Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation

V. Blair Journigan; David Alarcón-Alarcón; Zhiwei Feng; Yuanqiang Wang; Tianjian Liang; Denise C. Dawley; Arm R. Amin; Camila Montano; Wade D. Van Horn; Xiang-Qun Xie; Antonio Ferrer-Montiel; Asia Fernández-Carvajal

Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation

V. Blair Journigan
, David Alarcón-Alarcón
, Zhiwei Feng
, Yuanqiang Wang
, Tianjian Liang
, Denise C. Dawley
, Arm R. Amin
, Camila Montano
, Wade D. Van Horn
, Xiang-Qun Xie
, Antonio Ferrer-Montiel
, Asia Fernández-Carvajal

Research output: Contribution to journal › Article › peer-review

Abstract

TRPM8 antagonists derived from its cognate ligand, (−)-menthol, are underrepresented. We determine the absolute stereochemistry of a well-known TRPM8 antagonist, (−)-menthyl 1, using VCD and 2D NMR. We explore 1 for its antagonist effects of the human TRPM8 (hTRPM8) orthologue to uncover species-dependent inhibition versus rat channels. (−)-Menthyl 1 inhibits menthol- and icilin-evoked Ca2+ responses at hTRPM8 with IC50 values of 805 ± 200 nM and 1.8 ± 0.6 μM, respectively, while more potently inhibiting agonist responses at the rat orthologue (rTRPM8 IC50 (menthol) = 117 ± 18 nM, IC50 (icilin) = 521 ± 20 nM). Whole-cell patch-clamp recordings of hTRPM8 confirm the 1 inhibition of menthol-stimulated currents, with an IC50 of 700 ± 200 nM. We demonstrate that 1 possesses ≥400-fold selectivity for hTRPM8 versus hTRPA1/hTRPV1. (−)-menthyl 1 can be used as a novel chemical tool to study hTRPM8 pharmacology and differences in species commonly used in drug discovery.

Original language	American English
Journal	Pharmaceutical Science and Research
State	Published - May 1 2021

Access to Document

http://mds.marshall.edu/sp_psr/165

Cite this

Journigan, V. B., Alarcón-Alarcón, D., Feng, Z., Wang, Y., Liang, T., Dawley, D. C., Amin, A. R., Montano, C., Van Horn, W. D., Xie, X.-Q., Ferrer-Montiel, A., & Fernández-Carvajal, A. (2021). Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation. Pharmaceutical Science and Research. http://mds.marshall.edu/sp_psr/165

Journigan, VB, Alarcón-Alarcón, D, Feng, Z, Wang, Y, Liang, T, Dawley, DC, Amin, AR, Montano, C, Van Horn, WD, Xie, X-Q, Ferrer-Montiel, A & Fernández-Carvajal, A 2021, 'Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation', Pharmaceutical Science and Research. <http://mds.marshall.edu/sp_psr/165>

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title = "Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation",

abstract = "TRPM8 antagonists derived from its cognate ligand, (−)-menthol, are underrepresented. We determine the absolute stereochemistry of a well-known TRPM8 antagonist, (−)-menthyl 1, using VCD and 2D NMR. We explore 1 for its antagonist effects of the human TRPM8 (hTRPM8) orthologue to uncover species-dependent inhibition versus rat channels. (−)-Menthyl 1 inhibits menthol- and icilin-evoked Ca2+ responses at hTRPM8 with IC50 values of 805 ± 200 nM and 1.8 ± 0.6 μM, respectively, while more potently inhibiting agonist responses at the rat orthologue (rTRPM8 IC50 (menthol) = 117 ± 18 nM, IC50 (icilin) = 521 ± 20 nM). Whole-cell patch-clamp recordings of hTRPM8 confirm the 1 inhibition of menthol-stimulated currents, with an IC50 of 700 ± 200 nM. We demonstrate that 1 possesses ≥400-fold selectivity for hTRPM8 versus hTRPA1/hTRPV1. (−)-menthyl 1 can be used as a novel chemical tool to study hTRPM8 pharmacology and differences in species commonly used in drug discovery.",

author = "Journigan, \{V. Blair\} and David Alarc{\'o}n-Alarc{\'o}n and Zhiwei Feng and Yuanqiang Wang and Tianjian Liang and Dawley, \{Denise C.\} and Amin, \{Arm R.\} and Camila Montano and \{Van Horn\}, \{Wade D.\} and Xiang-Qun Xie and Antonio Ferrer-Montiel and Asia Fern{\'a}ndez-Carvajal",

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T1 - Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation

AU - Journigan, V. Blair

AU - Alarcón-Alarcón, David

AU - Feng, Zhiwei

AU - Wang, Yuanqiang

AU - Liang, Tianjian

AU - Dawley, Denise C.

AU - Amin, Arm R.

AU - Montano, Camila

AU - Van Horn, Wade D.

AU - Xie, Xiang-Qun

AU - Ferrer-Montiel, Antonio

AU - Fernández-Carvajal, Asia

PY - 2021/5/1

Y1 - 2021/5/1

N2 - TRPM8 antagonists derived from its cognate ligand, (−)-menthol, are underrepresented. We determine the absolute stereochemistry of a well-known TRPM8 antagonist, (−)-menthyl 1, using VCD and 2D NMR. We explore 1 for its antagonist effects of the human TRPM8 (hTRPM8) orthologue to uncover species-dependent inhibition versus rat channels. (−)-Menthyl 1 inhibits menthol- and icilin-evoked Ca2+ responses at hTRPM8 with IC50 values of 805 ± 200 nM and 1.8 ± 0.6 μM, respectively, while more potently inhibiting agonist responses at the rat orthologue (rTRPM8 IC50 (menthol) = 117 ± 18 nM, IC50 (icilin) = 521 ± 20 nM). Whole-cell patch-clamp recordings of hTRPM8 confirm the 1 inhibition of menthol-stimulated currents, with an IC50 of 700 ± 200 nM. We demonstrate that 1 possesses ≥400-fold selectivity for hTRPM8 versus hTRPA1/hTRPV1. (−)-menthyl 1 can be used as a novel chemical tool to study hTRPM8 pharmacology and differences in species commonly used in drug discovery.

AB - TRPM8 antagonists derived from its cognate ligand, (−)-menthol, are underrepresented. We determine the absolute stereochemistry of a well-known TRPM8 antagonist, (−)-menthyl 1, using VCD and 2D NMR. We explore 1 for its antagonist effects of the human TRPM8 (hTRPM8) orthologue to uncover species-dependent inhibition versus rat channels. (−)-Menthyl 1 inhibits menthol- and icilin-evoked Ca2+ responses at hTRPM8 with IC50 values of 805 ± 200 nM and 1.8 ± 0.6 μM, respectively, while more potently inhibiting agonist responses at the rat orthologue (rTRPM8 IC50 (menthol) = 117 ± 18 nM, IC50 (icilin) = 521 ± 20 nM). Whole-cell patch-clamp recordings of hTRPM8 confirm the 1 inhibition of menthol-stimulated currents, with an IC50 of 700 ± 200 nM. We demonstrate that 1 possesses ≥400-fold selectivity for hTRPM8 versus hTRPA1/hTRPV1. (−)-menthyl 1 can be used as a novel chemical tool to study hTRPM8 pharmacology and differences in species commonly used in drug discovery.

M3 - Article

JO - Pharmaceutical Science and Research

JF - Pharmaceutical Science and Research

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