[3H]nitrobenzylthioinosine is a photoaffinity probe for adenosine uptake sites in brain

Marangos, Paul J.; Clark-Rosenberg, R L; Patel, Jitendra

doi:10.1016/0014-2999(82)90228-x

Cited by 13 publications

(1 citation statement)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These experiments were carried out because of the structural similarity of the present adenosine derivatives to various 6-benzyl ethers or thioether derivatives of purine ribosides, known to be high affnity antagonists of adenosine uptake via this transporter. 24 The simple A^-benzyl derivative of adenosine was not selective for the receptors vs the adenosine transporter. In contrast, 2-chloro-2V6-(3-iodobenzyl)adenosine-5'-AT-methyluronamide, 13, was 46 000-fold selective for A3 receptors vs the Na+independent adenosine transporter, as indicated in displacement of [3H]-S-(4-nitrobenzyl)-6-thioinosine binding in rat brain membranes.…”

Section: Resultsmentioning

confidence: 99%

2-Substitution of N6-Benzyladenosine-5'-uronamides Enhances Selectivity for A3 Adenosine Receptors

Kim¹,

Ji²,

Siddiqi³

et al. 1994

J. Med. Chem.

200

225

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%