ED50 G(Na) block predictions for phenyl substituted and unsubstituted n-alkanols

To study the role the phenyl group plays in producing local anesthetic bloc k, a sequence of n-alkanols and phenyl-substituted alkanols (Phi -alkanols) were characterized in their ability to block Na channels. The sequence of 12-alkanols studied possess 3-5 carbons (propanol-pentanol). The action of phenol and 3-Phi -alkanols (benzyl alcohol, phenethyl alcohol, 3-phenyl-1-p ropanol) were also studied. Na currents (I-Na) were recorded from single fr og skeletal muscle fibers using the Vaseline-gap voltage clamp technique. I (Na)s were recorded prior to, during, and following the removal of the solu tes in Ringer's solution. All alkanols and phenol acted to block I-Na in a dose-dependent manner, Eff ective 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-dependen t 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 r elation. All solutes acted to speed up I-Na kinetics and cause hyperpolariz ing shifts in steady-state inactivation, The magnitude of the kinetic chang es 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. ED(50)s for G(Na) and AP block could be predicted as a function of int rinsic molar volume, hydrogen bond acceptor basicity (beta) and donor acidi ty (a), and polarity (P) of the solutes. The equivalency of EDNa predictions for AP and G(Na) block can be explained by the fact that AP block arises from channel block and solute-induced cha nges in I,, kinetics. Phi -alkanols were more effective at blocking and ina ctivating Na channels than their unsubstituted counterparts, Phenyl-substit uted alkanols are more likely to interact with the channel than their unsub stituted counterparts.