Subtype-Selective Fluorescent Ligands as Pharmacological Research Tools for the Human Adenosine A 2A Receptor

Among class A G protein-coupled receptors (GPCR), the human adenosine A receptor (hA AR) remains an attractive drug target. However, translation of A AR ligands into the clinic has proved challenging and an improved understanding of A AR pharmacology could promote development of more efficacious the...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 63; no. 5; pp. 2656 - 2672
Main Authors:	Comeo, Eleonora, Kindon, Nicholas D, Soave, Mark, Stoddart, Leigh A, Kilpatrick, Laura E, Scammells, Peter J, Hill, Stephen J, Kellam, Barrie
Format:	Journal Article
Language:	English
Published:	United States 12-03-2020
Subjects:	Adenosine A2 Receptor Antagonists - chemistry Adenosine A2 Receptor Antagonists - metabolism Adenosine A2 Receptor Antagonists - pharmacology Drug Discovery Fluorescent Dyes - chemistry Fluorescent Dyes - metabolism Fluorescent Dyes - pharmacology HEK293 Cells Humans Ligands Molecular Docking Simulation Optical Imaging Pyrimidines - chemistry Pyrimidines - metabolism Pyrimidines - pharmacology Receptor, Adenosine A2A - analysis Receptor, Adenosine A2A - metabolism Triazoles - chemistry Triazoles - metabolism Triazoles - pharmacology
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Summary:	Among class A G protein-coupled receptors (GPCR), the human adenosine A receptor (hA AR) remains an attractive drug target. However, translation of A AR ligands into the clinic has proved challenging and an improved understanding of A AR 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 hA AR selective antagonist preladenant (SCH 420814). Both families of fluorescent antagonists retained affinity at the hA AR, 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 hA AR 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 hA AR pharmacology and signaling.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.9b01856