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 <b>6l</b> (<i>K</i> _i = 5.2 nM) and <b>6m</b> (<i>K</i> _i = 5.7 nM) were found as the best binding compounds. The representative <i>N</i> ⁶-cyclopropyl compound <b>6m</b> was found to be a partial agonist, contrasting with the antagonist profiles of truncated 4'-oxo and 4'-thionucleosides. Computational docking highlighted <b>6m</b>'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.