N-6-Substituted 5'-N-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 Xray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among the compounds tested, N-6-3-iodobenzyl analogue 3d was found to be the most potent A(3)AR full agonist (K-i = 0.57 nM), which was >= 800- and 1900-fold selective for AIAR and A(2A)AR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA(3)AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N-6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N-9 isomers, but compound 3t lacked A(3)AR activation, appearing to be a weak antagonist. 2-Cl-N-6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at <50 mu M. This suggests the potential for the development of 4'-selenonucleoside A(3)AR agonists as novel antistroke agents.