Development Of Antiepileptic Drugs Research Articles

Reduced estradiol synthesis by letrozole, an aromatase inhibitor, is protective against development of pentylenetetrazole-induced kindling in mice

Neurosteroids, such as testosterone and their metabolites, are known to modulate neuronal excitability. The enzymes regulating the metabolism of these neurosteroids, thus, may be targeted as a noval strategy for the development of new antiepileptic drugs. The present work targeted two such enzymes i,e aromatase and 5α-reductase in order to explore the potential of letrozole (an aromatase inhibitor) on pentylenetetrazole (PTZ)-induced kindling in mice and the ability of finasteride (a 5α-reductase inhibitor) to modulate any such effects. PTZ (30 mg/kg, i.p.), when administered once every two days (for a total of 24 doses) induced kindling in Swiss albino mice. Letrozole (1 mg/kg, p.o.), administered prior to PTZ, significantly reduced the % incidence of kindling, delayed mean onset time of seizures and reduced seizure severity score. Letrozole reduced the levels of plasma 17β-estradiol after induction of kindling. The concurrent administration of finasteride and letrozole produced effects similar to letrozole on PTZ-kindling and on estradiol levels. This implies that the ability of letrozole to redirect the synthesis of dihydrotestosterone (DHT) and 5α-androstanediol from testosterone doesn't appear to play a significant role in the protective effects of letrozole against PTZ kindling. Letrozole, however, increased the levels of 5α-DHT in mice plasma. The aromatase inhibitors, thus, may be exploited for inhibiting the synthesis of proconvulsant (17β-estradiol) and/or redirecting the synthesis of anticonvulsant (DHT and 5α-androstanediol) neurosteroids.

Seletracetam enhances short term depression in vitro

Seletracetam (SEL), an analog of the antiepileptic drug levetiracetam (LEV), decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle protein SV2A with a higher affinity than LEV. Experiments were performed to determine if SEL, like LEV, reduces the later EPSPs in long trains of stimuli in a manner dependent upon access to the interior of synaptic vesicles and SV2A binding. When hippocampal slices were incubated in 3–30μM SEL for 3h, but not 30min, the relative amplitude of the CA1 field excitatory synaptic potentials decreased over the course of a train of high frequency stimuli more than for control slices. This short term depression was frequency and dose dependent and largely disappeared when the spontaneous activity during the loading period was removed by cutting the Schaffer collaterals. The SEL effect was also observed in slices loaded during prolonged stimulation at 1Hz, but not 10Hz. Hippocampal slices loaded with both SEL and FM1-43 to visualize synaptic boutons released the FM1-43 in response to prolonged stimulation much more slowly than control slices during prolonged stimulation. Like LEV, SEL produced a frequency-dependent decrement of synaptic transmission that was dependent upon the drug entering recycling synaptic vesicles and compatible with SV2A binding. Previous observations of SV2A binding affinity correlated with the current effect of SEL and the previously reported effect of LEV on synaptic transmission validate SV2A as an extremely attractive target for future antiepileptic drug development.

In silico Design, Synthesis and Pharmacological screening of Quinazolinones as NMDA receptor antagonists for Anticonvulsant activity: Part II

Background : N-methyl-D-Aspartate (NMDA) receptor plays a main role in eliptogenisis and its inhibition has therapeutic significance in development of anticonvulsants. Prioritized quinazolinone molecules were synthesized and then evaluated in vivo by AOT and then for anticonvulsant activity in NMDA induced convulsion model. Method: In silico Screening of prioritized molecule was done by biological activity predictions and partition coefficient predictions (Log P) using PASS server and mol inspiration software respectively. This gave biological activity (BA) score for anticonvulsant activity and predicted Log P values (p Log P). The standard Log P required for anticonvulsant activities being more than 2.00, therefore molecules were also prioritized based on this p Log P criteria. Docking was performed on Vlife MDS 4.3 software. Result: Quinazolinone molecules were prioritized based upon docking score, ADME and BA score, synthesized and pharmacologically screened for anticonvulsant activity. Conclusion: SMMB 1 , SMMB 2 , SMMB 3 showed the prominent anticonvulsant activity as compared with memantine used as standard for in vivo anticonvulsant activity. Key words: Anticovulsant, Mol inspiration, NMDA, PASS, Pre ADMET, Quinazolinone.

