Abstract | AIM: METHODS: The direct interaction of methyl eugenol with Na(+) channels was explored and characterized using electrophysiological recordings from Nav1.7-transfected CHO cells. RESULTS: In whole-cell patch clamp mode, methyl eugenol tonically inhibited peripheral nerve Nav1.7 currents in a concentration- and voltage-dependent manner, with an IC50 of 295 μmol/L at a -100 mV holding potential. Functionally, methyl eugenol preferentially bound to Nav1.7 channels in the inactivated and/or open state, with weaker binding to channels in the resting state. Thus, in the presence of methyl eugenol, Nav1.7 channels exhibited reduced availability for activation in a steady-state inactivation protocol, strong use-dependent inhibition, enhanced binding kinetics, and slow recovery from inactivation compared to untreated channels. An estimation of the affinity of methyl eugenol for the resting and inactivated states of the channel also demonstrated that methyl eugenol preferentially binds to inactivated channels, with a 6.4 times greater affinity compared to channels in the resting state. The failure of inactivated channels to completely recover to control levels at higher concentrations of methyl eugenol implies that the drug may drive more drug-bound, fast-inactivated channels into drug-bound, slow-inactivated channels. CONCLUSION:
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Authors | Ze-Jun Wang, Boris Tabakoff, Simon R Levinson, Thomas Heinbockel |
Journal | Acta pharmacologica Sinica
(Acta Pharmacol Sin)
Vol. 36
Issue 7
Pg. 791-9
(Jul 2015)
ISSN: 1745-7254 [Electronic] United States |
PMID | 26051112
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Analgesics
- Anesthetics
- NAV1.7 Voltage-Gated Sodium Channel
- SCN9A protein, human
- Sodium Channel Blockers
- methyleugenol
- Eugenol
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Topics |
- Analgesics
(pharmacology)
- Anesthetics
(pharmacology)
- Animals
- CHO Cells
- Cricetinae
- Cricetulus
- Dose-Response Relationship, Drug
- Eugenol
(analogs & derivatives, pharmacology)
- Humans
- NAV1.7 Voltage-Gated Sodium Channel
(physiology)
- Sodium Channel Blockers
(pharmacology)
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