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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

JILLIAN BARKER jillian.baker@nottingham.ac.uk
Professor of Drug Discovery and Respiratory Medicine

Luke A. Adams

Karolina Salchow

Richard J. Middleton

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

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)

Journal Article Type Article
Publication Date Oct 13, 2011
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
APA6 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. doi:10.1021/jm2008562
DOI https://doi.org/10.1021/jm2008562
Publisher URL https://pubs.acs.org/doi/abs/10.1021/jm2008562

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