Discovery of nonpungent Transient Receptor Potential Vanilloid (TRPV1) agonist antedrugs for treatment of dysphagia

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-22 DOI:10.1016/j.bmcl.2025.130287

Hiroyuki Kitano , Yuki Mizukami, Masanori Miyauchi, Itaru Natsutani, Kozo Yoshida

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引用次数: 0

Abstract

Transient Receptor Potential Vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel that functions as a cellular sensor for heat and chemical stimuli, such as vanilloids. In recent years, TRPV1 has gained attention as a therapeutic target for treating dysphagia, with both preclinical and clinical trials utilizing capsaicin, a member of the vanilloid family. However, TRPV1 agonists often have pronounced irritant properties and may potentially induce hypothermia upon systemic exposure. Here, we describe the synthesis and characterization of a series of nonpungent TRPV1 agonists with antedrug properties. The discovered compounds exhibit similar agonistic properties to capsaicin, while demonstrating low irritancy in animal models and showing no systemic exposure when administered orally. As these compounds selectively act within the oral cavity without causing a sensation of spiciness, they offer a useful alternative to address the challenges associated with TRPV1 agonists as therapeutic agents for improving dysphagia.

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发现非刺激性瞬时受体电位香草样蛋白（TRPV1）激动剂治疗吞咽困难

瞬时受体电位香草素1 （TRPV1）是一种配体门控的非选择性阳离子通道，其功能是对热和化学刺激（如香草素）的细胞传感器。近年来，TRPV1作为治疗吞咽困难的治疗靶点受到关注，临床前和临床试验都使用了辣椒素，辣椒素是香草素家族的一员。然而，TRPV1激动剂通常具有明显的刺激性，并可能在全身暴露时引起体温过低。在这里，我们描述了一系列具有药物前特性的非刺激性TRPV1激动剂的合成和表征。发现的化合物表现出与辣椒素相似的激动特性，同时在动物模型中显示出低刺激性，并且在口服时没有显示出全身暴露。由于这些化合物选择性地在口腔内起作用而不会引起辛辣感，因此它们为解决TRPV1激动剂作为改善吞咽困难治疗剂的相关挑战提供了有用的替代方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.