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Design, synthesis, and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechanoelectrical transducer channel

O'Reilly, Molly, Kirkwood, Nerissa K., Kenyon, Emma J., Huckvale, Rosemary, Cantillon, Daire M., Waddell, Simon J., Ward, Simon E., Richardson, Guy P., Kros, Corné J. and Derudas, Marco 2019. Design, synthesis, and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechanoelectrical transducer channel. Journal of Medicinal Chemistry 62 (11) , pp. 5312-5329. 10.1021/acs.jmedchem.8b01325

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Abstract

Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell’s mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol itself in cochlear cultures and also to bind more tightly to the MET channel. At higher concentrations, both carvedilol and this derivative were toxic in cochlear cultures but not in zebrafish, suggesting a good therapeutic window under in vivo conditions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: American Chemical Society
ISSN: 0022-2623
Date of First Compliant Deposit: 29 June 2020
Last Modified: 29 Jun 2020 12:15
URI: http://orca-mwe.cf.ac.uk/id/eprint/132804

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