Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship

TRPM3 is an ion channel that is highly expressed in nociceptive neurons and plays a key role in pain perception. In the presence of the endogenous TRPM3 ligand, pregnenolone sulfate (PS), the antifungal compound clotrimazole (Clt) augments Ca2+ signaling and opens a non-canonical pore, permeable to...

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Authors: Kahler, Jan Pascal, Aloi, Vincenzo Davide, Miedes Aliaga, Julia, Kerselaers, Sara, Voets, Thomas, Vriens, Joris, Verhelst, Steven, Barniol Xicota, Marta
Format: article
Status:Versión aceptada para publicación
Publication Date:2023
Country:España
Institution:Universitat Pompeu Fabra
Repository:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/70553
Online Access:http://hdl.handle.net/10230/70553
http://dx.doi.org/10.1021/acschembio.2c00672
Access Level:Open access
Keyword:Agonists
Anions
Fluorine
Imidazoles
Ions
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oai_identifier_str oai:repositori.upf.edu:10230/70553
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spelling Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationshipKahler, Jan PascalAloi, Vincenzo DavideMiedes Aliaga, JuliaKerselaers, SaraVoets, ThomasVriens, JorisVerhelst, StevenBarniol Xicota, MartaAgonistsAnionsFluorineImidazolesIonsTRPM3 is an ion channel that is highly expressed in nociceptive neurons and plays a key role in pain perception. In the presence of the endogenous TRPM3 ligand, pregnenolone sulfate (PS), the antifungal compound clotrimazole (Clt) augments Ca2+ signaling and opens a non-canonical pore, permeable to Na+, which aggravates TRPM3-induced pain. To date, little is known about structural features that govern the Clt modulatory effect of TRPM3. Here, we synthesized and evaluated several Clt analogues in order to gain insights into their structure-activity relationship. Our results reveal a tight SAR with the three phenyl rings on the trityl moiety being essential for the activity, as well as the presence of fluorine or chlorine substituents on the trityl group. Imidazole as a heterocycle is also necessary for activity. Interestingly, we identified a pentafluoro-trityl analogue (29a) that is able to act as a TRPM3 agonist in the absence of PS. The compounds we report in this work will be useful tools for the further study of TRPM3 modulation and its effect on pain perception.American Chemical Society (ACS)202520252023info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/70553http://dx.doi.org/10.1021/acschembio.2c00672reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésACS Chem Biol. 2023 Mar 17;18(3):456-64This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS chemical biology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acschembio.2c00672.info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/705532026-06-12T07:21:37Z
dc.title.none.fl_str_mv Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
title Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
spellingShingle Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
Kahler, Jan Pascal
Agonists
Anions
Fluorine
Imidazoles
Ions
title_short Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
title_full Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
title_fullStr Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
title_full_unstemmed Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
title_sort Clotrimazole-based modulators of the TRPM3 ion channel reveal narrow structure-activity relationship
dc.creator.none.fl_str_mv Kahler, Jan Pascal
Aloi, Vincenzo Davide
Miedes Aliaga, Julia
Kerselaers, Sara
Voets, Thomas
Vriens, Joris
Verhelst, Steven
Barniol Xicota, Marta
author Kahler, Jan Pascal
author_facet Kahler, Jan Pascal
Aloi, Vincenzo Davide
Miedes Aliaga, Julia
Kerselaers, Sara
Voets, Thomas
Vriens, Joris
Verhelst, Steven
Barniol Xicota, Marta
author_role author
author2 Aloi, Vincenzo Davide
Miedes Aliaga, Julia
Kerselaers, Sara
Voets, Thomas
Vriens, Joris
Verhelst, Steven
Barniol Xicota, Marta
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Agonists
Anions
Fluorine
Imidazoles
Ions
topic Agonists
Anions
Fluorine
Imidazoles
Ions
description TRPM3 is an ion channel that is highly expressed in nociceptive neurons and plays a key role in pain perception. In the presence of the endogenous TRPM3 ligand, pregnenolone sulfate (PS), the antifungal compound clotrimazole (Clt) augments Ca2+ signaling and opens a non-canonical pore, permeable to Na+, which aggravates TRPM3-induced pain. To date, little is known about structural features that govern the Clt modulatory effect of TRPM3. Here, we synthesized and evaluated several Clt analogues in order to gain insights into their structure-activity relationship. Our results reveal a tight SAR with the three phenyl rings on the trityl moiety being essential for the activity, as well as the presence of fluorine or chlorine substituents on the trityl group. Imidazole as a heterocycle is also necessary for activity. Interestingly, we identified a pentafluoro-trityl analogue (29a) that is able to act as a TRPM3 agonist in the absence of PS. The compounds we report in this work will be useful tools for the further study of TRPM3 modulation and its effect on pain perception.
publishDate 2023
dc.date.none.fl_str_mv 2023
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/70553
http://dx.doi.org/10.1021/acschembio.2c00672
url http://hdl.handle.net/10230/70553
http://dx.doi.org/10.1021/acschembio.2c00672
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv ACS Chem Biol. 2023 Mar 17;18(3):456-64
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society (ACS)
publisher.none.fl_str_mv American Chemical Society (ACS)
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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