Adenosine receptor prodrugs: towards kidney-selective dialkylxanthines

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.