The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat
Abstract
The development of novel anticonvulsant drugs with improved efficacy for the treatment of epilepsy is hindered by a lack of information regarding the quantitative relationship between target mechanism and in vivo efficacy. In the present study we have examined the correlation between the potency of structurally diverse compounds at voltage-gated sodium channels in vitro and their efficacy in a rodent model of acute generalised seizures induced by electroshock. We observed a significant correlation between the estimated affinity (Ki) of the compounds for the inactivated state of human recombinant Na(V)1.2 channels and the unbound brain concentration required for anticonvulsant efficacy. Furthermore, the data suggest that an unbound concentration equivalent to less than 50% of the Ki is sufficient for anticonvulsant effect. We noted that increasing sodium channel blocking potency was associated with increasing brain tissue binding and lipophilicity. These data suggest that there is a balance between sodium channel blocking potency in vitro and good pharmacokinetic characteristics necessary for anticonvulsant efficacy in vivo. Finally, we examined the sodium channel blocking potency of sodium valproate in relation to its anticonvulsant efficacy in vivo. We found that a higher unbound concentration of the drug in the brain was required for anticonvulsant efficacy than would be expected given its sodium channel blocking potency.
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Building on SHP836 as a lead compound, Novartis researchers developed SHP099 (IC50 = 0.07 μM), a compound with good selectivity and activity and good oral bioavailability.
“Subsequently, building on SHP836 as a lead compound, Novartis researchers developed SHP099 (90) (IC50 = 0.07 μM), a compound with good selectivity and activity and good oral bioavailability.285”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [285]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
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- Authors
- Large, C. H., Kalinichev, M., Lucas, A., Carignani, C., Bradford, A., Garbati, N., Sartori, I., Austin, N. E., Ruffo, A., Jones, D. N. C., Alvaro, G., & Read, K. D.
- Affiliations
- GlaxoSmithKline (Italy) (IT)
- GlaxoSmithKline (United Kingdom) (GB)
- University of Dundee (GB)
- Corresponding author
- Large, Charles H.
- Venue
- Epilepsy Research
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 85
- Issue
- 1
- Pages
- 96-106
- ISSN
- 0920-1211 (ISSN-L)
- OpenAlex
- W1991845725
- Cited by
- 45
- References
- 29
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2020: 2 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 6 · 2012: 5
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Epilepsy Research (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Academy of Finland
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- sodium channel inhibition, anticonvulsant activity, voltage-gated sodium channels, Nav1.2, generalized seizures, electroshock-induced seizures, binding affinity, lipophilicity, pharmacokinetics, valproic acid, in vitro-in vivo correlation
- MeSH terms
- Lamotrigine, Animals, Anticonvulsants, Biophysics, Cell Line, Transformed, Dialysis, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Interactions, Electric Stimulation, Electroshock, Humans, Male, Membrane Potentials, Seizures, Transfection, Triazines, Sodium Channels, Patch-Clamp Techniques, Sodium Channel Blockers, Rats
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