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This study explored the impact of structural modifications on truncated 4'-selenonucleosides as ligands for the A 3 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 hA 3 AR 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 A 3 AR binding site. This research not only advances our understanding of A 3 AR ligand interactions but also highlights the potential of truncated 4'-selenonucleosides as effective A 3 AR modulators., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)