Wells J N, Garst J E, Kramer G L
J Med Chem. 1981 Aug;24(8):954-8. doi: 10.1021/jm00140a008.
A series of xanthines with varied substituents in the 1, 3, and 8 positions were prepared in an attempt to understand the structure--activity relationship for alkylxanthines as inhibitors of two different forms of cyclic nucleotide phosphodiesterase. Polar substituents on the 1 or 3 position of the xanthine reduced the potency of the xanthines to inhibit both the calmodulin-sensitive and the "cyclic AMP specific" forms of phosphodiesterase. Polar substituents on the 8 position of the xanthine, other than a carboxylic acid, increased the potency to inhibit the calmodulin-sensitive form of phosphodiesterase, if they were capable of donating electrons to the xanthine nucleus. On the other hand, any substituent in the 8 position larger than H reduced the potency of the xanthines to inhibit the cyclic AMP specific form of phosphodiesterase. Topographical maps of the active sites of the two forms of phosphodiesterase are presented in summary.
制备了一系列在1、3和8位带有不同取代基的黄嘌呤，试图了解烷基黄嘌呤作为两种不同形式环核苷酸磷酸二酯酶抑制剂的构效关系。黄嘌呤1位或3位上的极性取代基会降低黄嘌呤抑制钙调蛋白敏感型和“环磷酸腺苷特异性”磷酸二酯酶形式的效力。除羧酸外，黄嘌呤8位上的极性取代基如果能够向黄嘌呤核供电子，则会增加抑制钙调蛋白敏感型磷酸二酯酶的效力。另一方面，8位上任何比氢大的取代基都会降低黄嘌呤抑制环磷酸腺苷特异性磷酸二酯酶形式的效力。总结了两种形式磷酸二酯酶活性位点的拓扑图。
