Skip to main content Accessibility help

High-affinity blockade of voltage-operated skeletal muscle sodium channels by 2,6-dimethyl-4-chlorophenol

  • G. Haeseler (a1), S. Gudehus (a1), J. Bufler (a2), R. Dengler (a2) and M. Leuwer (a3)...



Background and objective: The aromatic alcohol most closely resembling the aromatic tail of lidocaine is 2,6-dimethylphenol. This agent is as potent as lidocaine in blocking voltage-operated sodium channels. The aim of this study was to show the effect of halogenation in the para-position on the potency of this compound to block voltage-operated sodium channels. Methods: Insertion of the halogen chloride into the para-position of the molecule 2,6-dimethylphenol yielded 2,6-dimethyl-4-chlorophenol. Block of sodium currents by this compound was studied using heterologously expressed voltage-operated rat neuronal (rat IIa) sodium channels. Results: 2,6-dimethyl-4-chlorophenol reversibly suppressed depolarization-induced whole-cell sodium inward currents. The ECR50 for block of resting channels at a hyperpolarized holding potential (−150 mV) was 127 μmol, the Hill coefficient nH 1.7. Membrane depolarization inducing either fast or slow-inactivation strongly increased the blocking potency. This is an important feature of a local-anaesthetic-like action. The estimated half-maximum effect concentration for the fast-inactivated channel state ECI50 was 28 μmol, the Hill coefficient nH 3.8. When 20–30% of channels were slow-inactivated using long (2.5 s) prepulses, followed by a 10 ms repolarization period to allow recovery from fast inactivation, the IC50 at −100 mV holding potential was reduced to 53 μmol. Conclusion: These results, which show that 2,6-dimethyl-4-chlorophenol blocks voltage-operated sodium channels in a lidocaine-like manner while having a several fold higher potency than the non-halogenated parent compound, highlight a potentially meaningful principle of increasing the sodium channel blocking potency of phenol derivatives.


Corresponding author

Correspondence to: Gertrud Haeseler, Department of Anaesthesiology, OE8050, Hannover Medical School, D-30623 Hannover, Germany. E-mail:; Tel: +49 511 532 9375; Fax +49 511 532 5649


Hide All


Haeseler G, Bufler J, Merken S et al. Block of voltage-operated sodium channels by 2,6-dimethylphenol, a structural analogue of lidocaine`s aromatic tail. Br J Pharmacol 2002; 137: 285293.
Mitrovic N, George AL, Heine R et al. K+-aggravated myotonia: destabilization of the inactivated state of the human muscle sodium channel by the V1589M mutation. J Physiol 1994; 478: 395402.
Graham FL, Van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 1973; 52: 456467.
Haeseler G, Störmer M, Bufler J et al. Propofol blocks skeletal muscle sodium channels in a voltage-dependent manner. Anesth Analg 2001; 92: 11921198.
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 1981; 391: 85100.
Wang DW, George AL, Bennett PB. Comparison of heterologously expressed human cardiac and skeletal muscle sodium channels. Biophys J 1996; 70: 238245.
Haeseler G, Petzold J, Hecker H et al. Succinylcholine metabolite succinic acid alters steady-state activation in muscle sodium channels. Anesthesiology 2000; 92: 13851392.
Hodgkin AL, Horowicz P. The influence of potassium and chloride ions on the membrane potential of single muscle fibres. J Physiol 1959; 148: 127160.
Ragsdale DS, McPhee JC, Scheuer T, Catterall WA. Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 1994; 265: 17241728.
Haeseler G, Leuwer M, Kavan J et al. Voltage-dependent block of normal and mutant muscle sodium channels by 4-chloro-m-cresol. Br J Pharmacol 1999; 128: 12591267.
Haeseler G, Piepenbrink A, Bufler J et al. Structural requirements for voltage-dependent block of muscle sodium channels by phenol derivatives. Br J Pharmacol 2001; 132: 19161924.
Bean BP, Cohen CJ, Tsien RW. Lidocaine block of cardiac sodium channels. J Gen Physiol 1983; 81: 613642.
Scheuer T. A revised view of local anesthetic action: What channel state is really stabilized? J Gen Physiol 1999; 113: 36.
Leuwer M, Haeseler G, Hecker H et al. An improved model for the binding of lidocaine and structurally related local anaesthetics to depolarized states of voltage-operated sodium channels. Br J Pharmacol 2004; 141: 4754.
Fan Z, George AL, Kyle JW, Makielski JC. Two human paramyotonia congenita mutations have opposite effects on lidocaine block of Na+ channels expressed in a mammalian cell line. J Physiol 1996; 496: 275286.


High-affinity blockade of voltage-operated skeletal muscle sodium channels by 2,6-dimethyl-4-chlorophenol

  • G. Haeseler (a1), S. Gudehus (a1), J. Bufler (a2), R. Dengler (a2) and M. Leuwer (a3)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.