АНТИКОНВУЛЬСАНТИ, ЩО МАЮТЬ ГАМК-ЕРГІЧНИЙ МЕХАНІЗМ ДІЇ

<p align="center"><strong>ANTICONVULSANTS</strong><strong> </strong><strong>WITH GABA</strong><strong>ERGIC</strong><strong> </strong><strong>MECHANISM</strong><strong> </strong><strong>OF</strong><strong> </strong><strong>ACTION</strong><strong></strong></p><p align="center"><strong>L</strong><strong>.</strong><strong>O</strong><strong>. Perekhoda</strong></p><p align="center">NationalUniversityofPharmacy, Kharkiv</p><p><strong>Summary</strong>: A literary review of modern anticonvulsants that have predominantly GABAergic mechanism of action was given. Perspective directions of chemical modification will choose and recommendations for the search of the most promising ways of modification which allow to improve the efficiency of the search of new anticonvulsants that have predominantly GABAergic mechanism of action were summarized.</p><p><strong>Keywords</strong><strong>: </strong>epilepsy, mechanism of action, GABA, anticonvulsant.</p><p><strong>Introduction.</strong> The treatment of epilepsy is important because of the high prevalence of the disease and complex social, legal and economic issues associated with it. During the last decades there were new anticonvulsants, but unfortunately they have many side effects, so we need to continually improve drug therapy by expanding arsenal of anticonvulsants. In turn, the detailed study of the mechanism of action and the establishment of relations "structure - anticonvulsant activity" in the ranks of existing drugs require to expand arsenal of anticonvulsants. Analysis of the mechanism of action of anticonvulsants proves the existence of three mechanism (GABAergic, glutamatergic, direct influence on the regulation of electric pulse ion channels of neurons) predominant of which is GABAergic. The recognition of the role of GABAergic system violation in the development of seizures became the stimulus for the development of anticonvulsants affecting different parts of the GABAergic synaptic transmission.</p><p><strong>Methods.</strong> To achieve the goals and objectives the methods of information retrieval and comparative analysis were used.</p><p><strong>Results and discussion</strong>. Analyzing the published data we found that anticonvulsants affecting different parts of the GABAergic synaptic transmission are quite promising matrix based on which the search of new anticonvulsants can be done. One of the directions of the search of anticonvulsants activating GABAergic transmission was realized by the creation of drugs which are structurally similar to GABA. In this paper the examples of structures of the drugs which are structurally similar to GABA (Phenigaba, Lyoresalum, Gamibetalum) and possess an anticonvulsant effect were shown, the influence of substitution or the hirality on the activity of the molecular was explained. The second directions of the search of anticonvulsants activating GABAergic transmission was realized by the creation of the drugs, which are GABA agonists (benzodiazepines, barbiturates and derivatives of hydantoin). The paper has shown two groups of GABA agonists (benzodiazepines and barbiturates), which were compared with each other from the viewpoint of the effectiveness and safety. The detailed study of the prospective structures in the series of the agonists GABA receptor and the summarizing of the progress of recent years will allow to choose the most promising ways of modification in order to improve the search of the efficiency of new anticonvulsants. The relationship "structure-activity" among the group of barbiturates and general ways of metabolism of drugs in this group (Benzobarbitalum, Benzobamilum, Hexamidinum) have been analyzed.</p><p><strong>Conclusions.</strong> The relationship "structure-activity" among modern anticonvulsants with predominantly GABAergic mechanism of action has been analyzed. Perspective directions of chemical modification and recommendations for further search of anticonvulsants with GABAergic action have been generalized.</p>

A pharmacological basis of herbal medicines for epilepsy.

