Structural requirements for voltage-dependent block of muscle sodium channels by phenol derivatives

British Journal of Pharmacology
G HaeselerM Leuwer

Abstract

We have studied the effects of four different phenol derivatives, with methyl and halogen substituents, on heterologously expressed human skeletal muscle sodium channels, in order to find structural determinants of blocking potency. All compounds blocked skeletal muscle sodium channels in a concentration-dependent manner. The methylated phenol 3-methylphenol and the halogenated phenol 4-chlorophenol blocked sodium currents on depolarization from -100 mV to 0 mV with IC(50) values of 2161 and 666 microM respectively. Methylation of the halogenated compound further increased potency, reducing the IC(50) to 268 microM in 2-methyl-4-chlorophenol and to 150 microM in 3,5-dimethyl-4-chlorophenol. Membrane depolarization before the test depolarization increased sodium channel blockade. When depolarizations were started from -70 mV or when a 2.5 s prepulse was introduced before the test pulse inducing slow inactivation, the IC(50) was reduced more than 3 fold in all compounds. The values of K(D) for the fast-inactivated state derived from drug-induced shifts in steady-state availability curves were 14 microM for 3,5-dimethyl-4-chlorophenol, 19 microM for 2-methyl-4-chlorophenol, 26 microM for 4-chlorophenol and 115 microM for 3-methylp...Continue Reading

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Jul 25, 2000·British Journal of Pharmacology·G HaeselerM Leuwer

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Citations

Apr 16, 2009·Naunyn-Schmiedeberg's Archives of Pharmacology·Vanessa BuchholzGertrud Haeseler
Jul 12, 2014·Naunyn-Schmiedeberg's Archives of Pharmacology·Nilufar FoadiJörg Ahrens
Oct 4, 2006·British Journal of Pharmacology·C H R WallaceP E Light
Mar 27, 2002·European Journal of Anaesthesiology·G Haeseler, M Leuwer
Aug 31, 2002·European Journal of Anaesthesiology·G HaeselerM Leuwer
Mar 26, 2003·European Journal of Anaesthesiology·M SchywalskyH Schwilden
Mar 26, 2003·European Journal of Anaesthesiology·P BozkurtM Hacibekiroğlu
Mar 26, 2003·European Journal of Anaesthesiology·S G Sakka, A Meier-Hellmann
Mar 26, 2003·European Journal of Anaesthesiology·P KrankeN Roewer
Mar 26, 2003·European Journal of Anaesthesiology·J A BlunkW Koppert
Mar 26, 2003·European Journal of Anaesthesiology·T P WeberM Booke
Mar 25, 2018·Naunyn-Schmiedeberg's Archives of Pharmacology·Nilufar Foadi

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