4-isopropylcyclohexanol has potential analgesic effects through the inhibition of anoctamin 1, TRPV1 and TRPA1 channel activities.
4-isopropylcyclohexanol has potential analgesic effects through the inhibition of anoctamin 1, TRPV1 and TRPA1 channel activities.
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DOI：
10.1038/srep43132
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发表时间：
2017-02-22
影响因子：
4.6
通讯作者：
Tominaga M
中科院分区：
文献类型：
--
作者：
Takayama Y;Furue H;Tominaga M
钙激活的氯离子通道anoctamin 1（ANO 1）和瞬时受体电位香草素1（TRPV 1）之间的相互作用增强了小鼠的疼痛感觉，表明ANO 1抑制可能具有镇痛作用。在这里，我们表明，薄荷醇和薄荷醇类似物异丙基环己烷（iPr-CyH）抑制小鼠的ANO 1通道。iPr-CyH衍生物4-异丙基环己醇（4-iPr-CyH-OH）比iPr-CyH更有效地抑制小鼠ANO 1电流。此外，4-iPr-CyH-OH抑制TRPV 1、TRP锚蛋白1（TRPA 1）、TRP melastatin 8（TRPM 8）和TRPV 4的活性。单通道分析显示，4-iPr-CyH-OH减少TRPV 1和TRPA 1电流的开放时间，而不影响单位振幅或关闭时间，表明其影响门控而不是阻塞通道孔。4-iPr-CyH-OH在小鼠中抑制辣椒素诱导的动作电位产生和减少疼痛相关行为的能力表明4-iPr-CyH-OH可具有镇痛应用。因此，4-iPr-CyH-OH是开发靶向ANO 1和TRP通道的新型镇痛剂的有前途的基础化学品。
Interactions between calcium-activated chloride channel anoctamin 1 (ANO1) and transient receptor potential vanilloid 1 (TRPV1) enhance pain sensations in mice, suggesting that ANO1 inhibition could have analgesic effects. Here we show that menthol and the menthol analogue isopropylcyclohexane (iPr-CyH) inhibited ANO1 channels in mice. The iPr-CyH derivative 4-isopropylcyclohexanol (4-iPr-CyH-OH) inhibited mouse ANO1 currents more potently than iPr-CyH. Moreover, 4-iPr-CyH-OH inhibited the activities of TRPV1, TRP ankyrin 1 (TRPA1), TRP melastatin 8 (TRPM8) and TRPV4. Single-channel analysis revealed that 4-iPr-CyH-OH reduced TRPV1 and TRPA1 current open-times without affecting unitary amplitude or closed-time, suggesting that it affected gating rather than blocking the channel pore. The ability of 4-iPr-CyH-OH to inhibit action potential generation and reduce pain-related behaviors induced by capsaicin in mice suggests that 4-iPr-CyH-OH could have analgesic applications. Thus, 4-iPr-CyH-OH is a promising base chemical to develop novel analgesics that target ANO1 and TRP channels.