苷受体的结合中起重要作用。
