benzofurans and Seizures

There is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus

Topics: Alkaloids; Animals; Anticonvulsants; Aspergillus; Benzofurans; Disease Models, Animal; Drug Resistance; Epilepsy; Isoquinolines; Larva; Male; Mice; North Sea; Seizures; Zebrafish

Neuronal apoptosis is a regulated intrinsic cell mechanism and common pathological phenomenon after seizures, which involves the protein kinase B/cAMP response element binding protein / brain derived neurotrophic factor (AKT/CREB/ BDNF) signaling pathway. In this study, we aimed to identify the effects of salvianolic acid B (Sal B), a major water-soluble component of the Chinese herb, Danshen, on rats in which seizures had been induced by pentylenetetrazole (PTZ) and the underlying molecular mechanisms mediating these effects. For this, 60 adult male Sprague-Dawley rats were divided into a control group, a 'PTZ' group and a 'PTZ + Sal B' group. The animals in the control group received an intraperitoneal (i.p.) injection of saline on alternate days for a total of 15 injections and saline orally once a day for 29 days. The animals in the 'PTZ' group received PTZ (40 mg/kg, i.p.) on alternate days for a total of 15 injections and saline orally once a day for 29 days. Similarly, the animals in the 'PTZ + Sal B' group received PTZ (40 mg/kg, i.p.) on alternate days and Sal B (20 mg/kg) orally once a day for 29 days. Neural density was then evaluated using immunofluorescence (IF) staining of microtubule-associated protein 2 (MAP2). Neuronal apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. In addition, the expression of several proteins related to AKT/CREB/BDNF signaling was measured using Western blotting. The results indicated that more severe seizures, decreased neural density, decreased expression of Bcl-2, increased expression of Bax and cleaved caspase-3, and inactivation of AKT/CREB/BDNF signaling occurred in the 'PTZ' group in comparison with the control group. However, those changes were suppressed by Sal B. Thus, these data suggest that Sal B has anticonvulsant and anti-apoptotic effects in a PTZ-induced seizure model through activation of the AKT/CREB/BDNF signaling pathways.

Topics: Animals; Anticonvulsants; Apoptosis; Benzofurans; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Drugs, Chinese Herbal; Male; Neurons; Pentylenetetrazole; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Seizures; Signal Transduction; Treatment Outcome

A series of N-(2-(benzoyl/4-chlorobenzoyl)-benzofuran- 3-yl)-2-(substituted)-acetamide derivatives (4a-l, 5a-l) was synthesized in good yield. All synthesized compounds were in agreement with elemental and spectral data. The anticonvulsant activity of all synthesized compounds was assessed against the maximal electroshock induced seizures (MES) model in mice. Neurotoxicity was evaluated using the rotarod method. The majority of compounds exhibited anticonvulsant activity at a dose of 30 mg kg-1 body mass during 0.5-4 h, indicating their ability to prevent seizure spread at low doses. Relative to phenytoin, [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(cyclohexyl( methyl) amino)-acetamide] (5i) and [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-methylpiperidin-1- yl)-acetamide] (5c) demonstrated comparable relative anticonvulsant potency of 0.74 and 0.72, respectively, whereas [(N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-(furan-2-carbonyl)-piperazin-1-yl)-acetamide] (5f) exhibited the lowest relative potency of 0.16. The ALD50 of tested compounds ranged from 1.604 to 1.675 mmol kg-1 body mass. The ED50 of synthesized compounds ranged from 0.055 to 0.259 mmol kg-1 (~23.4 to 127.6 mg kg-1) body mass. The pharmacophore mapping of the examined compounds on standard drugs (phenobarbital, phenytoin, ralitolin and carbamazepine) strongly suggests that these compounds may exert their anticonvulsant activity via the same established mechanism as that of known drugs.

