oxadiazoles and Seizures

Epilepsy is the most common neurological disorder, which affects more than 50 million people worldwide. Despite the development and use of several antiepileptic drugs (AEDs), attempted seizure control fails in almost 30% of the individuals treated. Other patients benefit from seizure control by drug therapy at the expense of dose-related toxicity and side effects. These drawbacks with conventional AEDs demand the need for developing more effective and safer antiseizure agents. As a result, extensive efforts are devoted to design and develop new effective molecules as antiepileptics. This area of research to find more effective and safer AEDs is important and challenging. This review describes the future perspective of various 1,3,4-oxadiazole derivatives as anticonvulsant agents and focuses on the design and development of the new effective molecule.

Topics: Anticonvulsants; Drug Development; Humans; Oxadiazoles; Seizures

Malignant migrating partial seizure of infancy (MMPSI) is a devastating and pharmacoresistant form of infantile epilepsy. MMPSI has been linked to multiple gain-of-function (GOF) mutations in the KCNT1 gene, which encodes for a potassium channel often referred to as SLACK. SLACK channels are sodium-activated potassium channels distributed throughout the central nervous system (CNS) and the periphery. The investigation described here aims to discover SLACK channel inhibitor tool compounds and profile their pharmacokinetic and pharmacodynamic properties. A SLACK channel inhibitor VU0531245 (VU245) was identified via a high-throughput screen (HTS) campaign. Structure-activity relationship (SAR) studies were conducted in five distinct regions of the hit VU245. VU245 analogs were evaluated for their ability to affect SLACK channel activity using a thallium flux assay in HEK-293 cells stably expressing wild-type (WT) human SLACK. Selected analogs were tested for metabolic stability in mouse liver microsomes and plasma-protein binding in mouse plasma. The same set of analogs was tested via thallium flux for activity versus human A934T SLACK and other structurally related potassium channels, including SLICK and Maxi-K. In addition, potencies for selected VU245 analogs were obtained using whole-cell electrophysiology (EP) assays in CHO cells stably expressing WT human SLACK through an automated patch clamp system. Results revealed that this scaffold tolerates structural changes in some regions, with some analogs demonstrating improved SLACK inhibitory activity, good selectivity against the other channels tested, and modest improvements in metabolic clearance. Analog VU0935685 represents a new, structurally distinct small-molecule inhibitor of SLACK channels that can serve as an in vitro tool for studying this target.

Topics: Animals; Cricetinae; Cricetulus; HEK293 Cells; Humans; Mice; Nerve Tissue Proteins; Oxadiazoles; Potassium Channels; Potassium Channels, Sodium-Activated; Seizures; Thallium

Reaction of piperazine with chloroacetylchloride in dry acetone yield compound 1: , which on reaction with hydrazine hydrate yielded compound 2: , which was further reacted with various substituted phenylisothiocyanates in absolute alcohol to afford compounds 3-8: i. e. 2-(carbazolylacetyl)-N-(substitutedphenyl)-hydrazinepiperazinothioamides. Compounds 3-8: on reaction with aqueous NaOH, ethanolic NaOH and conc. H

Topics: Animals; Anticonvulsants; Disease Models, Animal; Female; Humans; Male; Mice; Oxadiazoles; Piperazine; Rats; Seizures; Structure-Activity Relationship; Thiadiazoles; Toxicity Tests, Acute; Triazoles

Epilepsy is one of the most common neurological disorders, and it is characterized by spontaneous seizures. In a previous study, we identified 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as a novel anti-epileptic agent in chemically- or genetically-induced epileptic zebrafish and mouse models. In this study, we investigated the anti-epileptic effects of GM-90432 through neurochemical profiling-based approach to understand the neuroprotective mechanism in a pentylenetetrazole (PTZ)-induced epileptic seizure zebrafish model. GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-β-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents.

