Adenosine Receptor Prodrugs: Towards Kidney-selective Dialkylxanthines

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 1989 Jul 1

PMID 2746513

Citations 7

Authors

S Barone

P C Churchill

K A Jacobson

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

PURINE FUNCTIONALIZED CONGENERS AS MOLECULAR PROBES FOR ADENOSINE RECEPTORS.

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A-adenosine receptors: design of selective ligands and therapeutic prospects.

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Xanthines as adenosine receptor antagonists.

Muller C, Jacobson K Handb Exp Pharmacol. 2010; (200):151-99.

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Renal selective N-acetyl-L-gamma-glutamyl prodrugs: studies on the selectivity of some model prodrugs.

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Effects of chronic administration of adenosine A1 receptor agonist and antagonist on spatial learning and memory.

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