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Discovery of novel adenosine receptor agonists that exhibit subtype selectivity
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Knight, Anthony, Hemmings, Jennifer L., Winfield, Ian J., Leuenberger, Michele, Frattini, Eugenia, Frenguelli, Bruno G., Dowell, Simon J., Lochner, Martin and Ladds, Graham (2016) Discovery of novel adenosine receptor agonists that exhibit subtype selectivity. Journal of Medicinal Chemistry, 59 (3). pp. 947-964. doi:10.1021/acs.jmedchem.5b01402
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Official URL: http://dx.doi.org/10.1021/acs.jmedchem.5b01402
Abstract
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.
| Item Type: | Journal Article | ||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||||
| Library of Congress Subject Headings (LCSH): | Adenosine--Receptors, Adenosine--Physiological effect, G proteins--Receptors, Neurosciences | ||||||
| Journal or Publication Title: | Journal of Medicinal Chemistry | ||||||
| Publisher: | American Chemical Society | ||||||
| ISSN: | 0022-2623 | ||||||
| Official Date: | 12 January 2016 | ||||||
| Dates: |
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| Date of first compliant deposit: | 24 February 2016 | ||||||
| Volume: | 59 | ||||||
| Number: | 3 | ||||||
| Page Range: | pp. 947-964 | ||||||
| DOI: | 10.1021/acs.jmedchem.5b01402 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||
| Funder: | Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung [Swiss National Science Foundation] (SNSF), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Medical Research Council (Great Britain) (MRC), Engineering and Physical Sciences Research Council (EPSRC) | ||||||
| Grant number: | PP00P2_123536 (SNSF), PP00P2_146321(SNSF), BB/G01227X/1(BBSRC), BB/M00015X/1(BBSRC), MR/J003964/1(MRC), EP/G500045/1 (EPSRC) |
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