Topics: Animals; Anticonvulsants; Antioxidants; Brain; Brain Chemistry; Dihydrotestosterone; Disease Models, Animal; Estradiol; gamma-Aminobutyric Acid; Hydrocortisone; Male; Neuroprotective Agents; Normetanephrine; Oxadiazoles; Oxidative Stress; Pentylenetetrazole; Pregnanolone; Progesterone; Reactive Oxygen Species; Seizures; Serotonin; Zebrafish

Epilepsy is a common chronic neurological disease characterized by recurrent epileptic seizures. A seizure is an uncontrolled electrical activity in the brain that can cause different levels of behavior, emotion, and consciousness. One-third of patients fail to receive sufficient seizure control, even though more than fifty FDA-approved anti-seizure drugs (ASDs) are available. In this study, we attempted small molecule screening to identify potential therapeutic agents for the treatment of seizures using seizure-induced animal models. Through behavioral phenotype-based screening, 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) was identified as a prototype. GM-90432 treatment effectively decreased seizure-like behaviors in zebrafish and mice with chemically induced seizures. These results were consistent with decreased neuronal activity through immunohistochemistry for pERK in zebrafish larvae. Additionally, electroencephalogram (EEG) analysis revealed that GM-90432 decreases seizure-specific EEG events in adult zebrafish. Moreover, we revealed the preferential binding of GM-90432 to voltage-gated Na

Topics: Animals; Anticonvulsants; Behavior, Animal; Blood-Brain Barrier; Electroencephalography; Immunohistochemistry; Larva; Male; MAP Kinase Signaling System; Mass Screening; Mice; Mice, Inbred ICR; Oxadiazoles; Patch-Clamp Techniques; Seizures; Small Molecule Libraries; Sodium Channels; Zebrafish

The signal transmission in the nervous system operates through a sensitive balance between excitatory (E) inputs and inhibitory (I) responses. Imbalances in this system contribute to the development of pathologies such as seizures. In Caenorhabditis elegans, the locomotor circuit operates via the coordinated activity of cholinergic excitatory (E) and GABAergic inhibitory (I) transmission. Changes in E/I inputs can cause uncontrolled electrical discharges, mimicking the physiology of seizures. Molecules derived from 1,3,4-oxadiazole have been found to exhibit diverse biological activities, including anticonvulsant effect. In this work, we study the activity of the compound 2-[(4-methoxyphenylselenyl)methylthio]-5-phenyl-1,3,4-oxadiazole (MPMT-OX) in the GABAergic and cholinergic systems. We demonstrate that MPMT-OX reduced the locomotor activity of C. elegans with a normal balance between the E/I systems and increased the resistance to paralysis in worms exposed to pentylenetetrazol and aldicarb. MPMT-OX increased seizure resistance and assisted in the recovery of locomotor activity in worms with deletions in the genes unc-46, which regulates the transport of GABA into vesicles, and unc-49, which encodes the GABA

Topics: Animals; Behavior, Animal; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Electrophysiological Phenomena; GABA Agonists; gamma-Aminobutyric Acid; Locomotion; Oxadiazoles; Parasympathetic Nervous System; Seizures; Synaptic Transmission; Synaptic Vesicles

A novel series of coumarin-1,2,4-oxadiazole hybrids were designed, synthesized, and evaluated as anticonvulsant agents. The title compounds were easily synthesized from reaction of appropriate coumarins and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivatives. In vivo anticonvulsant activity of the synthesized compounds were determined using pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures confirming that they were more effective against MES test than PTZ test. It should be noted that compounds 3b, 3c, and 3e showed the best activity in MES model which possessed drug-like properties with no neurotoxicity. Anticonvulsant activity of the most potent compound 3b was remarkably reduced after treatment with flumazenil which confirmed the participation of a benzodiazepine mechanism in the anticonvulsant activity. Also, docking study of compound 3b in the BZD-binding site of GABA

Topics: Animals; Anticonvulsants; Binding Sites; Coumarins; Drug Design; Male; Mice; Molecular Docking Simulation; Muscles; Oxadiazoles; Protein Structure, Tertiary; Receptors, GABA-A; Rotarod Performance Test; Seizures; Structure-Activity Relationship

A number of acridone-based oxadiazoles 11a-n have been synthesized and evaluated for their anticonvulsant activity against pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. Also, their neurotoxicity was evaluated by the rotarod test. Most of the compounds exhibited better anticonvulsant activity and higher safety respect to the standard drug, phenobarbital. Among the tested derivatives, compounds 11l with ED50 value of 2.08 mg/kg was the most potent compound in the PTZ test. The anticonvulsant effect of compound 11l was blocked by flumazenil, suggesting the involvement of benzodiazepine (BZD) receptors in the anticonvulsant activity of prototype compound 11l. Also, docking study of compound 11l in the BZD-binding site of GABAA receptor confirms possible binding of compound 11l with BZD receptors.

