163042-90-8Relevant articles and documents
2-Substitution of N6-benzyladenosine-5'-uronamides enhances selectivity for A3 adenosine receptors
Kim,Ji,Siddiqi,Olah,Stiles,Jacobson
, p. 3614 - 3621 (2007/10/02)
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.
