title: 4-isopropylcyclohexanol has potential analgesic effects through the inhibition of anoctamin 1, TRPV1 and TRPA1 channel activities.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Takayama
authors.affiliation: Department of Physiological Sciences, the Graduate University for Advanced Studies, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.|Division of Neural Signaling, National Institute for Physiological Sciences, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Furue
authors.affiliation: 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.|Institute for Environmental and Gender-Specific Medicine, Juntendo University, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
mesh_terms: D000200:Action Potentials; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000075369:Anoctamin-1 / Q000037:antagonists & inhibitors*; D002211:Capsaicin / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D000074025:TRPA1 Cation Channel / Q000037:antagonists & inhibitors*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D000700:Analgesics; D000075369:Anoctamin-1; D003511:Cyclohexanols; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C475685:Trpa1 protein, mouse; C000629082:4-isopropylcyclohexanol; D002211:Capsaicin