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. and Adams, Luke A. and Salchow, Karolina and Mistry, Shailesh N. and Middleton, Richard J. and Hill, Stephen J. and Kellam, Barrie (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). pp. 6874-6887. ISSN 0022-2623

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Abstract

he 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) (J. Cardiovasc. Pharmacol.1983, 5, 430–437.)

Item Type: Article
Schools/Departments: University of Nottingham UK Campus > Faculty of Science > School of Pharmacy
Depositing User: Snowden, Ms Diane
Date Deposited: 28 Mar 2014 16:19
Last Modified: 16 Sep 2016 02:58
URI: http://eprints.nottingham.ac.uk/id/eprint/2734

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