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

Abstract

1 We have studied the eects of four dierent phenol derivatives, with methyl and halogen substituents, on heterologously expressed human skeletal muscle sodium channels, in order to ®nd structural determinants of blocking potency. 2 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 7100 mV to 0 mV with IC 50 values of 2161 and 666 mM respectively. Methylation of the halogenated compound further increased potency, reducing the IC 50 to 268 mM in 2-methyl-4-chlorophenol and to 150 mM in 3,5-dimethyl-4-chlorophenol. 3 Membrane depolarization before the test depolarization increased sodium channel blockade. When depolarizations were started from 770 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 mM for 3,5-dimethyl-4-chlorophenol, 19 mM for 2-methyl-4-chlorophenol, 26 mM for 4-chlorophenol and 115 mM for 3-methylphenol. 4 All compounds accelerated the current decay during depolarization and slowed recovery from fast inactivation. No relevant frequency-dependent block after depolarizing pulses applied at 10, 50 and 100 Hz was detected for any of the compounds. 5 All the phenol derivatives that we examined are eective blockers of skeletal muscle sodium channels, especially in conditions that are associated with membrane depolarization. Blocking potency is increased by halogenation and by methylation with increasing numbers of methyl groups.

Interaction of phenol derivatives with ion channels

“…Analogous to the effects described for other Na 1 channel blocking drugs [18,57], channel repriming after a depolarization is delayed by phenol derivatives [19]. This might, on the one hand, be due to drug-induced stabilization of the inactivated state.…”

“…The addition of one to three substituents in the phenol molecule is sufficient to form compounds with equal or higher potency in blocking voltage-operated muscle sodium channels to lidocaine. For example, the IC 50 value for lidocaine block of heterologously expressed muscle sodium channels at 2 100 mV was 500 µM [18], compared with 150 µM for 3,5-dimethyl-4-chlorophenol [19].…”

“…Apparently, substituted phenol derivatives constitute a new group of sodium channel blocking agents. The potency of these compounds to block voltage-operated sodium channels is related to halogenation and to the size and position (with respect to the phenolic hydroxyl) of aliphatic substituents [19]. However, with the exception of propofol, most of the phenol derivatives studied are of experimental interest only at the present time and are in clinical use for applications other than the pharmacological blockade of sodium channels.…”

“…halogenation, induce substantial changes in pharmacological profile and receptor kinetics [39]. W hile the potency of a phenol derivati ve to block voltage-operated sodium channels was higher in halogenated compounds [19], halogenation of the propofol molecule did not further increase its ability to directly activate GABA A receptors [39]. Animal experiments revealed that the halogenated propofol analogue showed anticonvulsant, but no sedative-hypnotic effects [38].…”

“…With the excepti on of benzylalcohol, the dissociation of all compounds from inactivated channels occurs on a time-scale that is hardly discernibl e from the time-course of recovery from fast inactivation. Thus this leads to a slight prolongation of the fast component of recovery and introduction of a second, slow component, of about 30 ms for all phenolic compounds [19,20]. Use-dependent block during repetitive stimulation in the presence of a channel blocking agent is generally observed when the time of membrane repolarization between the pulses is too short to allow recovery from inactivated channel block.…”