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Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels
Open accessAbstract
Significance: Voltage-gated sodium (Na v ) channels contribute to physiological and pathophysiological electrical signaling in nerve and muscle cells. Because Na v channel isoforms exhibit tissue-specific expression, subtype selective modulation of this channel family provides important drug development opportunities. However, most available Na v channel modulators are unable to distinguish between Na v channel subtypes, which limits their therapeutic utility because of cardiac or nervous system toxicity. This study describes a new class of subtype selective Na v channel inhibitors that interact with a region of the channel that controls voltage sensitivity. This interaction site may enable development of selective therapeutic interventions with reduced potential for toxicity.
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“Since there is precedent for small molecule compounds that either enhance or diminish ion channel activity [60–62], it is conceivable to develop drugs for modulating NaV1.2 activity to treat IEE and ASD/ID.”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [60]
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Metadata
- Authors
- McCormack, K., Santos, S., Chapman, M. L., Krafte, D. S., Marron, B. E., West, C. W., Krambis, M. J., Antonio, B. M., Zellmer, S. G., Printzenhoff, D., Padilla, K. M., Lin, Z., Wagoner, P. K., Swain, N. A., Stupple, P. A., de Groot, M., Butt, R. P., & Castle, N. A.
- Affiliations
- Pfizer (United States) (US)
- Pfizer (United Kingdom) (GB)
- Pfizer Ltd., Sandwich, Kent CT13 9NJ, United Kingdom
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-07
- Volume
- 110
- Issue
- 29
- Pages
- E2724-32
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3718154
- OpenAlex
- W1979671751
- Cited by
- 244
- References
- 46
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 20 · 2023: 16 · 2022: 20 · 2021: 19 · 2020: 19 · 2019: 14 · 2018: 24 · 2017: 33 · 2016: 22 · 2015: 13 · 2014: 15 · 2013: 2
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- voltage-gated sodium channels, small molecule inhibitors, subtype selectivity, Nav1.3, Nav1.7, cardiac sodium channel, toxin binding site, alpha-scorpion toxin, species sensitivity, sodium channel inactivation
- MeSH terms
- Acetamides, Binding Sites, Humans, Molecular Sequence Data, Thiazoles, Sequence Alignment, Patch-Clamp Techniques, Inhibitory Concentration 50, Amino Acid Motifs, Electrophysiological Phenomena, HEK293 Cells, Voltage-Gated Sodium Channel Blockers, NAV1.3 Voltage-Gated Sodium Channel
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