American Chemical Society
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Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

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journal contribution
posted on 2016-02-05, 15:52 authored by Anthony Knight, Jennifer L. Hemmings, Ian Winfield, Michele Leuenberger, Eugenia Frattini, Bruno G. Frenguelli, Simon J. Dowell, Martin Lochner, Graham Ladds
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.