- Preparation of nucleoside uronamides as A3 adenosine receptor agonists.
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The present invention provides N 6-benzyladenosine-5'-N-uronamide and related substituted compounds, particularly those containing substituents on the benzyl and/or uronamide groups, and modified xanthine ribosides, as well as pharmaceutical compositions containing such compounds. The present invention also provides a method of selectively activating an A 3 adenosine receptor in a mammal, which method comprises acutely or chronically administering to a mammal in need of selective activation of its A 3 adenosine receptor a therapeutically effective amount of a compound which binds with the A. sub.3 receptor so as to stimulate an A 3 receptor-dependent response.
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- Structure-Activity Relationships of 9-Alkyladenine and Ribose-Modified Adenosine Derivatives at Rat A3 Adenosine Receptors
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9-Alkyladenine derivatives and ribose-modified N6-benzyladenosine derivatives were synthesized in an effort to identify selective ligands for the rat A3 adenosine receptor and leads for the development of antagonists.The derivatives
- Jacobson, Kenneth A.,Siddiqi, Suhaib M.,Olah, Mark E.,Ji, Xiao-duo,Melman, Neli,et al.
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p. 1720 - 1735
(2007/10/02)
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- 2-Substitution of N6-benzyladenosine-5'-uronamides enhances selectivity for A3 adenosine receptors
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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 β-D-ribofuranoside in 10 steps. Binding affinities at A1 and A(2a) 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 A(2a) 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 K(i) value of 1.4 nM and moderate selectivity for A3 receptors. 2-Chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide, which displayed a K(i) value of 0.33 nM, was selective for A3 vs A1 and A(2a) 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 receptors with an IC50 of 67 nM. 2- (Methylthio)-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide and 2- (methylamino)-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide were less potent, but nearly as selective for A3 receptors. Thus, 2-substitution (both small and sterically bulky) is well-tolerated at A3 receptors, and its A3 affinity-enhancing effects are additive with effects of uronamides at the 5'- position and a 3-iodobenzyl group at the N6-position.
- Kim,Ji,Siddiqi,Olah,Stiles,Jacobson
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p. 3614 - 3621
(2007/10/02)
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