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23 results on '"Hilton, Jacob K."'

11. 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

Author

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

Published
2019
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22. Implications of Human Transient Receptor Potential Melastatin 8 (TRPM8) Channel Gating from Menthol Binding Studies of the Sensing Domain.

Author

Rath, Parthasarathi, Hilton, Jacob K., Sisco, Nicholas J., and Van Horn, Wade D.

Subjects
*TRP channels, *MENTHOL, *PROTEIN binding, *COLD (Temperature), *LIGANDS (Biochemistry)
Abstract

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary cold sensor in humans. TRPM8 is gated by physiologically relevant cold temperatures and chemical ligands that induce cold sensations, such as the analgesic compound menthol. Characterization of TRPM8 ligand-gated channel activation will lead to a better understanding of the fundamental mechanisms that underlie TRPM8 function. Here, the direct binding of menthol to the isolated hTRPM8 sensing domain (transmembrane helices S1-S4) is investigated. These data are compared with two mutant sensing domain proteins, Y745H (S2 helix) and R842H (S4 helix), which have been previously identified in full length TRPM8 to be menthol insensitive. The data presented herein show that menthol specifically binds to the wild type, Y745H, and R842H TRPM8 sensing domain proteins. These results are the first to show that menthol directly binds to the TRPM8 sensing domain and indicates that Y745 and R842 residues, previously identified in functional studies as crucial to menthol sensitivity, do not affect menthol binding but instead alter coupling between the sensing domain and the pore domain. [ABSTRACT FROM AUTHOR]

Published
2016
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23. 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.

Author

Journigan VB, Feng Z, Rahman S, Wang Y, Amin ARMR, Heffner CE, Bachtel N, Wang S, Gonzalez-Rodriguez S, Fernández-Carvajal A, Fernández-Ballester G, Hilton JK, Van Horn WD, Ferrer-Montiel A, Xie XQ, and Rahman T

Subjects
Amides, Calcium metabolism, HEK293 Cells, Humans, Menthol analogs & derivatives, Patch-Clamp Techniques methods, TRPM Cation Channels drug effects, Transient Receptor Potential Channels drug effects, Transient Receptor Potential Channels metabolism, Biphenyl Compounds antagonists & inhibitors, Hyperalgesia drug therapy, Peripheral Nervous System Diseases drug therapy, Structure-Activity Relationship, TRPM Cation Channels metabolism
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 Ca 2+ entry in HEK-293 cells stably expressing human TRPM8 (hTRPM8) with an IC 50 of 2.4 ± 1.0 nM, while in whole-cell patch-clamp recordings this analogue inhibits menthol-evoked currents with a hTRPM8 IC 50 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.

Published
2020
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