Structure-Activity Relationship of Truncated 4'-Selenonucleosides: A3 Adenosine Receptor Activity and Binding Selectivity

ACS Med Chem Lett. 2024 Aug 22;15(9):1620-1626. doi: 10.1021/acsmedchemlett.4c00344. eCollection 2024 Sep 12.

Abstract

This study explored the impact of structural modifications on truncated 4'-selenonucleosides as ligands for the A3 adenosine receptor (AR). We synthesized and evaluated a series of these compounds for their binding affinities, functional activities, and structural interactions by using computational modeling. The SAR study revealed that all compounds exhibited selective and notable hA3AR binding, among which 6l (K i = 5.2 nM) and 6m (K i = 5.7 nM) were found as the best binding compounds. The representative N 6-cyclopropyl compound 6m was found to be a partial agonist, contrasting with the antagonist profiles of truncated 4'-oxo and 4'-thionucleosides. Computational docking highlighted 6m's unique interaction with Thr94 at the A3AR binding site. This research not only advances our understanding of A3AR ligand interactions but also highlights the potential of truncated 4'-selenonucleosides as effective A3AR modulators.