Topics: Acridines; Acridones; Animals; Anticonvulsants; Electroshock; Mice; Molecular Docking Simulation; Oxadiazoles; Pentylenetetrazole; Receptors, GABA-A; Seizures

The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles, possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4-oxadiazoles were designed and synthesized as novel benzodiazepine analogues. Most of them revealed similar to superior binding affinity to the GABAA/benzodiazepine receptor complex, relative to diazepam as the reference drug. Among them, 5-(4-chloro-2-(2-fluorophenoxy)benzyl)-3-benzylthio-4H-1,2,4-triazole (8l) showed the highest affinity (IC₅₀=0.892 nM) relative to diazepam (IC₅₀=2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the reference drug.

Topics: Animals; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Oxadiazoles; Pentylenetetrazole; Receptors, GABA-A; Seizures; Structure-Activity Relationship; Triazoles

A series of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives 8(a-o) were synthesized and characterized by elemental analyses, (1)H NMR, (13)C NMR and mass spectral studies. The newly synthesized compounds were screened for their anticonvulsant activity against maximal electroshock seizure (MES) model in male wistar rats and compared with the standard drug phenytoin. The neurotoxic effects were determined by rotorod test by using mice. Compounds 8d, 8e, 8f and 8h were found to be most potent of this series. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). The efforts were also made to establish the structure activity relationships among synthesized compounds. The pharmacophore model was used to validate the anticonvulsant activity of the synthesized molecules.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroshock; Male; Mice; Molecular Structure; Motor Activity; Oxadiazoles; Piperazines; Rats; Rats, Wistar; Seizures

Two novel series of N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide and N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide were synthesized to meet structural prerequisite indispensable for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. The rotorod test was conducted to evaluate neurotoxicity. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The outcome of the present investigations proved that the four binding sites pharmacophore model is vital for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among test compounds.

Topics: Acyclic Monoterpenes; Animals; Anticonvulsants; Binding Sites; Cyclohexenes; Disease Models, Animal; gamma-Aminobutyric Acid; Limonene; Monoterpenes; Oxadiazoles; Protein Binding; Rats; Seizures; Semicarbazones; Structure-Activity Relationship; Terpenes

The present study was designed to investigate the involvement of the nitric oxide (NO)/cyclic guanylate monophosphate pathway in pilocarpine-induced seizures in mice. Male Swiss mice (26-32 g) were used as the in vivo model. The following pharmacological tools were utilized: the non-selective NO synthase (NOS) inhibitor L-NAME (10 mg/kg, i.p.), a preferential inducible NOS (iNOS) inhibitor aminoguanidine (25 mg/kg, i.p.), a highly specific iNOS inhibitor 1400W (2.5 mg/kg, i.p.), the NO donor L-arginine (150 mg/kg, i.p.), and the soluble guanylyl cyclase inhibitor ODQ (10 mg/kg, i.p.). The animals were divided into groups (n = 8) and pretreated for 30 min before receiving pilocarpine (400 mg/kg, i.p.), while the control group received only pilocarpine. They were observed for 60 min to measure initial seizure latency, latency till death, and mortality. An administration of L-NAME or ODQ delayed the onset of initial seizure, increased latency till death, and produced a 25% survival rate. Aminoguanidine increased the initial seizure and latency until death, and administration of 1400W did not have an effect. Incremental increases of NO by L-arginine were capable of decreasing the seizure and death latency. These results support the idea that the constitutive NOS, probably neuronal NOS, followed by soluble guanylyl cyclase activation is involved in the convulsive responses caused by pilocarpine administration.

