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 Chem Neurosci. 2020 Feb 5;11(3):268-290. doi: 10.1021/acschemneuro.9b00404. Epub 2020 Jan 9.

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.

Keywords: Menthol; TRP channel; TRPM8; chemical probe; molecular dynamics simulations; sensory neuropathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides
  • Biphenyl Compounds / antagonists & inhibitors*
  • Calcium / metabolism
  • HEK293 Cells
  • Humans
  • Hyperalgesia / drug therapy*
  • Menthol / analogs & derivatives
  • Patch-Clamp Techniques / methods
  • Peripheral Nervous System Diseases / drug therapy*
  • Structure-Activity Relationship*
  • TRPM Cation Channels / drug effects
  • TRPM Cation Channels / metabolism*
  • Transient Receptor Potential Channels / drug effects
  • Transient Receptor Potential Channels / metabolism

Substances

  • Amides
  • Biphenyl Compounds
  • TRPM Cation Channels
  • Transient Receptor Potential Channels
  • Menthol
  • diphenyl
  • Calcium