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

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-05-09 DOI:10.1016/j.ejmech.2025.117732

Valentina Albanese , Matilde Marini , Martina Tesi , Lorenzo Landini , Elisa Bellantoni , Sandro Cosconati , Michele Roggia , Lorenzo Tagliazucchi , Lorenzo Gnudi , Valentina Puscio , Chiara Sturaro , Chiara Ruzza , Remo Guerrini , Pierangelo Geppetti , Romina Nassini , Delia Preti , Francesco De Logu , Salvatore Pacifico

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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.

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具有体内镇痛作用的异恶唑类TRPA1抑制剂的鉴定

瞬时受体电位锚蛋白1 （TRPA1）通道作为治疗不同类型疼痛的潜在治疗靶点已被广泛研究，与目前的治疗方法相比，它具有更好的疗效和安全性。由于TRPA1参与不同的病理生理过程，该通道的选择性拮抗剂可以提供除疼痛缓解外的治疗益处。在这项研究中，我们设计和合成了一系列含有异恶唑片段的新型羧酰胺衍生物，并对其抑制trpa1介导的信号传导的能力进行了评估。其中，我们发现TRPA1拮抗剂12和13在体外表现出纳摩尔效，对TRPA1激动剂异硫氰酸烯丙酯和小鼠福尔马林试验具有显著的镇痛作用。对接分析探讨了最具代表性的化合物与所提出的药理学靶点的结合模式。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.