Eleonora Comeo
Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A1 Receptor in Living Cells
Comeo, Eleonora; Trinh, Phuc; Nguyen, Anh T.; Nowell, Cameron J.; Kindon, Nicholas D.; Soave, Mark; Stoddart, Leigh A.; White, Jonathan M.; Hill, Stephen J.; Kellam, Barrie; Halls, Michelle L.; May, Lauren T.; Scammells, Peter J.
Authors
Phuc Trinh
Anh T. Nguyen
Cameron J. Nowell
Nicholas D. Kindon
Mark Soave
Leigh A. Stoddart
Jonathan M. White
STEPHEN HILL STEVE.HILL@NOTTINGHAM.AC.UK
Professor of Molecular Pharmacology
BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry
Michelle L. Halls
Lauren T. May
Peter J. Scammells
Abstract
The adenosine A1 receptor (A1AR) is a G-protein-coupled receptor (GPCR) that provides important therapeutic opportunities for a number of conditions including congestive heart failure, tachycardia, and neuropathic pain. The development of A1AR-selective fluorescent ligands will enhance our understanding of the subcellular mechanisms underlying A1AR pharmacology facilitating the development of more efficacious and selective therapies. Herein, we report the design, synthesis, and application of a novel series of A1AR-selective fluorescent probes based on 8-functionalized bicyclo[2.2.2]octylxanthine and 3-functionalized 8-(adamant-1-yl) xanthine scaffolds. These fluorescent conjugates allowed quantification of kinetic and equilibrium ligand binding parameters using NanoBRET and visualization of specific receptor distribution patterns in living cells by confocal imaging and total internal reflection fluorescence (TIRF) microscopy. As such, the novel A1AR-selective fluorescent antagonists described herein can be applied in conjunction with a series of fluorescence-based techniques to foster understanding of A1AR molecular pharmacology and signaling in living cells.
Citation
Comeo, E., Trinh, P., Nguyen, A. T., Nowell, C. J., Kindon, N. D., Soave, M., …Scammells, P. J. (2021). Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A1 Receptor in Living Cells. Journal of Medicinal Chemistry, 64(10), 6670-6695. https://doi.org/10.1021/acs.jmedchem.0c02067
Journal Article Type | Article |
---|---|
Acceptance Date | Mar 16, 2021 |
Online Publication Date | Mar 16, 2021 |
Publication Date | May 27, 2021 |
Deposit Date | Oct 23, 2023 |
Publicly Available Date | Nov 2, 2023 |
Journal | Journal of Medicinal Chemistry |
Print ISSN | 0022-2623 |
Electronic ISSN | 1520-4804 |
Publisher | American Chemical Society |
Peer Reviewed | Peer Reviewed |
Volume | 64 |
Issue | 10 |
Pages | 6670-6695 |
DOI | https://doi.org/10.1021/acs.jmedchem.0c02067 |
Keywords | Molecular Medicine; Drug Discovery |
Public URL | https://nottingham-repository.worktribe.com/output/5403074 |
Publisher URL | https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02067 |
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