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

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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 (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Hemmings, Jennifer Luise; Leuenberger, Michele and Lochner, Martin

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0022-2623

Publisher:

American Chemical Society

Funders:

[4] Swiss National Science Foundation
[UNSPECIFIED] BBSRC
[UNSPECIFIED] EPSRC
[UNSPECIFIED] MRC

Language:

English

Submitter:

Martin Lochner

Date Deposited:

04 Feb 2016 08:44

Last Modified:

02 May 2017 11:26

Publisher DOI:

10.1021/acs.jmedchem.5b01402

PubMed ID:

26756468

BORIS DOI:

10.7892/boris.76205

URI:

https://boris.unibe.ch/id/eprint/76205

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