N 6 -Substituted 5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A 3 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 A3 AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1 AR and A2A AR, respectively. In the N6 -cycloalkyl series, 2-Cl analogues generally exhibited better hA3 AR 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 A3 AR 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 A3 AR agonists as novel antistroke agents.