N6‑Substituted 5′‑N‑Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation

Potent and selective A3 adenosine receptor (AR) agonists were identified by the replacement of 4′-oxo- or 4′-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4′-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5′-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 μM. This suggests the potential for the development of 4′-selenonucleoside A3AR agonists as novel antistroke agents.