Topics: Amidines; Animals; Arginine; Benzylamines; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Guanidines; Guanylate Cyclase; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Pilocarpine; Receptors, Cytoplasmic and Nuclear; Seizures; Soluble Guanylyl Cyclase

In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, (1) H NMR, (13) C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Molecular Conformation; Oxadiazoles; Pentylenetetrazole; Seizures; Semicarbazones; Structure-Activity Relationship

A novel substituted oxa/thiadiazolylazetidinonyl/thiazolidinonylcarbazoles (4a-j), (5a-j) and (6a-j) were synthesized and screened for their antipsychotic and anticonvulsant activities. It is concluded from the results compound 6j showed promising antipsychotic as well as anticonvulsant activity.

Topics: Anticonvulsants; Antipsychotic Agents; Carbazoles; Lethal Dose 50; Oxadiazoles; Seizures; Thiadiazoles

A series of 3- and 5-aryl-1,2,4-oxadiazole derivatives were prepared and tested for anticonvulsant activity in a variety of models. These 1,2,4-oxadiazoles exhibit considerable activity in both pentylenetetrazole (PTZ) and maximal electroshock seizure (MES) models. Compound 10 was protective in the PTZ model in rats with an oral ED(50) of 25.5mg/kg and in the MES model in rats with an oral ED(50) of 14.6mg/kg. Neurotoxicity (rotarod) was observed with an ED(50) of 335mg/kg. We found several oxadiazoles that acted as selective GABA potentiating compounds with no interaction to the benzodiazepine binding site.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Male; Models, Molecular; Molecular Structure; Oxadiazoles; Rats; Seizures; Structure-Activity Relationship

The effect of the selective 5-hydroxytryptamine1B (5-HT1B) receptor agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP 94253) and the 5-HT1A/1B/1D receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) in maximal electroshock- and pentylenetetrazol-induced seizures in mice was examined. CP 94253 (10-40 mg/kg) afforded no protection against maximal electroshock-evoked convulsions, but produced anticonvulsant action in the pentylenetetrazol-induced seizures (ED50 = 29 mg/kg). The anticonvulsant effect of CP 94253 was abolished by the selective 5-HT1B receptor antagonist N-[3-(2-dimethylamino)ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide (SB 216641; 20 mg/kg) but it was maintained following the p-chlorophenylalanine (p-CPA; 3 x 300 mg/kg)-induced 5-HT depletion. Interestingly, CP 94253 potentiated the anticonvulsant activity of diazepam in the pentylenetetrazol test; on the other hand, the benzodiazepine receptor antagonist, flumazenil (10 mg/kg), did not modify the anticonvulsant effect of CP 94253. RU 24969 (5 mg/kg) evoked no effect in the maximal electroshock model, but it produced anticonvulsant activity in the pentylenetetrazol assay, the latter effect being attenuated by the selective 5-HT1A receptor antagonist N-(2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl)-N-(2-pyridyl)-cyclohexanecarboxamide (WAY 100635; 0.3 mg/kg) and SB 216641 (10-20 mg/kg). The obtained results suggest that CP 94253 exerts anticonvulsant activity on pentylenetetrazol-induced seizures in mice, as a consequence of stimulation of 5-HT1B receptors (probably located postsynaptically and/or as heteroreceptors); the antiseizure activity of RU 24969 seems to depend on the stimulation of both 5-HT1A and 5-HT1B receptors.

Topics: Animals; Anticonvulsants; Benzamides; Diazepam; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Fenclonine; Indoles; Male; Mice; Oxadiazoles; Pentylenetetrazole; Piperazines; Pyridines; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1B; Seizures; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists

A series of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Conformational analysis and superimposition of energy minima conformers of the designed molecules on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at para position of benzylthio moiety had the best anticonvulsant activity. It seems this effect is mediated through benzodiazepine receptors mechanism.

Topics: Animals; Anticonvulsants; Benzodiazepines; Convulsants; Diazepam; Drug Design; Electroshock; Flumazenil; GABA Modulators; GABA-A Receptor Agonists; Mice; Models, Molecular; Molecular Structure; Oxadiazoles; Pentylenetetrazole; Seizures; Structure-Activity Relationship

