calixmexitil: calixarene-based cluster of mexiletine with amplified anti-myotonic activity as a novel use-dependent sodium channel blocker

Mexiletine as the first choice drug in myotonia treatment is a chiral sodium channel blocker clinically used in its racemic form. the phenolic structure of this drug, prompted us to design its novel calix-are based cluster in a chalice shaped structure. therefore, the present study reports the synthesis and invitro antimyotonic activity of the chaliceshaped cluster of mexiletine (namely calixmexitil) in comparison to its simple drug unit (mexitil) as the reference medication. the synthetic route included chemical modification of the calix are structure by grafting four 2 aminopropoxy moieties at the lower rim of the scaffold. electrophysiological tests were performed for the determination of test compounds abilities to act as sodium channel blockers in inhibiting sodium currents (in usedependent manner) in single skeletal muscle fibers. the experimental results showed an amplified (10fold) potency in producing phasic block as an indication of the antimyotonic activity and improved (3fold) potency in producing usedependent block for the cluster (calixmexitil) in relation to its monomer (mexiletine). the potency in producing phasic block and usedependent block are two main factors to describe dose range, drug affinity, and side effects of an antimyotonic agent. therefore, compared to mexiletine, calixmexitil with these improved factors can be considered as a “selective” antimyotonic agent with low dose range. these improved pharmaceutical effects are maybe attributed to clustering effect and improved interaction of four impacted mexiletine units of the cluster with the sodium channels’ structure in skeletal muscle fibers.