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J Med Chem. 2016 Feb 11;59(3):947-64. doi: 10.1021/acs.jmedchem.5b01402. Epub 2016 Feb 1.

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.

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Systems Biology Doctoral Training Centre, University of Warwick , Coventry CV4 7AL, U.K.
Department of Chemistry and Biochemistry, University of Bern , 3012 Bern, Switzerland.
Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick , Coventry CV4 7AL, U.K.
Department of Pharmacology, University of Cambridge , Tennis Court Road, Cambridge CB2 1PD, U.K.
School of Life Sciences, University of Warwick , Coventry CV4 7AL, U.K.
Department of Platform Technology and Science, GlaxoSmithKline , Hertfordshire SG1 2NY, U.K.


A series of N(6)-bicyclic and N(6)-(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 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 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.

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