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; A. R.M.Ruhul Amin; Camila Montano; Wade D. Van Horn; Xiang Qun Xie; Antonio Ferrer-Montiel; Asia Fernández-Carvajal

doi:10.1021/acsmedchemlett.1c00001

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, A. R.M.Ruhul Amin, Camila Montano, Wade D. Van Horn, Xiang Qun Xie, Antonio Ferrer-Montiel, Asia Fernández-Carvajal

Molecular Sciences, School of (SMS)

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

7 Scopus citations

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	English (US)
Pages (from-to)	758-767
Number of pages	10
Journal	ACS Medicinal Chemistry Letters
Volume	12
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.1c00001
State	Published - May 13 2021

Keywords

TRPM8
antagonist
chemical regulation
menthol
species

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/acsmedchemlett.1c00001

Cite this

Journigan, V. B., Alarcón-Alarcón, D., Feng, Z., Wang, Y., Liang, T., Dawley, D. C., Amin, A. R. M. 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. ACS Medicinal Chemistry Letters, 12(5), 758-767. https://doi.org/10.1021/acsmedchemlett.1c00001

Journigan, VB, Alarcón-Alarcón, D, Feng, Z, Wang, Y, Liang, T, Dawley, DC, Amin, ARMR, Montano, C, Van Horn, WD, Xie, XQ, Ferrer-Montiel, A & Fernández-Carvajal, A 2021, 'Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation', ACS Medicinal Chemistry Letters, vol. 12, no. 5, pp. 758-767. https://doi.org/10.1021/acsmedchemlett.1c00001

@article{c828849c7e0040f1846d7fdc1e4f1505,

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.",

keywords = "TRPM8, antagonist, chemical regulation, menthol, species",

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, {A. R.M.Ruhul} and Camila Montano and {Van Horn}, {Wade D.} and Xie, {Xiang Qun} and Antonio Ferrer-Montiel and Asia Fern{\'a}ndez-Carvajal",

note = "Publisher Copyright: {\textcopyright} ",

year = "2021",

month = may,

day = "13",

doi = "10.1021/acsmedchemlett.1c00001",

language = "English (US)",

volume = "12",

pages = "758--767",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "5",

}

TY - JOUR

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, A. R.M.Ruhul

AU - Montano, Camila

AU - Van Horn, Wade D.

AU - Xie, Xiang Qun

AU - Ferrer-Montiel, Antonio

AU - Fernández-Carvajal, Asia

PY - 2021/5/13

Y1 - 2021/5/13

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.

KW - TRPM8

KW - antagonist

KW - chemical regulation

KW - menthol

KW - species

UR - http://www.scopus.com/inward/record.url?scp=85104907914&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85104907914&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.1c00001

DO - 10.1021/acsmedchemlett.1c00001

M3 - Article

AN - SCOPUS:85104907914

SN - 1948-5875

VL - 12

SP - 758

EP - 767

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this