CNQX and DNQX are compounds that have recently been reported to show potent non-NMDA excitatory amino acid receptor antagonist activity. Effects of these compounds on seizures induced by homocysteine thiolactone and quisqualic acid were studied in order to examine the pharmacological properties of these compounds. In a dosage of 1.16 micrograms intracerebroventricularly (ICV), CNQX prolonged the latency to the onset of quisqualate-, but not homocysteine-induced seizures. DNQX was not effective when given either ICV or systemically, although a 3.78 micrograms dose of DNQX given ICV markedly increased the variability in latency to seizure onset, suggesting a combination of pro- and anticonvulsant effects. Higher dosages of both CNQX and DNQX induced seizure-like activity after ICV injection. These data confirm that CNQX has pharmacological effects corresponding to its effects on cellular responses to quisqualate and kainate agonists, but these effects are weak and may limit its usefulness as a pharmacological tool.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anticonvulsants; Female; Homocysteine; Mice; Oxadiazoles; Quinoxalines; Quisqualic Acid; Seizures

Antagonism of N-methyl-D-aspartate (NMDA)-induced convulsions by a variety of drugs was compared with their ability to produce phencyclidine (PCP)-like behavioral effects (locomotion and falling) in mice. Convulsions produced by i.c.v. administration of NMDA were antagonized, at doses that did not block kainate- and quisqualate-induced convulsions, by competitive NMDA antagonists (e.g., CPP and CGS 19755), noncompetitive antagonists (e.g., PCP and MK-801) and also by some putative glycine antagonists (7-chlorokynurenic acid and HA-966). Only the competitive and the noncompetitive NMDA antagonists produced locomotion and falling, and their potencies to do so correlated (r = 0.92) with their relative potencies to antagonize NMDA-induced convulsions. However, the PCP-like behavioral effects produced by the competitive antagonists were of a lesser magnitude than those of the noncompetitive antagonists, and occurred at doses higher than those needed to block NMDA-induced convulsions. The putative glycine antagonists 7-chlorokynurenic acid and HA-966 selectively blocked NMDA-induced convulsions, without producing PCP-like behavioral effects. The extent to which compounds produce PCP-like behavioral effects might depend in part on the specific component of the NMDA receptor complex with which they interact: i.e., the NMDA receptor, the NMDA receptor-associated ion channel or the glycine-sensitive modulatory site.

Topics: Animals; Aspartic Acid; Dose-Response Relationship, Drug; Glycine; Kainic Acid; Kynurenic Acid; Male; Mice; Motor Activity; N-Methylaspartate; Oxadiazoles; Phencyclidine; Pyrrolidinones; Quisqualic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The effect of a spider toxin (JSTX-3)--a specific blocker of glutamate receptors--on the behavior of mice was studied using an intracerebroventricular (i.c.v.) injection technique. At higher doses (more than 12 nmol/brain), JSTX-3 increased motor activities and induced characteristic symptoms. JSTX-3 at a dose of 4.7 nmol/brain which per se did not produce any abnormal behavior, specifically antagonized quisqualate-induced convulsions but not NMDA- or kainate-induced convulsions. These results indicate that JSTX-3 is a selective antagonist of the quisqualate receptors in the mammalian central nervous system.

Topics: Animals; Arthropod Venoms; Dose-Response Relationship, Drug; Injections, Intraventricular; Kainic Acid; Mice; Motor Activity; Oxadiazoles; Quisqualic Acid; Receptors, Glutamate; Receptors, Neurotransmitter; Seizures; Spider Venoms

Mice withdrawn from exposure for 14 days to ethanol inhalation showed the expected signs of ethanol withdrawal including convulsive behaviour. Injection of chlormethiazole (100 mg/kg) 5 h after the start of withdrawal, at the time that the convulsive behaviour was near maximal, resulted in the virtual disappearance of the withdrawal-induced behaviour within 30 min, with its reappearance by 60 min. A dose of chlormethiazole of 40 mg/kg was without effect. The time course of the effect of chlormethiazole (100 mg/kg) in the withdrawal test was similar to its effect in raising seizure threshold and decreasing locomotor activity. Chlormethiazole did not alter in vitro binding of [3H]-PN 200-110 to the dihydropyridine sensitive Ca2+ channel. Chlormethiazole, a drug used clinically to treat ethanol withdrawal, has therefore been shown to be effective in this animal model of withdrawal. Dihydropyridine calcium antagonists are also active in the model but chlormethiazole is likely to work by a different mechanism and it is suggested that this may be by increasing GABAergic function.