Epilepsy is the most common chronic neurological disease, affecting about 1% of the world's population during their lifetime. Most people with epilepsy can attain a seizure-free life upon treatment with antiepileptic drugs (AEDs). Unfortunately, seizures in up to 30% do not respond to treatment. It is estimated that 90% of people with epilepsy live in developing countries, and most of them receive no drug treatment for the disease. This treatment gap has motivated investigations into the effects of plants that have been used by traditional healers all over the world to treat seizures. Extracts of hundreds of plants have been shown to exhibit anticonvulsant activity in phenotypic screens performed in experimental animals. Some of those extracts appear to exhibit anticonvulsant efficacy similar to that of synthetic AEDs. Dozens of plant-derived chemical compounds have similarly been shown to act as anticonvulsants in various in vivo and in vitro assays. To a significant degree, anticonvulsant effects of plant extracts can be attributed to widely distributed flavonoids, (furano)coumarins, phenylpropanoids, and terpenoids. Flavonoids and coumarins have been shown to interact with the benzodiazepine site of the GABAA receptor and various voltage-gated ion channels, which are targets of synthetic AEDs. Modulation of the activity of ligand-gated and voltage-gated ion channels provides an explanatory basis of the anticonvulsant effects of plant secondary metabolites. Many complex extracts and single plant-derived compounds exhibit antiinflammatory, neuroprotective, and cognition-enhancing activities that may be beneficial in the treatment of epilepsy. Thus, botanicals provide a base for target-oriented antiepileptic drug discovery and development. In the future, preclinical work should focus on the characterization of the effects of plant extracts and plant-derived compounds on well-defined targets rather than on phenotypic screening using in vivo animal models of acute seizures. At the same time, available data provide ample justification for clinical studies with selected standardized botanical extracts and plant-derived compounds. This article is part of a Special Issue entitled "Botanicals for Epilepsy".

Pro- and Anticonvulsant Effects of the Ant Dinoponera quadriceps (Kempf) Venom in Mice.

Epilepsy affects at least 50 million people worldwide, and the available treatment is associated with various side effects. Approximately 20-30% of the patients develop seizures that persist despite careful monitored treatment with antiepileptic drugs. Thus, there is a clear need for the development of new antiepileptic drugs, and the venoms can be an excellent source of probes. In this context, while there are studies on venoms from snakes, scorpions, and spiders, little is known regarding venom from ants. The aim of this study was to investigate the potential pro- and anticonvulsant effects of the venom from the ant Dinoponera quadriceps (Kempf) in Swiss mice. After the injection of the crude venom (DqTx-5, 50, and 500mg/mL) in the lateral ventricle of mice, we observed a reduction of exploration and grooming behaviors, as well as an increase in immobility duration. In addition, the crude venom induced procursive behavior and tonic-clonic seizures at the highest concentration. Conversely, the preadministration of the denatured venom (AbDq) at the concentration of 2mg/mL protected the animals against tonic-clonic seizures (66.7%) and death (100%) induced by administration of bicuculline. Taken together, the findings demonstrate that D. quadriceps venom might be potential source of new pro- and anticonvulsants molecules.

Effects of an Extract of Salvia Miltiorrhiza on a Penicillin-Induced Epilepsy Model in Rats

In a penciling-induced epilepsy model, Wistar rats (16 males, 16 females) were i.p. administered with an extract of Salvia miltiorrhiza (SmE; total dose 50 mg/kg) once a day for 15 days. The rats were divided into four equal groups, control and SmE-treated for each sex. After the treatment period, an epilepsy model was produced by penicillin G injection (500 IU) into the motor cortex; the electrocorticogram (EcoG) was recorded for 120 min, and statistical analysis was performed. In the male control group with penicillin-induced epilepsy, the spike frequency was significantly (P 0.05). Thus, the SmE exerts anticonvulsant effects in the male rat group, while its effect should be characterized as proconvulsant in the female group in the penicillin-induced epilepsy model. The difference (related to the presence of estrogen analogs in the SmE) is determined by dissimilar hormonal backgrounds in males and females. The SmE may be considered as the base for development of anticonvulsant drugs for clinical therapy of epilepsy in the future.

Effects of nucleosides on glia - neuron interactions open up new vistas in the development of more effective antiepileptic drugs.

One-third of epileptic patients are drug refractory due to the limited efficacy of antiepileptic therapy. Thus, there is an immense need to find more effective, safer and well-tolerated antiepileptic drugs. A great deal of results suggests that adenosine (Ado), guanosine (Guo), inosine (Ino) or uridine (Urd) are endogenous antiepileptogenic modulators. Furthermore, nucleosides and their derivatives may be safe and effective potential drugs in the treatment of epilepsy. Conversely, nucleosidergic modulatory system implying nucleoside levels, metabolism, receptors and transporters may also be involved in seizure pathomechanisms. Application of Ado receptor agonists as well as antagonists, elevation of nucleoside levels (e.g., by nucleoside metabolism inhibitors, and Adoreleasing implants) or utilization of non-Ado nucleosides may also turn to be useful approaches to decrease epileptic activity. However, all drugs exerting their effects on the nucleosidergic modulatory system may affect the fine regulation of glia-neuron interactions that are intimately governed by various nucleosidergic processes. Perturbation of the complex, bidirectional communication between neurons and astrocytes through these nucleosidergic modulatory mechanisms may lead to pathological changes in the central nervous system (CNS) and therefore may cause significant side effects. Thus, a deeper understanding of the nucleosidergic modulatory control over glia-neuron interactions is essential in order to develop more effective and safe nucleoside-based antiepileptic drugs. In this review article we focus on the role of Ado and Urd in glia-neuron interactions, placing emphasis on their implications for the treatment of epilepsy.

Use of the ketogenic diet as treatment for refractory epilepsy and autism in the paediatric age

There has been great progress in seizure control with the development of antiepileptic drugs, but 30% of epileptic children are refractory to antiepileptic drugs.In order to control intractable epilepsy and improve neurodevelopment prognosis, the non-drug therapy such as surgery, vagus nerve stimulation and ketogenic diet(KD) can be taken.Despite its indisputable effectiveness, the functioning of the KD has not been explained.Now the antiepileptic mechanism and neuroprotective mechanisms are studied mainly.It is reported that KD is effective in variety of refractory epilepsy, and recent studies have shown that KD promising in the treatment of children with autism.Although KD is effective, it is worth further study that including its mechanism, recipe, clinical application, and so on. Key words: Ketogenic diet; Epilepsy; Autism; Cognition

WONOEP appraisal: molecular and cellular imaging in epilepsy.

Great advancements have been made in understanding the basic mechanisms of ictogenesis using single-cell electrophysiology (e.g., patch clamp, sharp electrode), large-scale electrophysiology (e.g., electroencephalography [EEG], field potential recording), and large-scale imaging (magnetic resonance imaging [MRI], positron emission tomography [PET], calcium imaging of acetoxymethyl ester [AM] dye-loaded tissue). Until recently, it has been challenging to study experimentally how population rhythms emerge from cellular activity. Newly developed optical imaging technologies hold promise for bridging this gap by making it possible to simultaneously record the many cellular elements that comprise a neural circuit. Furthermore, easily accessible genetic technologies for targeting expression of fluorescent protein-based indicators make it possible to study, in animal models of epilepsy, epileptogenic changes to neural circuits over long periods. In this review, we summarize some of the latest imaging tools (fluorescent probes, gene delivery methods, and microscopy techniques) that can lead to the advancement of cell- and circuit-level understanding of epilepsy, which in turn may inform and improve development of next generation antiepileptic and antiepileptogenic drugs.

A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models

The role of complement system-mediated inflammation is of key interest in seizure and epilepsy pathophysiology, but its therapeutic potential has not yet been explored. We observed that the pro-inflammatory C5a receptor, C5ar1, is upregulated in two mouse models after status epilepticus; the pilocarpine model and the intrahippocampal kainate model. The C5ar1 antagonist, PMX53, was used to assess potential anticonvulsant actions of blocking this receptor pathway. PMX53 was found to be anticonvulsant in several acute models (6Hz and corneal kindling) and one chronic seizure model (intrahippocampal kainate model). The effects in the 6Hz model were not found in C5ar1-deficient mice, or with an inactive PMX53 analogue suggesting that the anticonvulsant effect of PMX53 is C5ar1-specific. In the pilocarpine model, inhibition or absence of C5ar1 during status epilepticus lessened seizure power and protected hippocampal neurons from degeneration as well as halved SE-associated mortality. C5ar1-deficiency during pilocarpine-induced status epilepticus also was accompanied by attenuation of TNFα upregulation by microglia, suggesting that C5ar1 activation results in TNFα release contributing to disease. Patch clamp studies showed that C5a-induced microglial K+ outward currents were also inhibited with PMX53 providing a potential mechanism to explain acute anticonvulsant effects. In conclusion, our data indicate that C5ar1 activation plays a role in seizure initiation and severity, as well as neuronal degeneration following status epilepticus. The widespread anticonvulsant activity of PMX53 suggests that C5ar1 represents a novel target for improved anti-epileptic drug development which may be beneficial for pharmaco-resistant patients.

Animal Models for Pre-Clinical Antiepileptic Drug Research

Animal models are essential in preclinical anti epileptic drug research. These models serve different purposes in epilepsy research and in drug discovery and development of anti epileptic drugs to evaluate efficacy, to determine mechanism of action, used to determine preclinical efficacy of new drugs during chronic administration, to study the mechanism of drug resistance and also used to study whether eplileptogenesis alters the adverse effect potential of a given drug. A large number of in vivo animals models are used, some important which can be adapted and acclimatized to institutional laboratory settings discussed.

Pentylenetetrazol Kindling Epilepsy Model

Epilepsy is one of the most common neurologic disorders affecting approximately 1% of the general population, and no alleviation was achieved in one third of the patients medicated with antiepileptic drugs. Current treatments of epilepsy are symptomatic and have more anti-seizure effects than antiepileptic effects. These therapies do not cure epilepsy. Basic mechanisms of epilepsy have not entirely been clarified yet. Using seizure and epilepsy animal models, our comprehension about basic mechanisms underlying epileptogenesis has improved. In addition, animal models of epilepsy and seizures are very useful in the discovery and development of new antiepileptic drugs. Pentylenetetrazole (PTZ) is widely used in antiepileptic drug discovery studies, and PTZ kindling model is very important to understand the pathophysiology of epilepsy. In this review, current information about PTZ kindling model was given in this aspect.

Improving clinical drug development regulatory procedures for anticonvulsants

Background: Clinical development of antiepileptic drugs is demanding due to complex character of the disorder and to diversity of its forms and etiologies. Objective: The aim of this review was to suggest improvements in regulatory procedures for clinical development of antiepileptic drugs. Methods: The following databases of scientific articles were searched: MEDLINE, SCOPUS and SCINDEKS. In total 558 publications were retrieved. The types of articles selected were reviews, reports on clinical trials and letters to the Editor. Results: There are several changes of regulatory documents necessary for improving process of clinical development of antiepileptic drugs: preference of parallel groups design for add-on trials should be explicit; the non-inferiority design for monotherapy clinical trials should be acceptable; restrictive formulations when trials of antiepileptic drugs in children are in question should be avoided; requirements in regard to the efficacy measures should be harmonized among the regulatory bodies; proactive attitude towards discovery of adverse events; and precise requirements for clinical trials specifically designed to prove anti-epileptogenic effects should be made clear. Conclusion: Current regulatory documents are incomplete in many aspects; an international effort to improve and harmonize guidelines for clinical development of antiepileptic drugs is necessary for improvement of this process.

Anticonvulsant effects of bis-1,4-dihydropyridines and the probable role of L-type calcium channels suggested by docking simulations

The influx/efflux of calcium (Ca2+) ions through channels in cellular membranes plays a pivotal role in many physiological and physiopathological processes. Among these are those involved in the physiopathology of epileptic seizures. Hence, the control of permeability of ions through these channels is considered a strategy for the development of anticonvulsant drugs. According to the previous reports, dihydropyridine derivatives have proven to be Ca2+ channel blockers and have anticonvulsive properties, presumably by means of their action on L-type Ca2+ channels (LCCs). The aim of the present study was to determine the anticonvulsant effects of four bis-1,4-dihydropyridines (bis-DHPs) in male CF1 mice (25–30 g bw) using two experimental models: maximal electroshock (MES, which induces convulsions with an alternating current of 60 Hz) and pentylenetetrazole administration (PTZ, 90 mg/kg administered i.p.). Additionally, the binding mode was explored with a docking study on a 3-D model of an LCC. The four bis-DHPs herein tested showed a protective effect in relation to the number of convulsions induced by MES, the recovery time after a convulsion, and the duration of the tonic phase. However, only bis-DHPs 01–03 reduced the duration of the clonic phase, and these compounds also produced a significant protective effect against the convulsions induced by PTZ administration. This effect may be related to the interaction of bis-DHPs with a cluster of aromatic residues (Tyr1152, Tyr1463, and Phe1159) involved in blocking calcium flow, as suggested by docking studies.

Mass spectrometric detection and characterization of atypical membrane-bound zinc-sensitive phosphatases modulating GABAA receptors.

BackgroundGABAA receptor (GABAAR) function is maintained by an endogenous phosphorylation mechanism for which the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is the kinase. This phosphorylation is specific to the long intracellular loop I2 of the α1 subunit at two identified serine and threonine residues. The phosphorylation state is opposed by an unknown membrane-bound phosphatase, which inhibition favors the phosphorylated state of the receptor and contributes to the maintenance of its function. In cortical nervous tissue from epileptogenic areas in patients with drug-resistant epilepsies, both the endogenous phosphorylation and the functional state of the GABAAR are deficient.Methodology/Principal FindingsThe aim of this study is to characterize the membrane-bound phosphatases counteracting the endogenous phosphorylation of GABAAR. We have developed a new analytical tool for in vitro detection of the phosphatase activities in cortical washed membranes by liquid chromatography coupled to mass spectrometry. The substrates are two synthetic phosphopeptides, each including one of the identified endogenous phosphorylation sites of the I2 loop of GABAAR α1 subunit. We have shown the presence of multiple and atypical phosphatases sensitive to zinc ions. Patch-clamp studies of the rundown of the GABAAR currents on acutely isolated rat pyramidal cells using the phosphatase inhibitor okadaic acid revealed a clear heterogeneity of the phosphatases counteracting the function of the GABAAR.Conclusion/SignificanceOur results provide new insights on the regulation of GABAAR endogenous phosphorylation and function by several and atypical membrane-bound phosphatases specific to the α1 subunit of the receptor. By identifying specific inhibitors of these enzymes, novel development of antiepileptic drugs in patients with drug-resistant epilepsies may be proposed.

Calcium signaling and epilepsy.

Calcium signaling is involved in a multitude of physiological and pathophysiological mechanisms. Over the last decade, it has been increasingly recognized as an important factor in epileptogenesis, and it is becoming obvious that the excess synchronization of neurons that is characteristic for seizures can be linked to various calcium signaling pathways. These include immediate effects on membrane excitability by calcium influx through ion channels as well as delayed mechanisms that act through G-protein coupled pathways. Calcium signaling is able to cause hyperexcitability either by direct modulation of neuronal activity or indirectly through calcium-dependent gliotransmission. Furthermore, feedback mechanisms between mitochondrial calcium signaling and reactive oxygen species are able to cause neuronal cell death and seizures. Unravelling the complexity of calcium signaling in epileptogenesis is a daunting task, but it includes the promise to uncover formerly unknown targets for the development of new antiepileptic drugs.

Neuropeptides as Targets for the Development of Anticonvulsant Drugs

Epilepsy is a common neurological disorder characterized by recurrent seizures. These seizures are due to abnormal excessive and synchronous neuronal activity in the brain caused by a disruption of the delicate balance between excitation and inhibition. Neuropeptides can contribute to such misbalance by modulating the effect of classical excitatory and inhibitory neurotransmitters. In this review, we discuss 21 different neuropeptides that have been linked to seizure disorders. These neuropeptides show an aberrant expression and/or release in animal seizure models and/or epilepsy patients. Many of these endogenous peptides, like adrenocorticotropic hormone, angiotensin, cholecystokinin, cortistatin, dynorphin, galanin, ghrelin, neuropeptide Y, neurotensin, somatostatin, and thyrotropin-releasing hormone, are able to suppress seizures in the brain. Other neuropeptides, such as arginine-vasopressine peptide, corticotropin-releasing hormone, enkephalin, β-endorphin, pituitary adenylate cyclase-activating polypeptide, and tachykinins have proconvulsive properties. For oxytocin and melanin-concentrating hormone both pro- and anticonvulsive effects have been reported, and this seems to be dose or time dependent. All these neuropeptides and their receptors are interesting targets for the development of new antiepileptic drugs. Other neuropeptides such as nesfatin-1 and vasoactive intestinal peptide have been less studied in this field; however, as nesfatin-1 levels change over the course of epilepsy, this can be considered as an interesting marker to diagnose patients who have suffered a recent epileptic seizure.

Synthesis, Anticonvulsant and Neurotoxicity Evaluation of Some Newer N-(2-benzoylbenzofuran-3-yl)-3-(substituted)-propanamide Analogs

A series of 12, N-(2-benzoylbenzofuran-3-yl)-3-(substituted)-propanamide analogs was designed and synthesized to meet the pharmacophore requirement essential for anticonvulsant activity. All the compounds were characterized by IR, (1)H NMR and mass spectral data followed by their anticonvulsant evaluation according to the Antiepileptic Drug Development Program (ADD) protocol. The present study has proved the hypothesis concerning the pharmacophore model with essential binding sites. N-(2-benzoylbenzofuran-3-yl)-3-(4-(2-fluorophenyl)piperazin-1-yl) propanamide, 6h was found to be the most active compound in both maximal electroshock seizure (MES) and subcutaneous metrazol (scMET) seizure test at 30 and100 mg/kg respectively at 0.5 and 4.0 h.

How predictive are photosensitive epilepsy models as proof of principle trials for epilepsy?

PurposeHuman photosensitive epilepsy models have been used as proof of principle (POP) trials for epilepsy. Photosensitive patients are exposed to intermittent photic stimulation and the reduction in sensitivity to the number of standard visual stimulation frequencies is used as an endpoint. The aim of this research was to quantify the predictive capabilities of photosensitive POP trials, through a survey of current literature. MethodsA literature search was undertaken to identify articles describing photosensitive POP trials. Minimally efficacious doses (MEDs) in epilepsy were compared to doses in the POP trials that produced 50–100% response (ED50–100). Ratios of these doses were calculated and summarised statistically. ResultsThe search identified ten articles describing a total of 17 anti-epileptic drugs. Of these, data for both MED and ED50–100 were available for 13 anti-epileptic drugs. The average ratio of MED to ED50–100 was 0.95 (95% CI 0.60–1.30). The difference in MED to ED50–100 ratios between partial epilepsy (0.82) was not significantly different from that of generalised epilepsy (1.08) (p=0.51). ConclusionPhotosensitive POP trials are a useful tool to quantitatively predict efficacy in epilepsy, and can be useful as early and informative indicators in anti-epileptic drug discovery and development.