Drug Treatment of Epilepsy: From Serendipitous Discovery to Evolutionary
Mechanisms

Lou, Shengying; Cui, Sunliang

doi:10.2174/0929867328666210910124727

Cited by 7 publications

(2 citation statements)

References 222 publications

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“…topiramate) or augmentation of inhibitory neurotransmission (e.g. vigabatrin) 6,7 . However, these drugs can be associated with psycho-behavioral, cognitive and sleep adverse events 8 , underscoring the need for novel therapeutic compounds with improved properties and efficacy in treating specific genetic disorders.…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel compounds and target mechanisms using a high throughput, multiparametric phenotypic screen in a human neuronal model of Tuberous Sclerosis

Williams,

Ryan,

Joshi

et al. 2024

Preprint

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SUMMARYTuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the mTOR pathway genesTSC1orTSC2. TSC can affect multiple organs including the brain, and most patients (75-90%) present with seizures during early childhood and intractable epilepsy throughout life. mTOR inhibitors, part of the current standard of care, lack the optimal characteristics to fully address patient phenotypes. Here, we report on the application of our all-optical electrophysiology platform for phenotypic screening in a human neuronal model of TSC. We used CRISPR/Cas9-isogenicTSC2−/−iPS cell lines to identify disease-associated changes to neuronal morphology, transcript expression and neuronal excitability. We established a robust multiparametric electrophysiological phenotype which we then validated in TSC patient-derived neurons. We used this phenotype to conduct a screen of ∼30,000 small molecule compounds in human iPS cell-derived neurons and identified chemical scaffolds that rescued the functional TSC disease parameters. Confirmed hits may act via different mechanisms than direct mTOR pathway inhibition. This strategy provides molecular starting points for therapeutic development in TSC and a framework for phenotype discovery and drug screening in other neurological disorders.

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Section: Introductionmentioning

confidence: 99%

Discovery of novel compounds and target mechanisms using a high throughput, multiparametric phenotypic screen in a human neuronal model of Tuberous Sclerosis

Williams,

Ryan,

Joshi

et al. 2024

Preprint

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“…Contrary to this, this could lead to the blockage of the synapse impulse transmission through the prevention of the neurotransmitter's binding to its receptor site as a result of blockage, or through the prevention of synthesis and/or its release [8,9]. A lot of research has been aimed at developing therapies in order to curb and prevent the occurrence of the seizures, attempting to alleviate them with medicine, leading to the development of various antiepileptic drugs (AEDs) [10][11][12][13]. Nonetheless, epileptic episodes are still experienced by about 25% of the patients, despite the optimal AED usage on the market, and it usually takes a couple of years for administering AED treatment.…”

Section: Introductionmentioning

confidence: 99%

Monte Carlo optimization based QSAR modeling, molecular docking studies, and ADMET predictions of compounds with antiMES activity

Živadinović,

Stamenović,

Živadinović

et al. 2023

Struct Chem

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The paper deals with QSAR modeling-based Monte Carlo optimization. The molecular descriptors involve the local molecular graph invariants and the SMILES notation for the molecules whose anti-MES activity is active against maximal electroshock seizure (MES). The developed QSAR model was validated with the use of various statistical parameters, such as the correlation coe cient, cross-validated correlation coe cient, standard error of estimation, mean absolute error, root-mean-square error R m 2 , MAE-based metrics, the Fischer ratio as well as the correlation ideality index. Along with the robustness of the developed QSAR model, the used statistical methods yielded an excellent predictability potential. The discovered molecular fragments utilized for the preparation of the computer-aided design of the new compounds were thought to have led to the increase and decrease of the examined activity. Molecular docking studies were referred to when making the nal assessment of the designed inhibitors. This emphasized excellent correlation with QSAR modeling results. The computation of physicochemical descriptors was conducted in order to predict ADME parameters, pharmacokinetic properties, the drug-like nature and medicinal chemistry friendliness, with the aim of supporting drug discovery. Based on the results, all the designed molecules indicate the presence of high drug-likeness.

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Recent Progresses in Development of Heterocyclic Compounds For Epilepsy Treatment: Key Research Highlights from 2019–2024

Singh,

Nisa,

Mavi

et al. 2024

Chemistry & Biodiversity

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Epilepsy which is a chronic neurological disorder is characterized by recurrent seizure poses a significant challenge to healthcare professionals worldwide. Most of antiepileptic drugs have serious side effects that might affect the quality of life such as fatigue, dizziness, weight gain and cognitive impairments. In this context, the search for more effective and potential antiepileptic drug candidate has led to a growing interest in the field of synthesis of heterocyclic compounds. This review will focus on the utilization of heterocyclic moieties including imidazole, indole, thiazole, triazine, quinazoline and oxazole which show remarkable anticonvulsant properties. Furthermore, the exploration of various methodologies for the synthesis of heterocyclic anticonvulsant drugs such as green methodologies and microwave assisted protocols have contributed to the development of environment friendly, more efficient and potential approaches. The review will distinguish from previous ones by specifically focusing on innovative synthetic methodologies, including greener methodologies and micro‐assisted techniques, that contribute to eco‐friendly and environment benign approaches during 2019–2024. In addition to this, the review will focus on the Structure Activity Relationship (SAR) studies of heterocyclic compounds in order to offer insight into the design of next generation antiepileptic drugs with improved efficacy and reduced side effects.

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Drug Treatment of Epilepsy: From Serendipitous Discovery to Evolutionary Mechanisms

Cited by 7 publications

References 222 publications

Discovery of novel compounds and target mechanisms using a high throughput, multiparametric phenotypic screen in a human neuronal model of Tuberous Sclerosis

Discovery of novel compounds and target mechanisms using a high throughput, multiparametric phenotypic screen in a human neuronal model of Tuberous Sclerosis

Monte Carlo optimization based QSAR modeling, molecular docking studies, and ADMET predictions of compounds with antiMES activity

Recent Progresses in Development of Heterocyclic Compounds For Epilepsy Treatment: Key Research Highlights from 2019–2024

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