Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

A series of N-6-bicyclic and N-6-(2-hydroxy)-cyclopentyl derivatives of adenosine were synthesized as novel A(1)R agonists and their A(1)R/A(2)R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N-6-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 A(1)R. Some selected compounds were also tested on A(1)R and A(3)R in mammalian cells revealing that four of them are entirely A(1)R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A(1)R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.