Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.
Department of Physiological Sciences, the Graduate University for Advanced Studies, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.
Sci Rep. 2017 Feb 22;7:43132. doi: 10.1038/srep43132.
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.
钙激活氯离子通道 anoctamin 1（ANO1）与瞬时受体电位香草酸 1（TRPV1）之间的相互作用增强了小鼠的疼痛感觉，这表明ANO1 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）抑制了小鼠的 ANO1 通道。iPr-CyH 的衍生物 4-异丙基环己醇（4-iPr-CyH-OH）比 iPr-CyH 更有效地抑制了小鼠的 ANO1 电流。此外，4-iPr-CyH-OH 抑制了 TRPV1、TRP 锚蛋白 1（TRPA1）、TRP 黑色素瘤 8（TRPM8）和 TRPV4 的活性。单通道分析表明，4-iPr-CyH-OH 减少了 TRPV1 和 TRPA1 电流的开启时间，而不影响单位幅度或关闭时间，这表明它影响门控而不是阻断通道孔。4-iPr-CyH-OH 抑制动作电位产生并减轻辣椒素诱导的小鼠相关行为的能力表明，4-iPr-CyH-OH 可能具有镇痛应用。因此，4-iPr-CyH-OH 是一种有前途的基础化学物质，可以开发针对 ANO1 和 TRP 通道的新型镇痛药。