Topics: Animals; Calcium Channels; Chlormethiazole; Dihydropyridines; Ethanol; Isradipine; Male; Mice; Motor Activity; Oxadiazoles; Seizures; Substance Withdrawal Syndrome

Long-term neuroleptic administration produces a behavioral supersensitivity to dopamine agonists. Tyrosine hydroxylase immunoreactive synapses in the striatum are closely associated with putative glutamate-mediated synapses, on dendrites and dendritic spines of the same neuronal population. The purpose of the present study was to determine whether chronic neuroleptic administration would alter the behavioral response to glutamatergic drugs. Mice were chronically administered haloperidol for 28 days. After four days of withdrawal, behavioral activity was measured following intraventricular administration of quisqualic acid or intraperitoneal injection of glutamic acid diethyl ester. Both agents decreased behavioral activity. This response to glutamatergic drugs at low dosages was attenuated by chronic haloperidol administration. It is concluded that chronic haloperidol administration alters the behavioral responsivity of animals to glutamatergic drugs.

Topics: Animals; Cerebral Ventricles; Convulsants; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Female; Glutamates; Haloperidol; Injections, Intraperitoneal; Injections, Intraventricular; Mice; Motor Activity; Oxadiazoles; Quisqualic Acid; Seizures

The prepiriform cortex (PPCx) shows high sensitivity to the epileptogenic action of chemo-convulsants and to the protective action of the NMDA receptor antagonist, 2-amino-7-phosphono-heptanoate (APH) against pilocarpine-induced (motor) limbic seizures in rats. In this study the interaction between agonists acting selectively on the three main excitatory amino acid receptor subtypes in the PPCx and the muscarinic agonist, pilocarpine, within the PPCx have been investigated. Kainate (KA) or quisqualate (QUIS) injected focally into the PPCx (100 pmoles or 5 nmoles per side respectively) induced motor limbic seizures when administered after a subconvulsant dose of pilocarpine (250 mg/kg, i.p.). KA, 100 pmoles injected into the same site in olfactory-bulboectomized rats (bulbectomy results in protection against pilocarpine-induced seizures) also facilitated seizures. However, activation of the NMDA receptor in the PPCx by focal injection of NMDA (250 fmoles-10 nmoles) failed to produce seizures after a subconvulsant dose of pilocarpine. Moreover NMDA in the same range of doses injected into the PPCx protected rats against the seizures induced by a fully convulsant dose of pilocarpine.

Topics: Animals; Aspartic Acid; Cerebral Cortex; Kainic Acid; Male; N-Methylaspartate; Olfactory Bulb; Oxadiazoles; Pilocarpine; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Reference Values; Seizures

Glutamic acid diethyl ester (GDEE) is a glutamate antagonist which acts preferentially at the quisqualate-sensitive receptor and has been shown to be an effective anticonvulsant in alcohol withdrawal and homocysteine-induced seizures but ineffective in other seizure models. To better characterize the role of the quisqualate-sensitive receptor in the generation of seizures, quisqualate was administered to mice by intracerebroventricular (ICV) route and immediate onset generalized seizures were observed. The anticonvulsant properties of GDEE and commonly used antiepileptic drugs (AEDs) were investigated with this seizure model. GDEE given by intraperitoneal blocked quisqualate-induced seizures dose-dependently. Diphenyl-hydantoin (50 mg/kg IP), carbamazepine (50 mg/kg IP), diazepam (1; 4 mg/kg IP), phenobarbital (40; 80 mg/kg IP), and valproic acid (250; 340 mg/kg IP) were also administered prior to quisqualate-seizure induction. Only valproic acid blocked seizures at nonsedating doses. The GABA transaminase inhibitor aminooxyacetic acid (20 mg/kg IP) was ineffective, suggesting that here valproic acid is active at excitatory receptors rather than by potentiating GABA post-synaptic inhibition. These data are consistent with the hypothesis that the quisqualate-sensitive receptor is involved in some forms of clinically observed seizures, particularly those which are controlled by valproic acid.

