Bruns R F, Daly J W, Snyder S H
Proc Natl Acad Sci U S A. 1983 Apr;80(7):2077-80. doi: 10.1073/pnas.80.7.2077.
Structure-activity analysis of alkylxanthine derivatives at adenosine receptor binding sites has been employed to design more potent adenosine receptor antagonists. Receptor affinities of xanthines were determined by measuring inhibition of the binding of N6-[3H]cyclohexyladenosine to bovine brain membranes. 1,3-Dipropyl substitutions enhance potency compared to the 1,3-dimethyl substitution in theophylline. An 8-phenyl substituent produces a considerable increase in potency, which is augmented by certain para substitutions on the 8-phenyl ring. Combining an ortho amino with a para-chloro substituent on the 8-phenyl ring affords further increases in potency. Combining all of these substituents results in 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine, a compound of extraordinary receptor affinity, with a Ki for adenosine A1 receptors of 22 pM. It is 4,000,000 times more potent than xanthine itself and 70,000 times more potent than theophylline.
对烷基黄嘌呤衍生物在腺苷受体结合位点进行构效分析，以设计出更有效的腺苷受体拮抗剂。通过测量N6-[3H]环己基腺苷与牛脑膜结合的抑制情况来确定黄嘌呤的受体亲和力。与茶碱中的1,3-二甲基取代相比，1,3-二丙基取代可增强效力。8-苯基取代会使效力显著增加，8-苯环上的某些对位取代会进一步增强这种效力。在8-苯环上结合邻氨基和对氯取代基可使效力进一步提高。将所有这些取代基组合在一起得到1,3-二丙基-8-(2-氨基-4-氯苯基)黄嘌呤，这是一种具有非凡受体亲和力的化合物，其对腺苷A1受体的Ki为22 pM。它的效力比黄嘌呤本身高400万倍，比茶碱高7万倍。
