We studied the phenylpropenes as voltage-gated sodium channel (VGSC) modulators in comparison with lidocaine, which is a popular local anesthetic used in humans and animals. Phenylpropenes eugenol, isoeugenol and anethole, and lidocaine bind to VGSC with similar affinity (IC50 = 1–2 mM). However, the biophysical properties of VGSC expressed in sensory neurons from rats are differently affected by these molecules. Phenylpropenes shift VGSC’s voltage-inactivation curve by up to −16 mV, a feature not shared by lidocaine. Exclusively, lidocaine delays VGSC’s recovery from inactivation and exhibits strong frequency-dependent blockade enhancement. Rightfully, literature credits these effects to a stabilization of the channels’ inactivated state promoted by lidocaine. Interestingly, shifts in channels’ inactivation curve like those produced by phenylpropenes are also credited to the same kind of stabilization. We propose that the recovery from inactivation test is suitable for testing inactivated channel stabilization, but not the test with inactivation curves. Phenylpropenes effectively shift inactivation curves to more negative voltages without delaying recovery from inactivation. Activation curves also changed differently between phenylpropenes and lidocaine—phenylpropenes shift activation curves to more positive membrane potentials while lidocaine does not affect the curve. We show various other tests on VGSC that attest to the different mechanisms of action of the phenylpropenes and lidocaine. We also show that phenylpropenes do not exhibit frequency-dependent effect like lidocaine does. On the other hand, only lidocaine stabilizes all inactivated states of the channels. Hence, we propose phenylpropenes and lidocaine have different mechanisms of action on VGSC. We hypothesize that phenylpropenes bind to pre-open closed states of VGSCs as an additional blocking mechanism besides the block of the hyperpolarized closed channels. This abstract proposes to open this discussion for a better understanding of the effects of these biologically active phenylpropenes on VGSC.
João L. Carvalho-de-Souza (Sun,) studied this question.