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

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 N⁶-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.