Topics: Aminooxyacetic Acid; Animals; Anticonvulsants; Carbamazepine; Diazepam; Female; Glutamates; Mice; Oxadiazoles; Phenobarbital; Phenytoin; Quisqualic Acid; Seizures; Valproic Acid

An effect of the beta-stereoisomer of kainic acid on seizures produced by intracerebroventricular injections of excitatory amino acids was tested in mice. beta-Kainic acid preferentially antagonizes myoclonic seizures induced by N-methyl-D-aspartate and quinolinate, has less pronounced anticonvulsant action against alpha-kainate, D-homocysteinesulphinate and quisqualate, and no effect on convulsions induced by L-glutamate. The anticonvulsant activity of beta-kainic acid matches that of 2-amino-7-phosphonoheptanoic and kynurenic acids, both preferential N-methyl-D-aspartate receptor antagonists, and differs considerably from the profile of anticonvulsant action of gamma-D-glutamylaminomethylsulphonic acid, a preferential kainate/quisqualate antagonist.

Topics: Animals; Anticonvulsants; Aspartic Acid; Excitatory Amino Acid Antagonists; Glutamic Acid; Homocysteine; Kainic Acid; Mice; N-Methylaspartate; Oxadiazoles; Pyrrolidines; Quinolinic Acid; Quinolinic Acids; Quisqualic Acid; Seizures; Stereoisomerism

The dipeptide N-[[[2'S-(2' alpha, 3' beta, 4' beta)]-2'-carboxy-4'-(1"-methylethenyl)-3'-pyrrolidinyl)acetyl]-L- glutamic acid (6) has been synthesized by a route that involves the selective protection of the alpha-carboxyl function of kainic acid. This dipeptide inhibits the stimulation of Na+ fluxes induced in brain slices by the neuroexcitant N-methyl-D-aspartic acid. Administered intracerebroventricularly, it is also effective in protecting mice from picrotoxin-induced convulsions with an ED50 of 0.17 mumol.

Topics: Animals; Aspartic Acid; Cell Membrane Permeability; Corpus Striatum; Dipeptides; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Kainic Acid; Male; Mice; N-Methylaspartate; Oxadiazoles; Picrotoxin; Quisqualic Acid; Rats; Seizures; Sodium

Two dicarboxylic piperazine derivatives, 1-(p-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (pCB-PzDA) and 1-(p-bromobenzoyl)-piperazine-2,3-dicarboxylic acid (pBB-PzDA), that block excitation at glutamate receptors have been evaluated as anticonvulsants in rodent models of epilepsy by i.c.v. or i.p. injection. In DBA/2 mice, pBB-PzDA (0.01 mumol i.c.v.) or pCB-PzDA (0.03 mumol i.c.v.) protects against the clonic and tonic seizures induced by loud sound. Protection is also seen following i.p. injection of pBB-PzDA (0.33-1.0 mmol/kg) or pCB-PzDA (0.66-1.0 mmol/kg). In Swiss S mice suppression of seizure activity induced by i.c.v. injection of excitatory amino acid agonists shows that both compounds are preferentially active against alpha-kainate, with the following rank orders (for pBB-PzDA); alpha-kainate greater than quisqualate greater than N-methyl-D-aspartate greater than quinolinate greater than L-glutamate; and (for pCB-PzDA): alpha-kainate greater than quinolinate greater than N-methyl-D-aspartate greater than quisqualate greater than L-glutamate. These compounds are the most potent preferential alpha-kainate antagonists so far tested. The relationship between antagonism at the various receptor subtypes and anticonvulsant action is not adequately defined.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Aspartic Acid; Chemical Phenomena; Chemistry; Glutamates; Kainic Acid; Mice; Mice, Inbred DBA; Mice, Inbred Strains; N-Methylaspartate; Oxadiazoles; Piperazines; Pyrrolidines; Quinolinic Acids; Quisqualic Acid; Seizures

An intrahippocampal injection of quisqualic acid (QA) was made in chronically implanted freely moving unanesthetized cats and electrographic and clinical observations were made. Fourteen to 40 micrograms of QA injection resulted in a mild limbic seizure within 24 h after QA injection. Some cats demonstrated a pure hippocampal seizure on an electroencephalogram. Electrographic changes and clinical manifestations were less prominent as compared with those of kainic acid. Histopathological examination showed a selective loss of pyramidal cell layer of the CA3 portion in the injected side of the dorsal hippocampus. A mild but constant epileptogenic potency of QA has an advantage for an experimental model of temporal lobe epilepsy in man.

