TRP channels are essential for detecting variations in external temperature and are ubiquitously expressed in both the peripheral and central nervous systems as integral channel proteins. They primarily mediate a range of sensory responses, including thermal sensations, nociception, mechanosensation, vision, and gustation, thus playing a critical role in regulating various physiological functions. In colder climates, individuals often experience pain associated with low temperatures, leading to significant discomfort. Within the TRP channel family, TRPM8 and TRPA1 ion channels serve as the primary sensors for cold temperature fluctuations and are integral to both cold nociception and neuropathic pain pathways. Recent advancements in the biosynthesis of inhibitors targeting TRPM8 and TRPA1 have prompted the need for a comprehensive review of their structural characteristics, biological activities, biosynthetic pathways, and chemical synthesis. This paper aims to delineate the distinct roles of TRPM8 and TRPA1 in pain perception, elucidate their respective protein structures, and compile various combinations of TRPM8 and TRPA1 antagonists and agonists. The discussion encompasses their chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, with a particular focus on the conformational relationships between antagonists and the channels. This review seeks to provide in-depth insights into pharmacological strategies for managing pain associated with TRPM8 and TRPA1 activation and will pave the way for future investigations into pharmacotherapeutic approaches for alleviating cold-induced pain.

中文翻译：

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TRPM8 和 TRPA1 治疗寒冷性疼痛的理想靶点


TRP 通道对于检测外部温度的变化至关重要，并且在外周和中枢神经系统中普遍表达为整合通道蛋白。它们主要介导一系列感觉反应，包括热感觉、伤害感受、机械感觉、视觉和味觉，从而在调节各种生理功能中发挥关键作用。在较冷的气候中，个人经常会经历与低温相关的疼痛，从而导致严重的不适。在 TRP 通道家族中，TRPM8 和 TRPA1 离子通道是低温波动的主要传感器，是寒冷伤害感受和神经性疼痛通路不可或缺的一部分。靶向 TRPM8 和 TRPA1 的抑制剂生物合成的最新进展促使需要对其结构特性、生物活性、生物合成途径和化学合成进行全面综述。本文旨在描述 TRPM8 和 TRPA1 在疼痛感知中的不同作用，阐明它们各自的蛋白质结构，并汇编 TRPM8 和 TRPA1 拮抗剂和激动剂的各种组合。讨论包括它们的化学结构、构效关系 （SARs）、生物活性、选择性和治疗潜力，特别关注拮抗剂与通道之间的构象关系。本综述旨在为管理与 TRPM8 和 TRPA1 激活相关的疼痛的药物策略提供深入的见解，并将为未来研究缓解寒冷诱发疼痛的药物治疗方法铺平道路。