Identification of isoxazole-based TRPA1 inhibitors with analgesic effects in vivo
The transient receptor potential ankyrin 1 (TRPA1) channel has been extensively studied as a potential therapeutic target for the treatment of different pain types, with better efficacy and safety profiles compared to current therapies. Because TRPA1 is implicated in different pathophysiological processes, selective antagonists of this channel could provide therapeutic benefits beyond pain relief. In this study, we report the design and synthesis of a novel series of carboxamide derivatives incorporating an isoxazole moiety, which were evaluated for their ability to inhibit TRPA1-mediated signalling. Among these, we identified the TRPA1 antagonists 12 and 13 displaying nanomolar potency in vitro and significant analgesic effects against the TRPA1 agonist, allyl isothiocyanate and in the formalin test in mice. Docking analyses were also conducted to explore the binding modes of the most representative compounds with the proposed pharmacological target.
Authors
- Pierangelo Geppetti (ORCID: https://orcid.org/0000-0003-3797-8371)
- Salvatore Pacifico (ORCID: https://orcid.org/0000-0002-3377-5107)
- Chiara Sturaro (ORCID: https://orcid.org/0000-0002-2708-9223)
- Matilde Marini (ORCID: https://orcid.org/0000-0002-2199-2905)
- M. Tesi (ORCID: https://orcid.org/0009-0004-2352-4277)
- Chiara Ruzza (ORCID: https://orcid.org/0000-0003-1360-202X)
- Delia Preti (ORCID: https://orcid.org/0000-0002-1075-3781)
- Lorenzo Landini (ORCID: https://orcid.org/0000-0002-3933-2497)
- Lorenzo Tagliazucchi (ORCID: https://orcid.org/0000-0002-7244-7106)
- Elisa Bellantoni
- Valentina Erminia Albanese (ORCID: https://orcid.org/0000-0002-1654-7321)
- Remo Guerrini (ORCID: https://orcid.org/0000-0002-7619-0918)
- Romina Nassini (ORCID: https://orcid.org/0000-0002-9223-8395)
- Francesco De Logu (ORCID: https://orcid.org/0000-0001-8360-6929)
- Sandro Cosconati (ORCID: https://orcid.org/0000-0002-8900-0968)
- Michele Roggia (ORCID: https://orcid.org/0009-0009-3860-2502)
- Lorenzo Gnudi
- Valentina Puscio
Institutions
- University of Modena and Reggio Emilia (IT)
- University of Ferrara (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- University of Florence (IT)
Publication Details
- Journal
- European Journal of Medicinal Chemistry
- Published
- 2025-05-09
- DOI
- https://doi.org/10.1016/j.ejmech.2025.117732
- Citations
- 1
- Primary Topic
- Ion Channels and Receptors
- Type
- article
- Field-Weighted Citation Impact
- 1.46
Funders
- European Commission
- Fondazione Telethon
- Associazione Italiana per la Ricerca sul Cancro
- Università degli Studi di Ferrara