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A new series of 4′-selenoadenosine-5′-<i>N,N</i>-dimethyluronamide derivatives as highly potent and selective human A₃ adenosine receptor (hA₃AR) antagonists, is described. The highly selective A₃AR agonists, 4′-selenoadenosine-5′-<i>N</i>-methyluronamides were successfully converted into selective antagonists by adding a second <i>N</i>-methyl group to the 5′-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hA₃AR. Among the synthesized compounds, 2-H-<i>N</i>⁶-3-iodobenzylamine derivative <b>9f</b> exhibited the highest binding affinity at hA₃AR. (<i>K_i</i> = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-<i>N</i>⁶-3-iodobenzylamine derivative <b>9l</b> demonstrated hA₃AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5′-uronamide as an essential hydrogen bonding donor for hA₃AR activation.