Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

A series of N⁶-bicyclic and N⁶-(2-hydroxy)­cyclopentyl derivatives of adenosine were synthesized as novel A₁R agonists and their A₁R/A₂R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N⁶-adamantyl substitution in combination with 5′-N-ethylcarboxamido or 5′-hydroxymethyl groups. In addition, we determined that 5′-(2-fluoro)­thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A₁R. Some selected compounds were also tested on A₁R and A₃R in mammalian cells revealing that four of them are entirely A₁R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A₁R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.