2. Academic Validation
  3. 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

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.
V Blair Journigan 1 2,  Zhiwei Feng 3 4 5,  Saifur Rahman 6,  Yuanqiang Wang 3 4 5,  A R M Ruhul Amin 1 2,  Colleen E Heffner 1,  Nicholas Bachtel 1,  Siyi Wang 3 4 5,  Sara Gonzalez-Rodriguez 7,  Asia Fernández-Carvajal 7,  Gregorio Fernández-Ballester 7,  Jacob K Hilton 8 9 10,  Wade D Van Horn 8 9 10,  Antonio Ferrer-Montiel 7,  Xiang-Qun Xie 3 4 5,  Taufiq Rahman 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, School of Pharmacy , Marshall University , Huntington , West Virginia 25755 , United States.
  • 2 Department of Biomedical Sciences, Joan C. Edwards School of Medicine , Marshall University , Huntington , West Virginia 25755 , United States.
  • 3 Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States.
  • 4 NIDA National Center of Excellence for Computational Drug Abuse Research , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States.
  • 5 Drug Discovery Institute , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States.
  • 6 Department of Pharmacology , University of Cambridge , Tennis Court Road , Cambridge CB2 1TN , United Kingdom.
  • 7 IDiBE: Instituto de Investigación, Desarrollo e innovación en Biotecnología sanitaria de Elche , Universitas Miguel Hernández , 03202 Elche , Spain.
  • 8 The School of Molecular Sciences , Arizona State University , Tempe , Arizona 85287 , United States.
  • 9 the Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute , Arizona State University , Tempe , Arizona 85281 , United States.
  • 10 The Magnetic Resonance Research Center , Arizona State University , Tempe , Arizona 85287 , United States.
PMID: 31850745 DOI: 10.1021/acschemneuro.9b00404
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.

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