Eleclazine exhibits enhanced selectivity for long QT syndrome type 3–associated late Na + current

El-Bizri, Nesrine; Xie, Congying; Liu, Lynda; Limberis, James T.; Krause, Michael; Hirakawa, Ryoko; Nguyen, Steven; Tabuena, Dennis R.; Belardinelli, Luiz; Kahlig, Kristopher M.

doi:10.1016/j.hrthm.2017.09.028

Cited by 19 publications

(24 citation statements)

References 25 publications

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“… 26 , 27 , 28 , 29 The inhibition of both I Na and I NaL by ELE has been shown to be voltage-dependent so that the IC 50 s for inhibition of the ATX-II-activated I NaL in atrial and ventricular myocytes in the present study (217 nM and 180 nM, respectively) were comparable with the value reported previously in rabbit ventricular myocytes at a corresponding HP of -80 mV (260 nM). 27 Consistent with previous reports on recordings of fast I Na from rabbit ventricular myocytes and recombinant human Na v 1.5 channels, 27 , 28 10 μM ELE produced significant use-dependent inhibition, with little difference between atrial and ventricular myocytes. The rates of accumulation of I Na inhibition evident during the repeated pulse protocol in the present study ( Figure 4 ) were very much faster than those reported previously for ranolazine in canine and rabbit cardiac myocytes using similar pulse widths, DI, and numbers of pulses, consistent with the unusually rapid kinetics of ELE.…”

Section: Discussionsupporting

confidence: 89%

“…ELE has been shown to block cardiac Na + channels with unusually rapid kinetics, interacting with the local anesthetic binding site and showing marked selectivity for I NaL relative to fast I Na . 28 The present study demonstrates that there was no difference between atrial and ventricular myocytes in the concentration-dependent inhibition of ATX-II-activated I NaL by ELE, indicating similar affinity of ELE for atrial and ventricular Na + channels. Our data are consistent with the inhibition of I NaL by ELE via open channel block, as suggested in previous reports.…”

Section: Discussionmentioning

confidence: 43%

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Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

et al. 2020

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Background Atrial-ventricular differences in voltage-gated Na + currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na + channel blocker ranolazine that has been shown to be safe and well tolerated in patients. Objective The present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na + currents. Methods The fast and late components of whole-cell voltage-gated Na + currents (respectively, I Na and I NaL ) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes. Results Atrial I Na activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular I Na . There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I NaL activated by 3 nM ATX-II (IC 50 s ∼200 nM). Eleclazine (10 μM) inhibited I Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of I Na from inactivation in both cell types. Conclusions Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I Na . The more negative voltage dependence of I Na activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 43%

Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

et al. 2020

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“…Na + channel inhibitors are supposed to bind to a local anesthetic site of Phe1760 and Tyr1767 in Nav1.5 (Kass and Moss, 2006). Mutations located in close to this binding site such as F1760A/Y1767A would disrupt the binding of drugs such as MEX, ELE, and propranolol (Sasaki et al, 2004;El-Bizri et al, 2018). The gating state of sodium channels also plays an important role in drug interaction (Desaphy et al, 2001).…”

Section: Molecular Insights Into Mex Sensitivitymentioning

confidence: 99%

Gating Properties of Mutant Sodium Channels and Responses to Sodium Current Inhibitors Predict Mexiletine-Sensitive Mutations of Long QT Syndrome 3

Woltz

Wang

et al. 2020

Front. Pharmacol.

