Open AccessStructural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation
Author(s) -
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,
XiangQun Xie,
Antonio Ferrer-Montiel,
Asia Fernández-Carvajal
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00001
Subject(s) - menthol , trpm8 , antagonist , ic50 , chemistry , agonist , pharmacology , stereochemistry , in vitro , biochemistry , receptor , biology , transient receptor potential channel , organic chemistry , trpv1
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 Ca 2+ responses at hTRPM8 with IC 50 values of 805 ± 200 nM and 1.8 ± 0.6 μM, respectively, while more potently inhibiting agonist responses at the rat orthologue (rTRPM8 IC 50 (menthol) = 117 ± 18 nM, IC 50 (icilin) = 521 ± 20 nM). Whole-cell patch-clamp recordings of hTRPM8 confirm the 1 inhibition of menthol-stimulated currents, with an IC 50 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.