Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechano-electrical 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, Corne 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 mechano-electrical transducer channel. Journal of Medicinal Chemistry. ISSN 0022-2623

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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 culture and in vivo zebrafish assays and investigated its mechanism of protection which we found may be mediated by block of the hair cell’s mechano-electrical 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
Keywords: Carvedilol, mechano-electrical transducer channel, aminoglycoside, ototoxicity
Schools and Departments: Brighton and Sussex Medical School > Global Health and Infection
School of Life Sciences > Neuroscience
Research Centres and Groups: Sussex Drug Discovery Centre
Sussex Neuroscience
Wellcome Trust Brighton and Sussex Centre for Global Health Research
Subjects: Q Science
Depositing User: Marco Derudas
Date Deposited: 21 May 2019 08:28
Last Modified: 01 Jul 2019 14:46
URI: http://sro.sussex.ac.uk/id/eprint/83857

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Project NameSussex Project NumberFunderFunder Ref
Mechanisms of aminoglyscoside ototoxicity and drug damage repair in sensory hair cells: towards the design of otoprotective strategies.G1025MRC-MEDICAL RESEARCH COUNCILMR/K005561/1