Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies

V. Blair Journigan, Zhiwei Feng, Saifur Rahman, Yuanqiang Wang, A. R.M.Ruhul Amin, Colleen E. Heffner, Nicholas Bachtel, Siyi Wang, Sara Gonzalez-Rodriguez, Asia Fernández-Carvajal, Gregorio Fernández-Ballester, Jacob K. Hilton, Wade D. Van Horn, Antonio Ferrer-Montiel, Xiang Qun Xie, Taufiq Rahman

Research output: Contribution to journalArticle

Abstract

Structure-activity relationship studies of a reported menthol-based transient receptor potential cation channel subfamily M member 8 channel (TRPM8) antagonist, guided by computational simulations and structure-based design, uncovers a novel series of TRPM8 antagonists with >10-fold selectivity versus related TRP subtypes. Spiro[4.5]decan-8-yl analogue 14 inhibits icilin-evoked Ca2+ entry in HEK-293 cells stably expressing human TRPM8 (hTRPM8) with an IC50 of 2.4 ± 1.0 nM, while in whole-cell patch-clamp recordings this analogue inhibits menthol-evoked currents with a hTRPM8 IC50 of 64 ± 2 nM. Molecular dynamics (MD) simulations of compound 14 in our homology model of hTRPM8 suggest that this antagonist forms extensive hydrophobic contacts within the orthosteric site. In the wet dog shakes (WDS) assay, compound 14 dose-dependently blocks icilin-triggered shaking behaviors in mice. Upon local administration, compound 14 dose dependently inhibits cold allodynia evoked by the chemotherapy oxaliplatin in a murine model of peripheral neuropathy at microgram doses. Our findings suggest that 14 and other biphenyl amide analogues within our series can find utility as potent antagonist chemical probes derived from (-)-menthol as well as small molecule therapeutic scaffolds for chemotherapy-induced peripheral neuropathy (CIPN) and other sensory neuropathies.

Original languageEnglish (US)
Pages (from-to)268-290
Number of pages23
JournalACS chemical neuroscience
Volume11
Issue number3
DOIs
StatePublished - Feb 5 2020

Keywords

  • chemical probe
  • Menthol
  • molecular dynamics simulations
  • sensory neuropathy
  • TRP channel
  • TRPM8

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Journigan, V. B., Feng, Z., Rahman, S., Wang, Y., Amin, A. R. M. R., Heffner, C. E., Bachtel, N., Wang, S., Gonzalez-Rodriguez, S., Fernández-Carvajal, A., Fernández-Ballester, G., Hilton, J. K., Van Horn, W. D., Ferrer-Montiel, A., Xie, X. Q., & Rahman, T. (2020). Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies. ACS chemical neuroscience, 11(3), 268-290. https://doi.org/10.1021/acschemneuro.9b00404