ArticleNeuropharmacology2017
Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.
Article in Neuropharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine.Journal of neuromuscular diseases · 2021Pooled it
- Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized double-blind placebo-controlled cross-over study.Clinical and translational science · 2022Trial
- Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors.bioRxiv : the preprint server for biology · 2025Article
- Pharmacological therapy of non-dystrophic myotonias.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2025Review
- Preclinical study of the antimyotonic efficacy of safinamide in the myotonic mouse model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Blockers of Skeletal Muscle NaInternational journal of molecular sciences · 2023Review
- Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner.International journal of molecular sciences · 2022Article
- The Beginning of Meiosis in Mammalian Female Germ Cells: A Never-Ending Story of Intrinsic and Extrinsic Factors.International journal of molecular sciences · 2022Review
- Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle.Cells · 2022Review
- Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use-Dependent Inhibitors of Voltage-Gated Sodium Channels.ChemMedChem · 2021Article
- Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy.Cells · 2021Review
- Calixmexitil: Calixarene-based Cluster of Mexiletine with Amplified Anti-myotonic Activity as A Novel Use-dependent Sodium Channel Blocker.Iranian journal of pharmaceutical research : IJPR · 2019Article
- Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.Frontiers in pharmacology · 2018Article
- Identification of Mepenzolate Derivatives With Long-Acting Bronchodilatory Activity.Frontiers in pharmacology · 2018Article
- Toward precision medicine in myotonic syndromes.Oncotarget · 2017Article
- Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential.Frontiers in pharmacology · 2017Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers. The current study was performed to verify their potential as antimyotonic agents. Patch-clamp experiments show that both compounds, especially To042, are greatly more potent and use-dependent blockers of human skeletal muscle hNav1.4 channels compared to tocainide and mexiletine. Reduced effects on F1586C hNav1.4 mutant suggest that the compounds bind to the local anesthetic receptor, but that the increased hindrance and lipophilia of the N-substituent may further strengthen drug-receptor interaction and use-dependence. Compared to mexiletine, To042 was 120 times more potent to block hNav1.4 channels in a myotonia-like cellular condition and 100 times more potent to improve muscle stiffness in vivo in a previously-validated rat model of myotonia. To explore toxicological profile, To042 was tested on hERG potassium currents, motor coordination using rotarod, and C2C12 cell line for cytotoxicity. All these experiments suggest a satisfactory therapeutic index for To042. This study shows that, owing to a huge use-dependent block of sodium channels, To042 is a promising candidate drug for myotonia and possibly other membrane excitability disorders, warranting further preclinical and human studies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.