ED₅₀ G _Na Block Predictions for Phenyl Substituted and Unsubstituted n-Alkanols

Abstract.

To study the role the phenyl group plays in producing local anesthetic block, a sequence of n-alkanols and phenyl-substituted alkanols (Φ-alkanols) were characterized in their ability to block Na channels. The sequence of n-alkanols studied possess 3–5 carbons (propanol-pentanol). The action of phenol and 3-Φ-alkanols (benzyl alcohol, phenethyl alcohol, 3-phenyl-1-propanol) were also studied. Na currents (I _Na ) were recorded from single frog skeletal muscle fibers using the Vaseline-gap voltage clamp technique. I _Na s were recorded prior to, during, and following the removal of the solutes in Ringer's solution.

All alkanols and phenol acted to block I _Na in a dose-dependent manner. Effective doses to produce half block (ED₅₀) of I _Na or Na conductance (G _Na ) were obtained from dose-response relations for all solutes used. The block of G _Na depended on voltage, and could be separated into voltage-dependent and -independent components. Each solute acted to shift G _Na -V relations in a depolarized direction and reduce the maximum G _Na and slope of the relation. All solutes acted to speed up I _Na kinetics and cause hyperpolarizing shifts in steady-state inactivation. The magnitude of the kinetic changes increased with dose.

Size was an important variable in determining the magnitude of the changes in I _Na ; however, size alone was not sufficient to predict the changes in I _Na . ED₅₀s for G _Na and AP block could be predicted as a function of intrinsic molar volume, hydrogen bond acceptor basicity (β) and donor acidity (α), and polarity (P) of the solutes.

The equivalency of ED₅₀ predictions for AP and G _Na block can be explained by the fact that AP block arises from channel block and solute-induced changes in I _Na kinetics. Φ-alkanols were more effective at blocking and inactivating Na channels than their unsubstituted counterparts. Phenyl-substituted alkanols are more likely to interact with the channel than their unsubstituted counterparts.