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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Pages (from-to)758-767
Number of pages10
JournalACS Medicinal Chemistry Letters
Volume12
Issue number5
DOIs
StatePublished - May 13 2021

Keywords

  • antagonist
  • chemical regulation
  • menthol
  • species
  • TRPM8

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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