<i>N</i>⁶-Substituted 5′-<i>N</i>-Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A₃ Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation

Abstract

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 (K_i = 0.57 nM), which was ≥800- and 1900-fold selective for A₁AR and A_2AAR, 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.