Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation
Document Type
Article
Publication Date
5-2021
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.
Recommended Citation
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; Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation. ACS Med. Chem. Lett. 13 May 2021; 12 (5): 758–767. https://doi.org/10.1021/acsmedchemlett.1c00001
Comments
The authors’ manuscript is open access at https://pmc.ncbi.nlm.nih.gov/articles/PMC8155240/. The version of record is available from the publisher at https://doi.org/10.1021/acsmedchemlett.1c00001. © 2021 American Chemical Society.