PUBLICATION

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

Authors
O'Reilly, M., Kirkwood, N.K., Kenyon, E.J., Huckvale, R., Cantillon, D.M., Waddell, S.J., Ward, S.E., Richardson, G.P., Kros, C.J., Derudas, M.
ID
ZDB-PUB-190516-3
Date
2019
Source
Journal of medicinal chemistry   62(11): 5312-5329 (Journal)
Registered Authors
Kenyon, Emma
Keywords
none
MeSH Terms
  • Aminoglycosides/adverse effects*
  • Animals
  • Carvedilol/chemical synthesis*
  • Carvedilol/chemistry
  • Carvedilol/pharmacology*
  • Chemistry Techniques, Synthetic
  • Cytoprotection/drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Electrophysiological Phenomena/drug effects
  • Hair Cells, Auditory/cytology*
  • Hair Cells, Auditory/drug effects*
  • Mechanotransduction, Cellular/drug effects*
  • Mice
  • Zebrafish
PubMed
31083995 Full text @ J. Med. Chem.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping