N⁶-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 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. N

SUBMITTER: Yu J 

PROVIDER: S-EPMC5479327 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature