Anticonvulsant Compounds Research Articles

Integration of In-vivo screening, molecular docking, and molecular dynamics simulations for studying the antiepileptic potential of newly synthesized 5-naphthalen-1-yl-5,10-dihydro-1H-pyrimido[4,5-b]quinoline-2,4-diones in optimized reaction conditions by utilizing l-proline as green catalyst

In a green, one-pot approach, several 5-naphthalen-1-yl-5,10-dihydro-1H-pyrimidoi-[4,5-b]-iquinoline-2,4-dionesi (4a-k) were synthesized via a three-component reaction comprising substituted anilines, naphthaldehyde, and barbituric acids. The reaction conditions were optimized by testing different catalysts (PTSA, CF3COOH, and l-proline) and different solvents. Most of the tested reaction conditions influenced the synthetic reaction. l-proline was more effective with water as a solvent in synthesizing the targeted compounds with high yields. All the synthesized compounds underwent antiepileptic screening using in vivo and in silico methods. In vivo, screening has been performed following the maximal electroshock seizure (MES), and subcutaneous pentylenetetrazole (scPTZ) animal screening methods. The antidepressant screening of the most potent antiepileptic compounds has been tested through a locomotor impairment test (using an actophotometer). The in silico molecular docking and simulation studies were determined by utilizing AutoDock 4.2 version and Groomacs. Among all, compounds 4b, 4d, 4e, and 4j have demonstrated significant antiepileptic activity with effective antidepressant properties. In silico studies (calculation of ADME parameters, molecular docking, and MD simulation) established that targeted molecules have good ADME parameters (good for oral use), the possible mechanism involved interactions primarily with GABAA receptors while interactions with other receptors like VGSCs and NMDA also took place.

The Study of the Influence of Pyridine Oxime Derivative (GIZh-298) And Sodium Valproate on the Neurotransmitter Amino Acids Content in the Brain Structures of Mice in the Maximal Electroconvulsive Seizures Test

The effect of the antiepileptic compound GIZH-298 and the reference drug sodium valproate (VN) on the content of excitatory and inhibitory amino acids in the frontal cortex, hypothalamus, striatum, and hippocampus of the brain of mice after an electric shock-induced generalized tonic-clonic seizure (MES) was studied. It has been shown that the application of MES reduces the levels of aspartate, glycine, GABA and the ratio of “GABA/glutamate” in the hypothalamus. In the latter, a decrease in the concentration of glutamate, glycine and taurine was noted. VN (200 mg/kg/g) counteracts the effects of MES by interfering with the resulting decrease in GABA and the GABA/glutamate ratio in the hypothalamus. In the hypothalamus, striatum, and hippocampus, VN causes a decrease in the aspartate content both in intact control groups and in the group of mice that received MES. GIZH-298 (60 mg/kg/int. gastric) prevented the MES-induced decrease in the levels of GABA, glycine and taurine and the GABA/glutamate ratio in the hypothalamus.

Herbal Extracts Exhibit Anti-Epilepsy Properties

Epilepsy refers to a group of persistent neurological illnesses characterized by seizures. It is a chronic brain disease that affects 50 million people in the world, being one of the most common neurological disorders. Developing countries account for over 90% of all epilepsy patients. Epileptic seizures are caused by aberrant, excessive, or hyper synchronized neuronal activity in the brain. The cause of most epileptic seizures is unknown. However, some people develop epilepsy as a result of a brain injury, stroke, brain tumor, or drug and alcohol abuse. Anti-seizure drugs remain the mainstay in the treatment of epilepsy and about 70% of epileptics become seizure-free when antiseizure medications are taken effectively. However, some of these medications have significant pharmacological interactions and undesirable side effects. Traditional utilization of plants extracts for treatment of epilepsy is widely practiced. Many plants extracts and herbal formulations have been studied to determine their efficacy in treatment of epilepsy. This paper presents a review on herbal extracts that have shown antiepileptic activity in animal models published in the last ten years (between 2014 and 2024). The study found that plant extracts from some 138 plant species belonging to 54 different plant families were evaluated for antiepileptic efficacy. The most studied plants belong to the Asteraceae family (19%) followed by Fabaceae (9%), Apiaceae (8%), Lamiaceae (8%), Apocynaceae (7%), Cucurbitaceae (3%), Euphorbiaceae (3%) and Rutaceae (3%). In most cases, the studies focused only on the crude extracts without any attempts to identify the antiepileptic compounds from the plants. The most commonly used model in the antiepileptic assays were found to be pentylenetetrazole and maximal electroshock models. The findings from this study confirm that plant extracts have significant efficacy that needs to be explored for antiepileptic formulation and drugs development. It is also necessary to perform bioassay guided phytochemical evaluation to isolate and characterize the antiepileptic principles.