Topics: Animals; Brain Diseases; Cats; Electroencephalography; Hippocampus; Oxadiazoles; Quisqualic Acid; Seizures

In order to study the role of excitatory amino acids on motor function, the effects of kainic, quisqualic, and N-methyl-DL-aspartic acids on locomotor activity were determined after their direct injection into the nucleus accumbens. These three amino acids have been used in previous studies to classify receptors for excitatory amino acids in the mammalian spinal cord. After injection into the nucleus accumbens all three amino acids stimulated locomotor activity, with kainic acid being the most potent and N-methyl-DL-aspartic acid the least potent. The maximum intensity of the stimulation produced by kainic and quisqualic acids was greater than that produced by N-methyl-DL-aspartic acid. These results suggest that receptors in the nucleus accumbens, sensitive to kainic and quisqualic acids, play a more important role in the stimulation of locomotor activity than those sensitive to N-methyl-DL-aspartic acid. In addition to the above amino acids, the administration of large doses of L-aspartic and D-glutamic acids also produced hyperactivity, while L-glutamic acid had no effect. To determine whether endogenous dopamine mediates the hypermotility produced by the excitatory amino acids, the response to these amino acids was studied after treatment with reserpine or dopamine receptor blocking agents. Reserpine (5 mg/kg, i.p.), haloperidol (0.8 mg/kg, i.p.) or fluphenazine [5.0 micrograms (total dose) injected into the nucleus accumbens] markedly attenuated the hypermotility induced by excitatory amino acids. These results suggest that the hypermotility produced by excitatory amino acids is mediated through release of dopamine and the subsequent stimulation of dopamine receptors in the nucleus accumbens.

Topics: Amino Acids; Animals; Aspartic Acid; Dose-Response Relationship, Drug; Glutamates; Glutamic Acid; Kainic Acid; Male; Motor Activity; N-Methylaspartate; Nucleus Accumbens; Oxadiazoles; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Seizures; Septal Nuclei; Synaptic Transmission

Quisqualic acid (QA) is a potent neuroexcitant and a heterocyclic analogue of glutamate as is kainic acid. Twenty micrograms of QA in unilateral lateral amygdaloid nucleus of cats produced a transient limbic status epilepticus lasting 20-30 hours. Over 14 days after recovery from the limbic status, the animals received daily electrical stimulation to the ipsilateral hippocampus at the intensity of afterdischarge threshold which was determined before the injection of QA. These stimulations resulted in secondarily generalized convulsive seizures in all animals within 4 to 12 days. Spontaneous secondarily generalized seizures were confirmed in two cats after completion of the hippocampal kindling. This rapid completion of the kindling process is interesting phenomenon in contrast to the report that the hippocampal kindling took nearly 60 days. This rapid completion of the kindling effect is considered to be due to the transfer effect (Goddard, 1975) established in the ipsilateral hippocampus by severe bombardments from the amygdala stimulated by the injection of QA as the primary focus. In addition, the pathological changes in the amygdala and hippocampus on the injected side might be related to the rapid kindling process of the ipsilateral hippocampus as the irritable foci.

Topics: Amygdala; Animals; Cats; Convulsants; Hippocampus; Kindling, Neurologic; Oxadiazoles; Quisqualic Acid; Seizures

Topics: Animals; Chemical Phenomena; Chemistry; Humans; Male; Mice; Mice, Inbred BALB C; Motor Activity; Oxadiazoles; Rats; Rats, Inbred Strains; Seizures; Stereotyped Behavior

Topics: Aminopyrine N-Demethylase; Animals; Blood Pressure; Drug Evaluation, Preclinical; Lethal Dose 50; Mice; Microsomes; Multienzyme Complexes; Nitrosamines; Oxadiazoles; Oxidoreductases, N-Demethylating; Pentylenetetrazole; Rats; Regression Analysis; Seizures; Structure-Activity Relationship

Topics: Antihypertensive Agents; Blood; Chlorides; Cholesterol; Dogs; Growth; Natriuresis; Oxadiazoles; Potassium; Rats; Research; Seizures; Sodium; Sydnones; Toxicology; Urine