Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization,Journal of Medicinal Chemistry

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Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-18 , DOI: 10.1021/acs.jmedchem.1c01579
Zhen Qiao ₁ , Jiajie Luo ₁ , Yi-Quan Tang ₂ , Qiqi Zhou ₃ , Hang Qi ₁ , Zhengji Yin ₁ , Xiaowen Tang ₁ , Wei Zhu ₁ , Yanru Zhang _{1,

4} , Ningning Wei _{1,

4} , KeWei Wang _{1,

4}

Affiliation

Transient receptor potential ankyrin 1 (TRPA1) channel, as a nonselective ligand-gated cation channel robustly in dorsal root ganglion sensory neurons, is implicated in sensing noxious stimuli and nociceptive signaling. However, small-molecule tools targeting TRPA1 lack temporal and spatial resolution, limiting their use for validation of TRPA1 as a therapeutic target for pain. In our previous work, we found that 4,4′-(diazene-1,2-diyl)dianiline (AB1) is a photoswitchable TRPA1 agonist, but the poor water solubility and activity hinder its further development. Here, we report a series of specific and potent azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2) that enable optical control of the TRPA1 channel. Two representative compounds 1g and 2c can alleviate capsaicin-induced pain in the cheek model of mice through channel desensitization but not in TRPA1 knockout mice. Taken together, our findings demonstrate that photoswitchable TRPA1 agonists can be used as pharmacological tools for study of pain signaling.

中文翻译：

光敏和光开关 TRPA1 激动剂通过通道脱敏光学控制疼痛

瞬时受体电位锚蛋白 1 (TRPA1) 通道作为一种非选择性配体门控阳离子通道，在背根神经节感觉神经元中具有很强的作用，它与感知有害刺激和伤害性信号传导有关。然而，针对 TRPA1 的小分子工具缺乏时间和空间分辨率，限制了它们用于验证 TRPA1 作为疼痛治疗靶点的用途。在我们之前的工作中，我们发现 4,4'-(diazene-1,2-diyl)dianiline (AB1) 是一种可光开关的 TRPA1 激动剂，但水溶性和活性较差，阻碍了其进一步发展。在这里，我们报告了一系列特定且有效的偶氮苯衍生的光可切换 TRPA1 激动剂（系列 1 和 2），它们能够对 TRPA1 通道进行光学控制。两种代表性化合物1g和2c可以通过通道脱敏减轻辣椒素引起的小鼠脸颊模型中的疼痛，但在 TRPA1 敲除小鼠中却没有。总之，我们的研究结果表明，光开关 TRPA1 激动剂可用作研究疼痛信号的药理学工具。

更新日期：2021-11-11

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