Structure-Activity Relationships of N6-Benzyladenosine-5′-uronamides as A3-Selective Adenosine Agonists

Carola Gallo-Rodriguez, Xiao duo Ji, Neli Melman, Barry D. Siegman, Lawrence H. Sanders, Jeraldine Orlina, Bilha Fischer, Quanlong Pu, Mark E. Olah, Philip J.M. van Galen, Gary L. Stiles, Kenneth A. Jacobson

Research output: Contribution to journalArticlepeer-review

230 Scopus citations

Abstract

Adenosine analogues modified at the 5′-position as uronamides and/or as N6 benzyl derivatives were synthesized. These derivatives were examined for affinity in radioligand binding assays at the newly discovered rat brain A3 adenosine receptor and at rat brain and A1 and A2a receptors. 5′- Uronamide substituents favored A3 selectivity in the order N-methyl > N-ethyl ≈ unsubstituted carboxamide > N-cyclopropyl. 5′-(N-Methylcarboxamido)-N6 benzyladenosine was 37–56-fold more selective for A3 receptors. Potency at A3 receptors was enhanced upon substitution of the benzyl substituent with nitro and other groups. 5′-N-Methyluronamides and N6(3-substitutedbenzyl) adenosines are optimal for potency and selectivity at A3 receptors. A series of 3-(halobenzyl)- 5′-N-ethyluronamide derivatives showed the order of potency at A1 and A2a receptors of I ∼ Br > Cl > F. At A3 receptors the 3-F derivative was weaker than the other halo derivatives. 5′-N-Methyl-N6-(3-iodobenzyl)adenosine displayed a Ki, value of 1.1 nM at A3 receptors and selectivity versus A11 and A2a receptors of 50-fold. A series of methoxybenzyl derivatives showed that a 4-methoxy group best favored A3 selectivity. A 4-sulfobenzyl derivative was a specific ligand at A3 receptors of moderate potency. An aryl amino derivative was prepared as a probe for radioiodination and receptor cross-linking.

Original languageEnglish
Pages (from-to)636-646
Number of pages11
JournalJournal of Medicinal Chemistry
Volume37
Issue number5
DOIs
StatePublished - 4 Mar 1994
Externally publishedYes

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