Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the μ-Opioid Receptor

Schembri, Luke S.; Stoddart, Leigh A.; Briddon, Stephen J.; Kellam, Barrie; Canals, Meritxell; Graham, Bim; Scammells, Peter J.

Abstract

Fluorescently labeled ligands are useful pharmacological research tools for studying receptor localization, trafficking, and signaling processes via fluorescence imaging. They are also employed in fluorescent binding assays. This study is centered on the design, synthesis, and pharmacological evaluation of fluorescent probes for the opioid receptors, for which relatively few non-peptidic fluorescent probes currently exist. The known μ-opioid receptor (MOR) partial agonist, buprenorphine, was structurally elaborated to include an amidoalkylamine linker moiety that was coupled with a range of fluorophores to afford new fluorescent probes. All compounds proved to be selective MOR antagonists. Confocal fluorescence microscopy studies revealed that the probe incorporating a sulfonated cyanine-5 fluorophore was the most appropriate for imaging studies. This ligand was subsequently employed in an automated fluorescence-based competition binding assay, allowing the pKi values of several well-known opioid ligands to be determined. Thus, this new probe will prove useful in future studies of MOR receptor pharmacology.

Citation

Schembri, L. S., Stoddart, L. A., Briddon, S. J., Kellam, B., Canals, M., Graham, B., & Scammells, P. J. (2015). Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the μ-Opioid Receptor. Journal of Medicinal Chemistry, 58(24), 9754-9767. https://doi.org/10.1021/acs.jmedchem.5b01664

• Journal Article Type: Article
• Acceptance Date: Oct 26, 2015
• Online Publication Date: Dec 3, 2015
• Publication Date: Dec 3, 2015
• Deposit Date: Mar 22, 2018
• Publicly Available Date: Mar 22, 2018
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 58
• Issue: 24
• Pages: 9754-9767
• DOI: https://doi.org/10.1021/acs.jmedchem.5b01664
• Public URL: https://nottingham-repository.worktribe.com/output/770332
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01664
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01664
• Contract Date: Mar 22, 2018