ED50 AP block predictions for phenyl substituted and unsubstituted n-alkanols

A series of n-alkanols and phenyl-substituted n-alkanols (Phi,-alkanols) of increasing chain length and phenol were characterized for their ability to block action potentials (APs) in frog sciatic nerves. APs were recorded using the single sucrose-gap method. The degree of AP attenuation when the nerve was exposed to different concentrations of an alcohol was used to construct dose-response curves. The reciprocals of the half-blocking doses (ED(50)s) were used to obtain a measure of the potency of the alcohols. For n-alkanols and Phi -alkanols, increasing the chain length by the addition of a methylene group increased the potency on average by 3.1 for both groups of alkanols. The addition of a phenyl group caused a potency increase that ranged between the values of 77 and 122. The ED50 for both groups of alkanols could not be solely predicted by the log octanol-water partition coefficient (K-OW). Using linear solvation energy relations (LSER), the log ED50 could be described as a linear combination of the intrinsic (van der Waals) molar volume (V-l), polarity (P), and hydrogen bond acceptor basicity (beta) and donor acidity (alpha). Size alone could not predict the ED50 for both 12-alkanols and Phi -alkanols, The results art: consistent with the hypothesis that alkanols bind to and interact with Na channels to cause AP block. Phenyl group addition to an alkanol markedly increases the molecule's potency.