Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium‐dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure–activity relationships (SARs) focusing on new strategies to target this channel.

中文翻译：

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TRPV1受体拮抗剂的药物化学，药理作用和临床意义

瞬态受体电位香草酸1（TRPV1）是在感觉神经元上表达的离子通道，可触发阳离子流入。TRPV1受体起同四聚体的作用，对热，促炎物质，脂氧合酶产物，树脂毒素，内源性大麻素，质子和肽毒素有反应。它的磷酸化增加了对化学和热刺激的敏感性，而脱敏涉及钙依赖性机制，导致受体脱磷酸化。TRPV1用作有害刺激的传感器，可能代表避免疼痛和伤害的目标。TRPV1激活与慢性炎症性疼痛和周围神经病变有关。还可以在非神经区域（例如膀胱，肺和耳蜗）中检测到它的表达，其中TRPV1激活是导致膀胱炎，哮喘，和听力损失。这篇综述提供了有关TRPV1受体在慢性疼痛，癫痫，咳嗽，膀胱疾病，糖尿病，肥胖症和听力损失的病理生理学方面的全面概述，突出了针对该通道的药物开发如何具有临床治疗潜力。此外，它总结了药物化学研究的进展，这些研究导致了对高选择性TRPV1拮抗剂的鉴定以及对结构-活性关系（SAR）的分析，重点是针对该通道的新策略。