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

Autor:	Journigan VB; Department of Pharmaceutical Sciences, School of Pharmacy, Marshall University, Huntington, West Virginia 25755, United States.; Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, United States., Alarcón-Alarcón D; IDiBE: Instituto de Investigación, Desarrollo e innovación en Biotecnología Sanitaria de Elche, Universitas Miguel Hernández, 03202 Elche, Spain., Feng Z; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States., Wang Y; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States., Liang T; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States., Dawley DC; Department of Pharmaceutical Sciences, School of Pharmacy, Marshall University, Huntington, West Virginia 25755, United States., Amin ARMR; Department of Pharmaceutical Sciences, School of Pharmacy, Marshall University, Huntington, West Virginia 25755, United States.; Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, United States., Montano C; The School of Molecular Sciences, Arizona State University, Tempe, Arizona 85287, United States.; The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona 85281, United States.; The Magnetic Resonance Research Center, Arizona State University, Tempe, Arizona 85287, United States., Van Horn WD; The School of Molecular Sciences, Arizona State University, Tempe, Arizona 85287, United States.; The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona 85281, United States.; The Magnetic Resonance Research Center, Arizona State University, Tempe, Arizona 85287, United States., Xie XQ; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States., Ferrer-Montiel A; IDiBE: Instituto de Investigación, Desarrollo e innovación en Biotecnología Sanitaria de Elche, Universitas Miguel Hernández, 03202 Elche, Spain., Fernández-Carvajal A; IDiBE: Instituto de Investigación, Desarrollo e innovación en Biotecnología Sanitaria de Elche, Universitas Miguel Hernández, 03202 Elche, Spain.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Mar 31; Vol. 12 (5), pp. 758-767. Date of Electronic Publication: 2021 Mar 31 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.1c00001
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.)
Databáze:	MEDLINE
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