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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 ISSN 0022-2623.

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Official URL: http://dx.doi.org/10.1021/acs.jmedchem.5b01402

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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
Subjects: Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > 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:
DateEvent
12 January 2016Published
10 September 2015Submitted
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
Date of first compliant deposit: 24 February 2016
Date of first compliant Open Access: 12 January 2017
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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