JILLIAN BAKER jillian.baker@nottingham.ac.uk
Professor of Drug Discovery and Respiratory Medicine
Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-labeled fluorescent ligands for human β-adrenoceptors
Baker, Jillian G.; Adams, Luke A.; Salchow, Karolina; Mistry, Shailesh N.; Middleton, Richard J.; Hill, Stephen J.; Kellam, Barrie
Authors
Luke A. Adams
Karolina Salchow
Dr SHAILESH MISTRY Shailesh.Mistry@nottingham.ac.uk
Associate Professor
Richard J. Middleton
STEPHEN HILL STEVE.HILL@NOTTINGHAM.AC.UK
Professor of Molecular Pharmacology
BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry
Abstract
The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and single molecule level demands the availability of high-quality fluorescent ligands. To this end, this study evaluated a new series of red-emitting ligands for the human β-adrenoceptor family. Upon the basis of the orthosteric ligands propranolol, alprenolol, and pindolol, the synthesized linker-modified congeners were coupled to the commercially available fluorophore BODIPY 630/650-X. This yielded high-affinity β-adrenoceptor fluorescent ligands for both the propranolol and alprenolol derivatives; however, the pindolol-based products displayed lower affinity. A fluorescent diethylene glycol linked propranolol derivative (18a) had the highest affinity (log KD of −9.53 and −8.46 as an antagonist of functional β2- and β1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human β2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent β2-selective antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118551)
Citation
Baker, J. G., Adams, L. A., Salchow, K., Mistry, S. N., Middleton, R. J., Hill, S. J., & Kellam, B. (2011). Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-labeled fluorescent ligands for human β-adrenoceptors. Journal of Medicinal Chemistry, 54(19), 6874-6887. https://doi.org/10.1021/jm2008562
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 29, 2011 |
Online Publication Date | Aug 29, 2011 |
Publication Date | Oct 13, 2011 |
Deposit Date | Nov 23, 2018 |
Publicly Available Date | Jan 31, 2019 |
Journal | Journal of Medicinal Chemistry |
Print ISSN | 0022-2623 |
Electronic ISSN | 1520-4804 |
Publisher | American Chemical Society |
Peer Reviewed | Peer Reviewed |
Volume | 54 |
Issue | 19 |
Pages | 6874-6887 |
DOI | https://doi.org/10.1021/jm2008562 |
Public URL | https://nottingham-repository.worktribe.com/output/1304279 |
Publisher URL | https://pubs.acs.org/doi/abs/10.1021/jm2008562 |
Contract Date | Jan 31, 2019 |
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