Calixmexitil: Calixarene-based Cluster of Mexiletine with Amplified Anti-myotonic Activity as A Novel Use-dependent Sodium Channel Blocker

摘要

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[4]arene-based cluster in a chalice-shaped structure. Therefore, the present study reports the synthesis and in-vitro anti-myotonic activity of the chalice-shaped 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[4]arene 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 use-dependent manner) in single skeletal muscle fibers. The experimental results showed an amplified (10-fold) potency in producing phasic block as an indication of the anti-myotonic activity and improved (3-fold) potency in producing use-dependent block for the cluster (calixmexitil) in relation to its monomer (mexiletine). The potency in producing phasic block and use-dependent block are two main factors to describe dose range, drug affinity, and side effects of an anti-myotonic agent. Therefore, compared to mexiletine, calixmexitil with these improved factors can be considered as a a??selectivea?? anti-myotonic 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 channelsa?? structure in skeletal muscle fibers.