Anti‑epileptic mechanism of isopimaric acid from Platycladi cacumen based on network pharmacology, molecular docking and biological validation.

Platycladi cacumen (PC) is derived from the dry twigs and leaves of Platycladi orientalis (L.) Franco and exerts anti-epileptic effects. However, its mechanism of action remains unknown. The present study explored the potential anti-epileptic components and mechanisms of PC. The primary active components and targets of PC were analyzed using network pharmacology and a lipopolysaccharide (LPS)-induced murine microglial cell line (BV2) was used to confirm anti-epileptic effects by detecting reactive oxygen species (ROS), apoptosis, inflammatory markers, cell migration and signaling pathways. A total of 13 core active components showed druggable properties, of which deoxypicrop odophyllotoxin, hinokinin and isopimaric acid (IPA) were predicted to cross the blood-brain barrier. In total, 255 potential targets of these three compounds were predicted using SwissTargetPrediction and Similarity Ensemble Approach websites and 150 were associated with epilepsy. In vitro experiments confirmed that IPA significantly inhibited LPS-induced microglial oxidative stress and inflammation by decreasing the migration area, cellular ROS content, lactate dehydrogenase release and early phase of apoptosis. IPA also increased the mRNA expression of anti-oxidative enzymes (superoxide dismutase-1 and -2) and suppressed inflammatory cytokines (interleukin-1β and tumor necrosis factor-α). Furthermore, IPA phosphorylated AKT and mTOR proteins. Taken together, the present findings suggested that IPA is a potential anti-epileptic compound derived from PC.

Neuroprotective Properties of Antiepileptics: What are the Implications for Psychiatric Disorders?

Since the discovery of the first antiepileptic compound, increasing attention has been paid to antiepileptic drugs (AEDs), and recently, with the understanding of the molecular mechanism underlying cells death, a new interest has revolved around a potential neuroprotective effect of AEDs. While many neurobiological studies in this field have focused on the protection of neurons, growing data are reporting how exposure to AEDs can also affect glial cells and the plastic response underlying recovery; however, demonstrating the neuroprotective abilities of AEDs remains a changeling task. The present work aims to summarize and review the literature available on the neuroprotective properties of the most commonly used AEDs. Results highlighted how further studies should investigate the link between AEDs and neuroprotective properties; while many studies are available on valproate, results for other AEDs are very limited and the majority of the research has been carried out on animal models. Moreover, a better understanding of the biological basis underlying neuro-regenerative defects may pave the way for the investigation of further therapeutic targets and eventually lead to an improvement in the actual treatment strategies.

An In Vivo and In Silico Approach Reveals Possible Sodium Channel Nav1.2 Inhibitors from Ficus religiosa as a Novel Treatment for Epilepsy.

Epilepsy is a neurological disease that affects approximately 50 million people worldwide. Despite an existing abundance of antiepileptic drugs, lifelong disease treatment is often required but could be improved with alternative drugs that have fewer side effects. Given that epileptic seizures stem from abnormal neuronal discharges predominately modulated by the human sodium channel Nav1.2, the quest for novel and potent Nav1.2 blockers holds promise for epilepsy management. Herein, an in vivo approach was used to detect new antiepileptic compounds using the maximum electroshock test on mice. Pre-treatment of mice with extracts from the Ficus religiosa plant ameliorated the tonic hind limb extensor phase of induced convulsions. Subsequently, an in silico approach identified potential Nav1.2 blocking compounds from F. religiosa using a combination of computational techniques, including molecular docking, prime molecular mechanics/generalized Born surface area (MM/GBSA) analysis, and molecular dynamics (MD) simulation studies. The molecular docking and MM/GBSA analysis indicated that out of 82 compounds known to be present in F. religiosa, seven exhibited relatively strong binding affinities to Nav1.2 that ranged from -6.555 to -13.476 kcal/mol; similar or with higher affinity than phenytoin (-6.660 kcal/mol), a known Na+-channel blocking antiepileptic drug. Furthermore, MD simulations revealed that two compounds: 6-C-glucosyl-8-C-arabinosyl apigenin and pelargonidin-3-rhamnoside could form stable complexes with Nav1.2 at 300 K, indicating their potential as lead antiepileptic agents. In summary, the combination of in vivo and in silico approaches supports the potential of F. religiosa phytochemicals as natural antiepileptic therapeutic agents.

Synthesis, crystal structure and screening for anticonvulsant and antianxiety activities of three new Ni(II), Cu(II), and Zn(II) dithiocarbamate complexes

A potassium N-(4-fluorobenzyl) N-(naphthalen-1-ylmethyl) dithiocarbamate ligand (fbnm) has been isolated in a basic medium and its Ni(II), Cu(II), and Zn(II) complexes 1–3 were synthesized. All new compounds have been characterized by elemental analyses, magnetic susceptibility, IR, NMR, and UV–Vis techniques. Complexes 2 and 3 have been further characterized by single-crystal X-ray diffraction data. Zn(II) complex adopts tetrahedral geometry whereas Ni(II) and Cu(II) complexes adopt square planar geometry around the metal ions. In addition, the bite angles found around the metal chelate rings in complexes 2 and 3 suggest that these geometries are slightly distorted from regular geometry. Complexes 2 and 3 are stabilized by intermolecular CH···S, CH···π and CH···F interactions. The thermal degradations of metal complexes 1–3 have been examined by TG-DTA data which designates that metal sulfide is formed as the final entity. The anticonvulsant activity of ligand fbnm and its Ni(II), Cu(II), and Zn(II) complexes have been tested through MES test and PTZ induced convulsion test and found that complex 2 may be used as an anticonvulsant compound in the future by further biochemical or neurotransmitter estimations to control the onset of generalized tonic-clonic seizures. The antianxiety activity has also been performed via Elevated plus maze and Open field test and observed that all synthesized compounds are non-significant for anti-anxiety effect.

Magnetic layered double hydroxides with carbamazepine for breast cancer treatment

Current cancer chemotherapy is associated with many side effects and, in some cases, drug resistance, which makes the search for new active molecules and drug delivery strategies imperative. Carbamazepine is an antiepileptic compound that has shown efficacy against breast cancer cell lines. In this study, it was incorporated into layered double hydroxide nanoclays, the percentage of drug loading was increased compared to previous research, and the clays were impregnated with magnetic Fe3O4 nanoparticles. The goal of the magnetic Fe3O4-impregnation was to direct the nanocomposites to the therapeutic target with an external magnetic field. The nanoclay-carbamazepine composites had a carbamazepine loading of 51 %, and the nanoclay-carbamazepine-nanoparticles had a drug loading of 13 % due to the addition of more ingredients. The structure of the composites was analyzed by X-ray diffraction and Scherrer equation, showing a layered double hydroxide organization with crystal sizes of 9–15 nm; from transmission electron microscopy, the final compounds showed a particle size of 97–158 nm, small enough for systemic circulation. In vibrating sample magnetization studies, the composites showed a superparamagnetic behavior with high magnetic saturation (9–17 emu/gr), which should allow a good material attraction by an external magnetic field located near the tumor. In vitro drug release studies were done in Franz cells and measured by UV/Vis spectrophotometry; they showed that carbamazepine release from the nanocomposites responds to the media pH: a good drug release at the lysosome pH and slow release at the blood pH. Finally, the efficacy was tested in vitro in MDA-MB-231 breast cancer cells, and the composites showed an enhanced efficacy in comparison with that produced by the free drug (96 % and 62 % of cell inhibition respectively). Carbamazepine administered with magnetic clays as a carrier is a promising treatment for breast cancer, and further studies should be done to measure the arrival time and the efficacy in vivo.

Network Analysis and In Silico Molecular Modeling of Bioactive Compounds from Sida cordifolia Against NMDA Receptor

Epilepsy, one of the most common neurological disorders, is characterized by continuing predisposition of epileptic seizures. Abnormal discharges of seizures burst the electrical functions in the brain leading to unprompted behaviors of brain activity. Recently, more attention has been focused on bioactive substances from plants as therapeutic agents for neurodegenerative disorders because of their efficacy, low toxicity, and less side-effects. This study has utilized in silico molecular modeling as a tool for screening effective antiepileptic compounds from Sida cordifolia which could be further explored for the treatment of epilepsy. Twenty-six bioactive compounds were identified through data repository and their structures were retrieved from PubChem database. Based on the Graph theoretical network analysis, NMDA protein was identified as an ideal drug target. The effective compound was chosen based on the docking scores and its drug-likeness properties were analyzed by in silico prediction of pharmacokinetic and physicochemical properties. Based on molecular docking, 5,7-dihydroxy-3-isoprenyl flavone was identified as a better binder as this exhibited higher binding towards the target with lower binding energy (−10.5 kcal × mol[Formula: see text]. The stability of the protein–ligand complex was confirmed by molecular dynamics simulation study. The intermolecular interaction assessed during dynamic conditions indicated that the bioactive compound, 5,7-dihydroxy-3-isoprenyl flavone, from Sida cordifolia could be a potential lead molecule that can be developed as a candidate drug for anti-epileptic therapy.

Hybridization of the effective pharmacophores for treatment of epilepsy: design, synthesis, in vivo anticonvulsant activity, and in silico studies of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids

BackgroundEpilepsy is a common neurological disorder. The available drugs for this disease only control convulsions in nearly 70% of patients, while bearing many side effects. In this study, a new series of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids 8a-m was designed, synthesized, and evaluated as potent anticonvulsant agents.MethodsPhenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid derivatives 8a-m were synthesized with well-known chemical reactions and anticonvulsant activity of them was determined by pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid scaffold has the necessary pharmacophores to be a benzodiazepine (BZD) receptor agonist, thus, the most potent anticonvulsant compounds were assayed in vivo and in silico as BZD receptor agonist. Furthermore, in vivo neurotoxicity evaluation and in silico physicochemical, pharmacokinetic, and toxicity study on the most potent compounds were also performed.ResultsObtained results demonstrated that two compounds among the title new compounds have anticonvulsant activity in PTZ test while all of the new compounds are active in the MES test. The best anticonvulsant activities were obtained with nitro derivatives 8k and 8L. In vivo evaluation of flumazenil effect (a BZD receptor antagonist) on anticonvulsant activity of compound 8k confirmed that this compound is a BZD receptor agonist. The most potent compounds 8k and 8L interacted with the important residues of BZD-binding site of GABAA receptor. Furthermore, neurotoxicity of the latter compounds was lower than positive control diazepam.ConclusionAccording to these results, our designed scaffold can be a valuable lead structure for further structural developments and assessments to obtain a new potent anticonvulsant agent.

Potent anticonvulsant compounds with anti-hyperalgesic activity in mouse formalin test of hyperalgesia

Potent anticonvulsant compounds with anti-hyperalgesic activity in mouse formalin test of hyperalgesia

Therapeutic Administration of Oxcarbazepine Saves Cerebellar Purkinje Cells from Ischemia and Reperfusion Injury Induced by Cardiac Arrest through Attenuation of Oxidative Stress.

Research reports using animal models of ischemic insults have demonstrated that oxcarbazepine (a carbamazepine analog: one of the anticonvulsant compounds) extends neuroprotective effects against cerebral or forebrain injury induced by ischemia and reperfusion. However, research on protective effects against ischemia and reperfusion cerebellar injury induced by cardiac arrest (CA) and the return of spontaneous circulation has been poor. Rats were assigned to four groups as follows: (Groups 1 and 2) sham asphyxial CA and vehicle- or oxcarbazepine-treated, and (Groups 3 and 4) CA and vehicle- or oxcarbazepine-treated. Vehicle (0.3% dimethyl sulfoxide/saline) or oxcarbazepine (200 mg/kg) was administered intravenously ten minutes after the return of spontaneous circulation. In this study, CA was induced by asphyxia using vecuronium bromide (2 mg/kg). We conducted immunohistochemistry for calbindin D-28kDa and Fluoro-Jade B histofluorescence to examine Purkinje cell death induced by CA. In addition, immunohistochemistry for 4-hydroxy-2-nonenal (4HNE) was carried out to investigate CA-induced oxidative stress, and immunohistochemistry for Cu, Zn-superoxide dismutase (SOD1) and Mn-superoxide dismutase (SOD2) was performed to examine changes in endogenous antioxidant enzymes. Oxcarbazepine treatment after CA significantly increased the survival rate and improved neurological deficit when compared with vehicle-treated rats with CA (survival rates ≥ 63.6 versus 6.5%), showing that oxcarbazepine treatment dramatically protected cerebellar Purkinje cells from ischemia and reperfusion injury induced by CA. The salvation of the Purkinje cells from ischemic injury by oxcarbazepine treatment paralleled a dramatic reduction in 4HNE (an end-product of lipid peroxidation) and increased or maintained the endogenous antioxidant enzymes (SOD1 and SOD2). In brief, this study shows that therapeutic treatment with oxcarbazepine after CA apparently saved cerebellar neurons (Purkinje cells) from CA-induced neuronal death by attenuating oxidative stress and suggests that oxcarbazepine can be utilized as a therapeutic medicine for ischemia and reperfusion brain (cerebellar) injury induced by CA.

Reducing the shock factor with new anti-epilepsy drugs

Epilepsy is one of the most common serious neurological conditions, affecting 1 in 131 people in the UK. Patients with epilepsy suffer recurrent spontaneous seizures when neuronal activity elevates beyond physiological limits. Although current anti-epileptic drugs can effectively prevent seizures in some patients, up to 20% of paediatric and 40% of adult patients are refractory to treatment. One therapeutic avenue that has not yet been pursued for epilepsy is targeting neuronal homeostasis. PUMILIO (PUM) is a transcriptional repressor that maintains neuron action potentials within physiological limits and, importantly, is abnormally reduced in patients with epilepsy. In their recent article, Richard Baines and colleagues, therefore, investigated PUM as a therapeutic target for epilepsy.The authors identified a new compound, 4-tert-butyl-benzaldehyde (4-TBB), which could increase expression and stability of PUM in Drosophila and mice, and had physiochemical properties compatible with clinical use. They pre-treated diverse Drosophila and mouse models of epilepsy with 4-TBB prior to electrical or chemical induction of seizures. The team found that 4-TBB acts as an anticonvulsant, significantly reducing behavioural and physiological signs of seizure. The authors also confirmed that 4-TBB acts – at least in part – through modulation of PUM, as protein levels of downstream targets of PUM were reduced in treated mouse brains and because RNAi-induced reduction of PUM significantly diminished the anticonvulsant activity of 4-TBB in Drosophila.The authors then identified RAB216, a more-potent analogue of 4-TBB, which also increased PUM expression, and induced anticonvulsant activity in Drosophila and mice, at significantly lower concentrations than 4-TBB. Moreover, RAB216 also reduced the duration of seizures in an electrically induced seizure assay within a murine model that recapitulates drug-refractory epilepsy.The Baines lab identified two anticonvulsant compounds that modulate PUM expression and activity to oppose the high neuronal activity associated with seizures. This approach modulates neuronal homeostasis, which may incur fewer side effects, as these mechanisms are tightly controlled to avoid under- or over-activation. Interestingly, although mice were pre-treated with 4-TBB for 3 days prior to seizure induction, there were no overt signs of side effects. However, future work is required to investigate the full mode of action of the new compounds, beyond the modulation of PUM activity. Moreover, as PUM is expressed systemically, the development of compounds targeting central nervous system-specific downstream targets or co-factors of PUM could further minimise potential side effects. Nevertheless, the authors have demonstrated the potential of a novel approach to treating epilepsy, which may reduce the proportion of drug-refractory patients.

Targeting firing rate neuronal homeostasis can prevent seizures

ABSTRACTManipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, to date, no drug-based interventions have been reported that manipulate this type of neuronal homeostatic mechanism. Here, we used a combination of Drosophila and mouse, and, in the latter, both a pentylenetetrazole (PTZ)-induced seizure model and an electrically induced seizure model for refractory seizures to evaluate the anticonvulsant efficacy of a novel class of anticonvulsant compounds, based on 4-tert-butyl-benzaldehyde (4-TBB). The mode of action included increased expression of the firing rate homeostatic regulator Pumilio (PUM). Knockdown of pum expression, in Drosophila, blocked anticonvulsive effects of 4-TBB, while analysis of validated PUM targets in mouse brain revealed significant reductions following exposure to this compound. A structure-activity study identified the active parts of the molecule and, further, showed that the pyrazole analogue demonstrates highest efficacy, being active against both PTZ-induced and electrically induced seizures. This study provides a proof of principle that anticonvulsant effects can be achieved through regulation of firing rate neuronal homeostasis and identifies a possible chemical compound for future development.

Intracardiac echocardiography-guided endomyocardial biopsy for the early detection of giant cell myocarditis causing recurrent ventricular tachycardia

Adenosine is present in all cells and is implicated in the control of the function of every tissue and organ. The elevated adenosine levels seem to play a significant role in a protection against cellular damage in the regions with increased metabolic demand and prevent the subsequent dysfunction of the affected organs. Furthermore, adenosine has been shown to play an important role not only in the regulation of pathophysiological processes, but also in the modulation of normal physiological processes, for example, the regulation of sleep and arousal as well as by impact on pre- or postsynaptic receptors involved in releasing neurotransmitters (e.g. glutamate, acetylcholine, norepinephrine, 5-hydroxytryptamine, dopamine, GABA and others).Experimental studies provide evidence supporting the role of adenosine as an endogenous anticonvulsant agent. Numerous adenosine agonists acting through A1, A2 and A3 receptors were proven as potent anticonvulsant compounds in a wide variety of animal models of epilepsy. However, despite their efficacy in such models, adenosine receptor agonists do not appear to be good candidates for successful clinical applications. The therapeutic range of systemically administered adenosine receptor agonists is very narrow and they often produce profound adverse events. It seems, therefore, that adenosine receptor agonists could only be used clinically when co-administered with other antiepileptic drugs or when used in local therapies, where their side effect profile is much more tolerable. An alternative strategy would be to enhance the natural adenosinergic feedback mechanism triggered by seizures by using adenosine uptake inhibitors. This approach seems very attractive as it would allow limiting the action only in the active areas such as seizure foci and thus, preventing the systemic side effects.

GluN2C selective inhibition is a target to develop new antiepileptic compounds.

Many early-onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N-methyl-d-aspartate receptor (NMDA-R) subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA-R with slow deactivation kinetic results in increased neuronal excitation and synchronization. Starting from an available GluN2C/D antagonist, NMDA-R-modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/- mice brain slices with multielectrode array, and then in vivo at postnatal ages P14-P17, comparable with the usual age at epilepsy onset in human TSC. Using a double-electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in six Tsc1+/- mice at P14-P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal-like discharges stopped on a human brain sample from an infant with epilepsy due to TSC. Subunit-selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA-R subunit-mediated transmission.

Structure-Based Virtual Screening Identifies Novobiocin, Montelukast, and Cinnarizine as TRPV1 Modulators with Anticonvulsant Activity In Vivo.

The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel, known to be involved in the regulation of many important physiological and pathological processes. In the last few years, it has been proposed as a promising target to develop novel anticonvulsant compounds. However, thermoregulatory effects associated with the channel inhibition have hampered the path for TRPV1 antagonists to become marketed drugs. In this regard, we conducted a structure-based virtual screening campaign to find potential TRPV1 modulators among approved drugs, which are known to be safe and thermally neutral. To this end, different docking models were developed and validated by assessing their pose and score prediction powers. Novobiocin, montelukast, and cinnarizine were selected from the screening as promising candidates for experimental testing and all of them exhibited nanomolar inhibitory activity. Moreover, the in vivo profiles showed promising results in at least one of the three models of seizures tested.

Anti-Epileptic Effect of Crocin on Experimental Temporal Lobe Epilepsy in Mice.

Temporal lobe epilepsy (TLE) is a common kind of refractory epilepsy. More than 30% TLE patients were multi-drug resistant. Some patients may even develop into status epilepticus (SE) because of failing to control seizures. Thus, one of the avid goals for anti-epileptic drug development is to discover novel potential compounds to treat TLE or even SE. Crocin, an effective component of Crocus sativus L., has been applied in several epileptogenic models to test its anti-epileptic effect. However, it is still controversial and its effect on TLE remains unclear. Therefore, we investigated the effects of crocin on epileptogenesis, generalized seizures (GS) in hippocampal rapid electrical kindling model as well as SE and spotaneous recurrent seizure (SRS) in pilocarpine-induced TLE model in ICR mice in this study. The results showed that seizure stages and cumulative afterdischarge duration were significantly depressed by crocin (20 and 50 mg/kg) during hippocampal rapid kindling acquisition. And crocin (100 mg/kg) significantly reduced the incidence of GS and average seizure stages in fully kindled animals. In pilocarpine-induced TLE model, the latency of SE was significantly prolonged and the mortality of SE was significantly decreased by crocin (100 mg/kg), which can also significantly suppress the number of SRS. The underlying mechanism of crocin may be involved in the protection of neurons, the decrease of tumor necrosis factor-α in the hippocampus and the increase of brain derived neurotrophic factor in the cortex. In conclusion, crocin may be a potential and promising anti-epileptic compound for treatment of TLE.

