Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

Knight, Anthony; Hemmings, Jennifer Luise; Winfield, Ian; Leuenberger, Michele; Frattini, Eugenia; Frenguelli, Bruno G.; Dowell, Simon J.; Lochner, Martin; Ladds, Graham (2016). Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity. Journal of medicinal chemistry, 59(3), pp. 947-964. American Chemical Society 10.1021/acs.jmedchem.5b01402

Preview	Text Revised Manuscript jm-2015-014024 LochnerM.pdf - Accepted Version Available under License Publisher holds Copyright. Download (2MB) | Preview
	Text acs.jmedchem.5b01402.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (3MB) | Request a copy

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.

Interest & Impact

Downloads

387 since deposited on 04 Feb 2016
45 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item