2-Substitution of N6-benzyladenosine-5'-uronamides enhances selectivity for A3 adenosine receptors

Journal of Medicinal Chemistry
H O KimK A Jacobson

Abstract

Adenosine derivatives bearing an N6-(3-iodobenzyl) group, reported to enhance the affinity of adenosine-5'-uronamide analogues as agonists at A3 adenosine receptors (J. Med. Chem. 1994, 37, 636-646), were synthesized starting from methyl beta-D-ribofuranoside in 10 steps. Binding affinities at A1 and A2a receptors in rat brain membranes and at cloned rat A3 receptors from stably transfected CHO cells were compared. N6-(3-Iodobenzyl)adenosine was 2-fold selective for A3 vs A1 or A2a receptors; thus it is the first monosubstituted adenosine analogue having any A3 selectivity. The effects of 2-substitution in combination with modifications at the N6- and 5'-positions were explored. 2-Chloro-N6-(3-iodobenzyl)adenosine had a Ki value of 1.4 nM and moderate selectivity for A3 receptors. 2-Chloro-N6-(3-iodobenzyl)adenosine- 5'-N-methyluronamide, which displayed a Ki value of 0.33 nM, was selective for A3 vs A1 and A2a receptors by 2500- and 1400-fold, respectively. It was 46,000-fold selective for A3 receptors vs the Na(+)-independent adenosine transporter, as indicated in displacement of [3H]N6-(4- nitrobenzyl)-thioinosine binding in rat brain membranes. In a functional assay in CHO cells, it inhibited adenylate cyclase via rat A3 re...Continue Reading

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Citations

Oct 1, 1995·Bioorganic & Medicinal Chemistry·S M SiddiqiK A Jacobson
Jun 5, 2002·European Journal of Pharmacology·Zhan-guo Gao, Kenneth A Jacobson
Dec 4, 2002·European Journal of Pharmacology·Sidney R SmithCarol Terminelli
Aug 1, 1998·European Journal of Pharmacology·S SatohO Hayaishi
Mar 17, 1999·European Journal of Pharmacology·D K Von LubitzK A Jacobson
Aug 31, 2001·Pharmacology, Biochemistry, and Behavior·C M KnappC Kornetsky
Apr 4, 2003·Behavioural Brain Research·Andrzej RubajMaria Sieklucka-Dziuba
Mar 6, 2003·Bioorganic & Medicinal Chemistry Letters·Moo Hong LimLak Shin Jeong
Jan 5, 1999·Bioorganic & Medicinal Chemistry Letters·J P MogensenL J Knutsen
Jul 29, 1998·Bioorganic & Medicinal Chemistry·S A Poulsen, R J Quinn
Mar 18, 2005·Journal of Medicinal Chemistry·Susanna TchilibonKenneth A Jacobson
Apr 4, 2012·Journal of Medicinal Chemistry·Pier Giovanni BaraldiKatia Varani
Jun 8, 2000·Journal of Medicinal Chemistry·K A JacobsonR G Ravi
Apr 12, 2008·Nucleosides, Nucleotides & Nucleic Acids·Moon Woo ChunLak Shin Jeong
Feb 22, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Zhoumou ChenDaniela Salvemini
Jul 29, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Tulasi R JinkaKelly L Drew
Jul 11, 2001·Journal of Molecular and Cellular Cardiology·V ShneyvaysA Shainberg
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·B T Liang, K A Jacobson
Mar 7, 2014·Purinergic Signalling·Chi Ting LeungMortimer M Civan
Sep 19, 2007·Expert Opinion on Emerging Drugs·Zhan-Guo Gao, Kenneth A Jacobson
Nov 14, 2006·Experimental Cell Research·Marina HermesDoris Kloor
Mar 26, 2002·Biochemical Pharmacology·Seong Gon KimKenneth A Jacobson
Oct 19, 2016·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Kenneth A Jacobson, Mortimer M Civan

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