Hydroxylated Analogs of Mexiletine as Tools for Structural-Requirements Investigation of the Sodium Channel Blocking Activity

[2‐(2‐Aminopropoxy)‐1,3‐phenylene]dimethanol 1 and 4‐(2‐aminopropoxy)‐3‐(hydroxymethyl)‐5‐methylphenol 2, two dihydroxylated analogs of mexiletine – a well known class IB anti‐arrhythmic drug – were synthesized and used as pharmacological tools to investigate the blocking‐activity requirements of human skeletal muscle, voltage‐gated sodium channel. The very low blocking activity shown by newly synthesized compounds corroborates the hypothesis that the presence of a phenolic group in the para‐position to the aromatic moiety and/or benzylic hydroxyl groups on the aromatic moiety of local anesthetic‐like drugs impairs either the transport to or the interaction with the binding site in the pore of Na+ channels.