High-affinity block of voltage-operated rat IIA neuronal sodium channels by 2,6 di-tert-butylphenol, a propofol analogue.
OBJECTIVE
Propofol is a phenol derivative (2,6 di-isopropylphenol) with a unique effect profile including activating effects on GABA(A) and blocking effects on voltage-operated sodium channels. If the substituents in the 2- and the 6-positions are replaced by tert-butyl groups, the resulting phenol derivative, 2,6 di-tert-butylphenol, despite being a close structural propofol analogue, completely lacks GABA(A) receptor effects. The aim of this in vitro study was to investigate the effects of 2,6 di-tert-butylphenol on voltage-operated neuronal sodium channels in order to determine whether and, if so, how these structural changes alter the sodium channel-blocking effect seen with propofol.


METHODS
Whole-cell sodium inward currents through heterologously expressed rat type IIA sodium channels were recorded in the absence and presence of definite concentrations of 2,6 di-tert-butylphenol and propofol.


RESULTS
When applied at concentrations > or = 30 micromol, 2,6 di-tert-butylphenol completely and irreversibly blocked sodium inward currents. The blockade equilibrium time was about 2 min. A partial washout was possible only if the application was stopped before the equilibrium of the blockade was achieved.


CONCLUSIONS
2,6 Di-tert-butylphenol exerts a high-affinity block of neuronal sodium channels. Apparently, the slight structural differences of 2,6 di-tert-butylphenol in comparison with propofol--which account for the lack of GABA(A) receptor effects--enhance its voltage-operated sodium channel-blocking effects. As 2,6 di-tert-butylphenol is much more potent than most sodium channel blockers in clinical use, it might be of interest in the development of local anaesthetics.
Haeseler
G
G
Hannover Medical School, Department of Anesthesiology, Hannover, Germany. Haeseler.Gertrud@MH-Hannover.de
Leuwer
M
M
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000494:pharmacology*; D015742:Propofol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
D018686:Anesthetics, Intravenous; D058787:GABA-A Receptor Antagonists; D010636:Phenols; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C035407:2,6-di-tert-butylphenol; D015742:Propofol