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

ACS Med Chem Lett. 2021 Mar 31;12(5):758-767. doi: 10.1021/acsmedchemlett.1c00001. eCollection 2021 May 13.

Authors

V Blair Journigan^{1

2}, David Alarcón-Alarcón³, Zhiwei Feng^{4

5

6}, Yuanqiang Wang^{4

5

6}, Tianjian Liang^{4

5

6}, Denise C Dawley¹, A R M Ruhul Amin^{1

2}, Camila Montano^{7

8

9}, Wade D Van Horn^{7

8

9}, Xiang-Qun Xie^{4

5

6}, Antonio Ferrer-Montiel³, Asia Fernández-Carvajal³

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy, Marshall University, Huntington, West Virginia 25755, United States.
² Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, United States.
³ IDiBE: Instituto de Investigación, Desarrollo e innovación en Biotecnología Sanitaria de Elche, Universitas Miguel Hernández, 03202 Elche, Spain.
⁴ Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
⁵ NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
⁶ Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
⁷ The School of Molecular Sciences, Arizona State University, Tempe, Arizona 85287, United States.
⁸ The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona 85281, United States.
⁹ The Magnetic Resonance Research Center, Arizona State University, Tempe, Arizona 85287, United States.

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.

Abstract

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