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 (phi)-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-phi-alkanols (benzyl alcohol, phenethyl alcohol, 3-phenyl-1-propanol) were also studied. Na currents (INa) were recorded from single frog skeletal muscle fibers using the Vaseline-gap voltage clamp technique. INas were recorded prior to, during, and following the removal of the solutes in Ringer's solution. All alkanols and phenol acted to block INa in a dose-dependent manner. Effective doses to produce half block (ED50) of INa or Na conductance (GNa) were obtained from dose-response relations for all solutes used. The block of GNa depended on voltage, and could be separated into voltage-dependent and -independent components. Each solute acted to shift GNa-V relations in a depolarized direction and reduce the maximum GNa and slope of the relation. All solutes acted to speed up INa 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 INa; however, size alone was not sufficient to predict the changes in INa. ED50s for GNa and AP block could be predicted as a function of intrinsic molar volume, hydrogen bond acceptor basicity (beta) and donor acidity (alpha), and polarity (P) of the solutes. The equivalency of ED50 predictions for AP and GNa block can be explained by the fact that AP block arises from channel block and solute-induced changes in INa kinetics. phi-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.