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Subtype-Selective Fluorescent Ligands as Pharmacological Research Tools for the Human Adenosine A2A Receptor

Comeo, Eleonora; Kindon, Nicholas D.; Soave, Mark; Stoddart, Leigh A.; Kilpatrick, Laura E.; Scammells, Peter J.; Hill, Stephen J.; Kellam, Barrie

Authors

Eleonora Comeo

Mark Soave

Leigh A. Stoddart

Peter J. Scammells

STEPHEN HILL steve.hill@nottingham.ac.uk
Professor of Molecular Pharmacology

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BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry



Abstract

© 2019 American Chemical Society. Among class A G protein-coupled receptors (GPCR), the human adenosine A2A receptor (hA2AAR) remains an attractive drug target. However, translation of A2AAR ligands into the clinic has proved challenging and an improved understanding of A2AAR pharmacology could promote development of more efficacious therapies. Subtype-selective fluorescent probes would allow detailed real-time pharmacological investigations both in vitro and in vivo. In the present study, two families of fluorescent probes were designed around the known hA2AAR selective antagonist preladenant (SCH 420814). Both families of fluorescent antagonists retained affinity at the hA2AAR, selectivity over all other adenosine receptor subtypes and allowed clear visualization of specific receptor localization through confocal imaging. Furthermore, the Alexa Fluor 647-labeled conjugate allowed measurement of ligand binding affinities of unlabeled hA2AAR antagonists using a bioluminescence resonance energy transfer (NanoBRET) assay. The fluorescent ligands developed here can therefore be applied to a range of fluorescence-based techniques to further interrogate hA2AAR pharmacology and signaling.

Citation

Comeo, E., Kindon, N. D., Soave, M., Stoddart, L. A., Kilpatrick, L. E., Scammells, P. J., …Kellam, B. (2020). Subtype-Selective Fluorescent Ligands as Pharmacological Research Tools for the Human Adenosine A2A Receptor. Journal of Medicinal Chemistry, 63(5), 2656-2672. https://doi.org/10.1021/acs.jmedchem.9b01856

Journal Article Type Article
Acceptance Date Nov 8, 2019
Online Publication Date Dec 30, 2019
Publication Date Mar 12, 2020
Deposit Date Jan 13, 2020
Publicly Available Date May 1, 2020
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 63
Issue 5
Pages 2656-2672
DOI https://doi.org/10.1021/acs.jmedchem.9b01856
Keywords Molecular Medicine; Drug Discovery
Public URL https://nottingham-repository.worktribe.com/output/3706208
Publisher URL https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.9b01856

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