Synthetic and natural coumarins as potent anticonvulsant agents: A review with structure-activity relationship.

The main objective of this review is to highlight the most relevant studies since 1990 (to date) in the area of medicinal chemistry aspects to provide a panoramic view to the biologists/medicinal chemists working in this area and would assist them in their efforts to design, synthesize and extract (from natural source) coumarin-based anticonvulsant agents. Also, the structure-activity relationship (SAR) studies are also discussed for further rational design of this kind of derivatives. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic coumarin-based antiepileptic agents. A literature review emphasizing the application of coumarin core as antiepileptic agents identify articles related to the topic; we performed a standardized search from 1990 to November 2021, using search engines like Scifinder, web of Science, Pubmed and Scopus. This review gives an overview of attempts to shed light and compile published reports on coumarin derivatives along with some opinions on different approaches to help the medicinal chemists in designing future generation potent yet safer anticonvulsant agents. The possible structure-activity relationships (SARs) will also be discussed to indicate the direction for the rational design of more effective candidates. The findings from this review provide new indications or directions for the discovery of new and better drugs from synthetic and naturally occurring coumarins as antiepileptic agents. In our review, we have tried to depict the recent researches which made in the design and development of novel anticonvulsant compounds with coumarin nucleus. Also, SAR of expressed derivatives indicated that the choice of a fitting substitution containing electron-withdrawing/donating groups to coumarin or with some heterocyclic moieties joined to parent coumarin skeleton assumes an essential role in changing the anticonvulsant activity of synthesized derivatives. These findings encourage the scientific community towards the optimization of the pharmacological profile of this structural moiety as an important scaffold for the treatment of epilepsy.

Synthesis and Biological Evaluation of Some Newer 1h-Benzo[b][1,5]diazepin-2(3h)-One Derivatives as Potential Anticonvulsant Agents

Background: Regardless of the availability of all novel and earlier treatments, seizure control is notoriously complicated. In the hopes of discovering the latest and ultimate therapy, medicinal chemists will keep on to hunt for new antiepileptic compounds with high specificity and low CNS toxicity. The biological effects of benzodiazepine compounds have been examined. Benzene and a diazepine ring are fused together to form the chemical structure. Diverse combinations of moieties attached to the innermost structure in positions 1, 2, 5, and 7 the pharmacological qualities, effect potency, and pharmacokinetic conditions are all influenced by the various side groups. Method: This paper describes the synthesis of several 1H-benzo[b][1,5]diazepin-2(3H)-one derivatives. The substituents at N1 are benzoyl, 5-substituted-1,3,4-thiadiazoles-2-yl-aminoacetyl. Condensation of orthophenylene diamine with ethyl acetoacetate gave 7-substituted-4-methyl-1H-benzo[b][1,5]diazepin-2(3H)-ones, which were then linked to benzoyl chloride and chloroacetyl chloride to yield N1-benzoyl and N1-chloroacetyl derivatives. N1- chloroacetyl derivatives were further linked with 5-substituted-1,3,4-thiadiazoles amines using microwave irradiation. Result: IR, 1H-NMR, and mass spectroscopy were used to authenticate the synthesized compounds. The PTZ produced convulsions method was used to test the compounds for anticonvulsant activity. Compounds 4a and 4c gave 80% protection at 0.4 mg/kg, whereas Compounds 2a and 2c offered 80% protection at 20 and 30 mg/kg, respectively, when compared to the Control. Conclusion: When compared to a control, the experimental synthesis and pharmacological assessment of the 1,5-benzodiazepin-2-one moiety replaced with 1,3,4-thiadiazole yields a potentially active anticonvulsant drug.