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

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.

Berbamine Analogs Exhibit Differential Protective Effects From Aminoglycoside-Induced Hair Cell Death

“…This would allow for temporary charges to reside within the structure which may form favorable electrostatic interactions with its target and could explain why quaternary versions of protective drugs such as ORC-13661 are more active. This is further supported by evidence from Chowdhury et al ( 2018 ) and O’Reilly et al ( 2019 ). Both studies found that aminoglycoside otoprotection required a basic center with a positive charge to engage in electrostatic interactions, such as basic nitrogen or a quaternary ammonium salt.…”

“…Nevertheless, aryl groups are present in other protective compounds such as tacrine, berbamine, carvedilol, ORC-13661, and phenoxybenzamine, suggesting the importance of the aryl moiety for otoprotection (Ou et al, 2012 ; Kruger et al, 2016 ; Chowdhury et al, 2018 ; O’Reilly et al, 2019 ). It is likely that the phenyl group, among other aryl groups, may be necessary for protection due to their unusual stability and ability to delocalize charges within their structure by resonance.…”

“…These compounds were half the weight of the other analogs tested. Additionally, analogs BA-13 through BA-16 have a carbon center, similar to some non-protective carvedilol derivatives that substituted the center nitrogen with carbon or nonbasic nitrogen (O’Reilly et al, 2019 ).…”

“…To date, the zebrafish lateral line has served as a platform for the discovery of several drug candidates with otoprotective potentials, such as PROTO- 1 (the precursor to ORC-13661), berbamine, tacrine, afimoxifene, and linopirdine (e.g., Ton and Parng, 2005 ; Owens et al, 2008 ; Ou et al, 2009 ; Vlasits et al, 2012 ; Kruger et al, 2016 ; Kenyon et al, 2017 ). Furthermore, some of these drugs confer similar protections in the mammalian inner ear (Ou et al, 2009 ; Kenyon et al, 2017 ; Kirkwood et al, 2017 ; Majumder et al, 2017 ; Chowdhury et al, 2018 ; Kitcher et al, 2019 ; O’Reilly et al, 2019 ).…”

ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity

“…A similar channel interaction has been reported for the alkaloid d-tubocurarine (29). These results demonstrate that ORC-13661 is, similar to the AGs themselves and other positively charged compounds, a permeant blocker of the MET channel (12, 29, 55).…”