title: 2-Substitution of N6-benzyladenosine-5'-uronamides enhances selectivity for A3 adenosine receptors.
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 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.
authors.affiliation: Molecular Recognition Section, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: H O
authors.initials: HO
authors.lastname: Kim
authors.forename: X D
authors.initials: XD
authors.lastname: Ji
authors.forename: S M
authors.initials: SM
authors.lastname: Siddiqi
authors.forename: M E
authors.initials: ME
authors.lastname: Olah
authors.forename: G L
authors.initials: GL
authors.lastname: Stiles
authors.forename: K A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D015394:Molecular Structure; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C090035:2-(methylamino)-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide; C090036:2-(methylthio)-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide; D000067956:Adenylyl Cyclase Inhibitors; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide