Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential

Abstract

Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.

Synthesis and Evaluation of Voltage‐Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

“…2 a – e with 1 a – e , respectively). This result agrees with those previously observed on myoblasts [19] and may be related to the 2 a – e increased lipophilicity (cf. Table 2).…”

“…While p K a values were substantially unchanged throughout the three compounds series, Log D 7.4 values spanned a three order of magnitude range thus reflecting corresponding variations in Log P values. Despite possible overestimation, [19] the observed positive relationship between lipophilicity and antiarrhythmic potency agreed with previous observations [18,19] . The elongation of the intermediate chain connecting the aryloxy moieties to the basic functional groups may also be beneficial [19,23,24] .…”

“…Despite possible overestimation, [19] the observed positive relationship between lipophilicity and antiarrhythmic potency agreed with previous observations [18,19] . The elongation of the intermediate chain connecting the aryloxy moieties to the basic functional groups may also be beneficial [19,23,24] . Furthermore, the tetramethylpyrroline basic nitrogen is inserted in a lipophilic structural environment and, when protonated, distributes the cationic charge in the form of partial charges delocalized on the surrounding carbon atoms [19] .…”

“…Recently, two tetramethylpyrroline derivatives of both mexiletine and its potent use‐dependent isopropyl analogue were tested for their ability to block native Na V 1.4 and to exert cytoprotective effects against oxidative‐stress injury in myoblasts. Both compounds showed an improved pharmacological profile as sodium channel blockers, with the isopropyl analog being the strongest use‐dependent mexiletine‐like compound so far, and remarkable cytoprotection at concentrations effective for use‐dependent block [19] . Herein, we report the synthesis of the above two pyrroline derivatives ( 2 a , d ) and of three additional analogues ( 2 b , c , e , Figure 1) which were studied for their antiarrhythmic and antioxidant properties.…”

Deracemisation Processes Employing Organocatalysis and Enzyme Catalysis

“…In the same year, a similar method was carried out for the effective deracemisation of mexiletine ( 3b , Scheme ), a chiral amine clinically used in cardiac disorders, and currently employed as the racemate. Besides, the ( S )‐enantiomer has attracted attention due to a potential use in neuromuscular disorders . The authors developed a one‐pot two‐steps procedure featuring a kinetic resolution followed by a stereoselective amination.…”