ArticleNeuropharmacology2007
A pharmacophore derived phenytoin analogue with increased affinity for slow inactivated sodium channels exhibits a desired anticonvulsant profile.
Article in Neuropharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- Phenytoin Derivatives as Antagonists of AMPA Receptors and Voltage-Gated Sodium Channels: A Structure-Function Study.International journal of molecular sciences · 2026Article
- Validated LC-MS/MS Assays for Novel Triazolyl-Oxazolidinones with Anticonvulsant Activities and Their Potential Applications in Stability and Pharmacokinetic Studies.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Screening for Activity Against AMPA Receptors Among Anticonvulsants-Focus on Phenytoin.Frontiers in pharmacology · 2021Article
- Isoflurane modulates activation and inactivation gating of the prokaryotic NaThe Journal of general physiology · 2017Article
- The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin.Epilepsia · 2016Article
- Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin.Marine drugs · 2016Article
- Current understanding of the mechanism of action of the antiepileptic drug lacosamide.Epilepsy research · 2015Review
- Evaluation of anticonvulsant actions of dibromophenyl enaminones using in vitro and in vivo seizure models.PloS one · 2014Article
- Synthesis and biological evaluation of a fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain and imaging agent.Bioorganic & medicinal chemistry · 2012Article
- Article
- Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore.Molecular pharmacology · 2010Article
- Fast- or slow-inactivated state preference of Na+ channel inhibitors: a simulation and experimental study.PLoS computational biology · 2010Article
- Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis.Acta pharmacologica Sinica · 2009Article
- Modulation of sodium channel inactivation gating by a novel lactam: implications for seizure suppression in chronic limbic epilepsy.The Journal of pharmacology and experimental therapeutics · 2009Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
Phenytoin (DPH) is a clinically useful sodium (Na) channel blocker with efficacy against partial and generalized seizures. We have developed a novel hydantoin compound (HA) using comparative molecular field analysis (CoMFA) and evaluated its effects on hNa(v)1.2 channels. Both DPH and HA demonstrated affinity for resting (K(r)=13.9microM for HA, K(r)=464microM for DPH) and slow inactivated channels (K(I)=975nM for HA, K(I)=20.6microM for DPH). However, HA also exhibited an affinity for fast inactivated channels (K(I)=2.5microM) and shifted the V(1/2) for activation in the depolarizing direction. Furthermore, HA exhibited profound use dependent block at both 5 and 10Hz stimulation frequencies. In the 6Hz seizure model (32mA) HA had an ED(50) of 47.1mg/kg and a TD(50) of 131mg/kg (protective index (PI)=2.8). In comparison, the ED(50) for DPH was approximately 27.5mg/kg with a TD(50) of 35.6mg/kg (PI approximately 1.3). These findings provide evidence for the utility of CoMFA in the design of novel anticonvulsants and support the hypothesis that states selectivity plays an important role in achieving optimal protection with minimal side effects.
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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.