2. Academic Validation
  3. Identification of isoxazole-based TRPA1 inhibitors with analgesic effects in vivo

Identification of isoxazole-based TRPA1 inhibitors with analgesic effects in vivo

  • Eur J Med Chem. 2025 Sep 15:294:117732. doi: 10.1016/j.ejmech.2025.117732.
Valentina Albanese 1,  Matilde Marini 2,  Martina Tesi 2,  Lorenzo Landini 2,  Elisa Bellantoni 2,  Sandro Cosconati 3,  Michele Roggia 3,  Lorenzo Tagliazucchi 4,  Lorenzo Gnudi 5,  Valentina Puscio 5,  Chiara Sturaro 6,  Chiara Ruzza 6,  Remo Guerrini 7,  Pierangelo Geppetti 2,  Romina Nassini 8,  Delia Preti 9,  Francesco De Logu 2,  Salvatore Pacifico 5
Affiliations

Affiliations

  • 1 Department of Environmental and Prevention Sciences, University of Ferrara, Palazzo Turchi di Bagno, C.so Ercole I D'Este 32, 44121, Ferrara, Italy.
  • 2 Department of Health Sciences, Clinical Pharmacology and Oncology Section, Viale Pieraccini 6, University of Florence, Florence, 50139, Italy.
  • 3 DiSTABiF, Università della Campania Luigi Vanvitelli, Via Vivaldi 43, Caserta, 81100, Italy.
  • 4 Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
  • 5 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy.
  • 6 Department of Neuroscience and Rehabilitation, University of Ferrara, Via Luigi Borsari 46, Ferrara, 44121, Italy.
  • 7 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy; Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121, Ferrara, Italy.
  • 8 Department of Health Sciences, Clinical Pharmacology and Oncology Section, Viale Pieraccini 6, University of Florence, Florence, 50139, Italy. Electronic address: romina.nassini@unifi.it.
  • 9 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy. Electronic address: prtdle@unife.it.
PMID: 40378573 DOI: 10.1016/j.ejmech.2025.117732
Abstract

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.

Keywords

Isoxazole derivatives; Pain signalling; TRPA1 inhibitors; TRPA1 receptor.

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