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Background: Long QT syndrome 3 (LQT3) is caused by SCN5A mutations. Late sodium current (late I Na) inhibitors are current-specific to treat patients with LQT3, but the mechanisms underlying mexiletine (MEX)-sensitive (N1325S and R1623Q) and-insensitive (M1652R) mutations remains to be elucidated. Methods: LQT3 patients with causative mutations were treated with oral MEX following i.v. lidocaine. Whole-cell patch-clamp techniques and molecular remodeling were used to determine the mechanisms underlying the sensitivity to MEX. Results: Intravenous administration of lidocaine followed by MEX orally in LQT patients with N1325S and R1623Q sodium channel mutation shortened QTc interval, abolished arrhythmias, and completely normalized the ECG. In HEK293 cells, the steady-state inactivation curves of the M1652R channels were rightward shifted by 5.6 mV relative to the WT channel. In contrast, the R1623Q mutation caused a leftward shift of the steady-state inactivation curve by 15.2 mV compared with WT channel, and N1325S mutation did not affect steady-state inactivation (n = 5-13, P < 0.05). The extent of the window current was expanded in all three mutant channels compared with WT. All three mutations increased late I Na with the greatest amplitude in the M1652R channel (n = 9-15, P < 0.05). MEX caused a hyperpolarizing shift of the steady-state inactivation and delayed the recovery of all three mutant channels. Furthermore, it suppressed late I Na in N1325S and R1623Q to a greater extent compared to that of M1652R mutant channel. Mutations altered the sensitivity of Na v 1.5 to MEX through allosteric mechanisms by changing the conformation of Na v 1.5 to become more or less favorable for MEX binding. Late I Na inhibitors suppressed late I Na in N1325S and R1623Q to a greater extent than that in the M1652R mutation (n = 4-7, P < 0.05).

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“…A similar mechanism has been assumed for inhibition by riluzole in a recent computational study (Phillips & Rubin, 2019). To illustrate how this compares to offset kinetics of other well-known sodium channel inhibitors, we re-plotted the data from a comparative study of nine inhibitor compounds (El-Bizri et al, 2018), which included six antiarrhythmic drugs, and the three best known I NaP selective inhibitors. We supplemented these data with our results on the effects of riluzole (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Calculated binding and unbinding rates of riluzole to 9 sodium channel inhibitor compounds. The figure was re-plotted from El-Bizri et al, (2018)., and supplemented with our data with riluzole, in which case we calculated binding and unbinding rates for both the fast and the slow recovery processes. (AMDamiodarone; ELEC -eleclazine; FLC -flecainide; LID -lidocaine; MEX -mexiletine; PRF -propafenone; QUI -quinidine; RIL -riluzole).…”

Section: Figure Legendsmentioning

confidence: 99%

The mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling

Foldi

Pesti

Zboray

et al. 2020

Preprint

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Hyperexcitability-related diseases include epilepsies, pain syndromes, neuromuscular disorders, and cardiac arrhythmias. Sodium channel inhibitors can be used to treat these conditions, however, their applicability is limited by their nonspecific effect on physiological function. They act by channel block (obstructing ion conduction, since the binding site is within the channel pore), and by modulation (delaying recovery from the non-conducting inactivated state). Channel block inhibits healthy and pathological tissue equally, while modulation can preferentially inhibit pathological activity. Therefore, an ideal sodium channel inhibitor drug would act by modulation alone. Unfortunately, thus far no such drug has been known to exist. Here we present evidence that riluzole acts by this "ideal" mechanism, "non-blocking modulation" (NBM). We propose that, being a relatively small molecule, riluzole is able to stay bound to the binding site, but nonetheless stay off the conduction pathway, by residing in one of the "fenestrations" (cavities connecting the central cavity to the membrane phase). Using precisely timed UV pulses to photolabel specific conformations of the channel, we show that association to the local anesthetic binding site requires prior inactivation. We discuss why kinetics of binding is crucial for selective inhibition of pathological activity, and how the NBM mechanism can be recognized using a special voltage-and drug application-protocol. Our results identify riluzole as the prototype of this new class of sodium channel inhibitors. Drugs of this class are expected to selectively prevent hyperexcitability, while having minimal effect on cells firing at a normal rate from a normal resting potential.

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Eleclazine exhibits enhanced selectivity for long QT syndrome type 3–associated late Na + current

Cited by 19 publications

References 25 publications

Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

Gating Properties of Mutant Sodium Channels and Responses to Sodium Current Inhibitors Predict Mexiletine-Sensitive Mutations of Long QT Syndrome 3

The mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling

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