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.
Barone
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Laboratory of Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland.
Churchill
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PC
Jacobson
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D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D011188:Potassium / Q000652:urine; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D012964:Sodium / Q000652:urine; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D007202:Indicators and Reagents; D011355:Prodrugs; D011983:Receptors, Purinergic; D014970:Xanthines; C027513:N(6)-cyclohexyladenosine; C051869:8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1,3-dipropylxanthine; D012964:Sodium; D000241:Adenosine; D011188:Potassium