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Nebivolol as a Potent TRPM8 Channel Blocker: A Drug-Screening Approach through Automated Patch Clamping and Ligand-Based Virtual Screening

Jahanfar, Farhad; Sadofsky, Laura; Morice, Alyn; D’Amico, Massimo

Authors

Farhad Jahanfar

Massimo D’Amico



Abstract

Transient Receptor Potential Melastatin 8 (TRPM8) from the melastatin TRP channel subfamily is a non-selective Ca2+-permeable ion channel with multimodal gating which can be activated by low temperatures and cooling compounds, such as menthol and icilin. Different conditions such as neuropathic pain, cancer, overactive bladder syndrome, migraine, and chronic cough have been linked to the TRPM8 mode of action. Despite the several potent natural and synthetic inhibitors of TRPM8 that have been identified, none of them have been approved for clinical use. The aim of this study was to discover novel blocking TRPM8 agents using automated patch clamp electrophysiology combined with a ligand-based virtual screening based on the SwissSimilarity platform. Among the compounds we have tested, nebivolol and carvedilol exhibited the greatest inhibitory effect, with an IC50 of 0.97 ± 0.15 µM and 9.1 ± 0.6 µM, respectively. This study therefore provides possible candidates for future drug repurposing and suggests promising lead compounds for further optimization as inhibitors of the TRPM8 ion channel.

Citation

Jahanfar, F., Sadofsky, L., Morice, A., & D’Amico, M. (2022). Nebivolol as a Potent TRPM8 Channel Blocker: A Drug-Screening Approach through Automated Patch Clamping and Ligand-Based Virtual Screening. Membranes, 12(10), Article 954. https://doi.org/10.3390/membranes12100954

Journal Article Type Article
Acceptance Date Sep 24, 2022
Online Publication Date Sep 28, 2022
Publication Date Oct 1, 2022
Deposit Date Oct 19, 2022
Publicly Available Date Oct 20, 2022
Journal Membranes
Electronic ISSN 2077-0375
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 12
Issue 10
Article Number 954
DOI https://doi.org/10.3390/membranes12100954
Keywords TRPM8; Repurposing; Nebivolol; Carvedilol; Automated patch clamp
Public URL https://hull-repository.worktribe.com/output/4100188

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0

Copyright Statement
Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://cre‐ ativecommons.org/licenses/by/4.0/)





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