Barone S, Churchill P C, Jacobson K A
Laboratory of Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland.
J Pharmacol Exp Ther. 1989 Jul;250(1):79-85.
XAC (xanthine amine congener, 8-[4-[(2-aminoethyl)-aminocarbonylmethyloxy]phenyl]-1,3-dipropy lxanthine is a potent adenosine antagonist that reverses the reduction in urine flow, sodium excretion and heart rate produced by the adenosine agonist, N6-cyclohexyladenosine. New derivatives of XAC in which the primary amino group has been condensed to the gamma-carboxyl group of glutamic acid have been synthesized as prodrugs. These amino acid-XAC conjugates, which are considerably less potent than XAC in competitive binding assays at A1-adenosine receptors, are designed for selective enzymatic activation in the kidneys. The gamma-glutamyl xanthine derivatives are substrates for gamma-glutamyl transferase (EC 2.3.2.2) to generate an amine-functionalized xanthine. N-acetyl-gamma-L-glutamyl-XAC is not active in vivo, consistent with inability of renal acylase (EC 3.5.1.14) to hydrolyze the acetyl group, a prerequisite step for the production of XAC from this molecule. The xanthine derivatives, gamma-L-glutamyl-XAC and gamma-L-glutamyl-gamma-L-glutamyl-XAC are metabolized to XAC and produce a diuresis in vivo.
XAC（黄嘌呤胺类似物，8-[4-[(2-氨基乙基)-氨基羰基甲氧基]苯基]-1,3-二丙基黄嘌呤）是一种强效腺苷拮抗剂，可逆转腺苷激动剂N6-环己基腺苷引起的尿流、钠排泄和心率降低。已合成了XAC的新衍生物，其中伯氨基已与谷氨酸的γ-羧基缩合形成前药。这些氨基酸-XAC缀合物在A1-腺苷受体的竞争性结合试验中比XAC的效力低得多，其设计目的是在肾脏中进行选择性酶促活化。γ-谷氨酰黄嘌呤衍生物是γ-谷氨酰转移酶（EC 2.3.2.2）的底物，可生成胺功能化的黄嘌呤。N-乙酰-γ-L-谷氨酰-XAC在体内无活性，这与肾酰基转移酶（EC 3.5.1.14）无法水解乙酰基一致，而乙酰基水解是由该分子产生XAC的前提步骤。黄嘌呤衍生物γ-L-谷氨酰-XAC和γ-L-谷氨酰-γ-L-谷氨酰-XAC在体内代谢为XAC并产生利尿作用。
