Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121, Ferrara, Italy.
Section of Pharmacology, Department of Medical Sciences, University of Ferrara, 44121, Ferrara, Italy.
Med Res Rev. 2017 Jul;37(4):936-983. doi: 10.1002/med.21427. Epub 2016 Dec 15.
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.
瞬时受体电位香草酸 1 型（TRPV1）是一种表达在感觉神经元上的离子通道，可引发阳离子内流。TRPV1 受体作为同源四聚体发挥作用，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。其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，导致受体去磷酸化。TRPV1 作为有害刺激的传感器，可能是避免疼痛和损伤的靶点。TRPV1 的激活与慢性炎症性疼痛和周围神经病变有关。它的表达也在非神经元区域检测到，如膀胱、肺和耳蜗，其中 TRPV1 的激活负责膀胱炎、哮喘和听力损失的病理发展。本综述全面概述了 TRPV1 受体在慢性疼痛、癫痫、咳嗽、膀胱疾病、糖尿病、肥胖和听力损失的病理生理学中的作用，强调了针对该通道的药物开发如何具有临床治疗潜力。此外，它还总结了药物化学研究的进展，导致了高度选择性 TRPV1 拮抗剂的鉴定及其对结构-活性关系（SAR）的分析，重点介绍了针对该通道的新策略。
