TY - JOUR
T1 - 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
AU - Journigan, V. Blair
AU - Feng, Zhiwei
AU - Rahman, Saifur
AU - Wang, Yuanqiang
AU - Amin, A. R.M.Ruhul
AU - Heffner, Colleen E.
AU - Bachtel, Nicholas
AU - Wang, Siyi
AU - Gonzalez-Rodriguez, Sara
AU - Fernández-Carvajal, Asia
AU - Fernández-Ballester, Gregorio
AU - Hilton, Jacob K.
AU - Van Horn, Wade D.
AU - Ferrer-Montiel, Antonio
AU - Xie, Xiang Qun
AU - Rahman, Taufiq
PY - 2020/2/5
Y1 - 2020/2/5
N2 - 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.
AB - 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.
KW - chemical probe
KW - Menthol
KW - molecular dynamics simulations
KW - sensory neuropathy
KW - TRP channel
KW - TRPM8
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U2 - 10.1021/acschemneuro.9b00404
DO - 10.1021/acschemneuro.9b00404
M3 - Article
C2 - 31850745
AN - SCOPUS:85079017585
VL - 11
SP - 268
EP - 290
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 3
ER -