Topics: 4-Aminobutyrate Transaminase; Acetamides; Animals; Anticonvulsants; Benzofurans; Binding Sites; Cerebellum; Dose-Response Relationship, Drug; Drug Design; GABA Agonists; gamma-Aminobutyric Acid; Glycine; Lethal Dose 50; Male; Medulla Oblongata; Mesencephalon; Mice; Models, Molecular; Molecular Docking Simulation; Neurons; Neurotoxicity Syndromes; Rats, Wistar; Seizures; Sus scrofa

For more than 60years, lithium has been the mainstay in the treatment of mental disorders as a mood stabilizer. In addition to the antimanic and antidepressant responses, lithium also shows some anticonvulsant properties. In spite of the ascertained neuroprotective effects of this alkali metal, the underlying mechanisms through which lithium regulates behavior are still poorly understood. Among different targets, some authors suggest neuromodulatory effects of lithium are the consequences of interaction of this agent with the brain neurotransmitters including adrenergic system. In order to study the involvement of α2-adrenergic system in anticonvulsant effect of lithium, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice. Injection of a single effective dose of lithium chloride (30mg/kg, i.p.) significantly increased the seizure threshold (p<0.01). The anticonvulsant effect of an effective dose of lithium was prevented by pre-treatment with low and per se non-effective dose of clonidine [α2-adrenoceptor agonist] (0.05, 0.1 and 0.25mg/kg). On the other hand, yohimbine [α2-adrenoceptor antagonist] augmented the anticonvulsant effect of sub-effective dose of lithium (10mg/kgi.p.) at relatively low doses (0.1, 0.5, 1 and 2.5mg/kg). Moreover, UK14304 [a potent and selective α2-adrenoceptor agonist] (0.05 and 0.1mg/kg) and RX821008 [a potent and selective α2D-adrenoceptor antagonist] (0.05, 0.1 and 0.25mg/kg) repeated the same results confirming that these modulatory effects are conducted specifically through the α2D-adrenoceptors. In summary, our findings demonstrated that α2-adrenoceptor pathway could be involved in the anticonvulsant properties of lithium chloride in the model of chemically induced clonic seizure.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Benzofurans; Brimonidine Tartrate; Clonidine; Drug Interactions; Imidazoles; Lithium Chloride; Male; Mice; Pentylenetetrazole; Receptors, Adrenergic, alpha-2; Seizures; Yohimbine

The multifaceted pathogenesis of temporal lobe epilepsy (TLE) offers a number of adjunctive therapeutic prospects. One such therapeutic strategy could be targeting H3 receptor (H3R) by selective H3R antagonists which are perceived to have antiepileptic and neuroprotective potential. Kainic acid (KA) induced seizure, a reliable model of TLE, triggers epileptogenic events resulting from initial neuronal death and ensuing recurring seizures. The present study aimed to determine whether pre-treatment with ABT-239, a novel H3R antagonist, and its combinations with sodium valproate (SVP) and TDZD-8 (glycogen synthase kinase-3β (GSK3β) inhibitor) can prevent the excitotoxic events in mice exposed to KA (10 mg/kg i.p.). ABT-239 (1 and 3 mg/kg i.p.) significantly attenuated KA-mediated behavioural and excitotoxic anomalies and restored altered expression of Bax, cleaved caspase-3, phospho-Akt (Ser473) and cAMP response element binding protein (CREB). Surprisingly, restoration of Bcl2 and phospho-GSK3β (Ser9) by ABT-239 did not reach the level of statistical significance. Co-administration of ABT-239 (1 and 3 mg/kg) with a sub-effective dose of SVP (150 mg/kg i.p.) yielded improved efficacy than when given alone. Similarly, low and high dose combinations of ABT-239 (1 and 3 mg/kg) with TDZD-8 (5 and 10 mg/kg i.p.) produced greater neuroprotection than any other treatment group. Our findings suggests a neuroprotective potential of ABT-239 and its combinations with SVP and TDZD-8 against KA-induced neurotoxicity, possibly mediated through in part each by modulating Akt/GSK3β and CREB pathways. The use of H3R antagonists as adjuvant in the treatment of human TLE might find potential utility, and can be pursued further.

Topics: Animals; Anticonvulsants; Benzofurans; Dose-Response Relationship, Drug; Drug Therapy, Combination; Gene Expression; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Histamine H3 Antagonists; Kainic Acid; Male; Mice; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Protein Kinase Inhibitors; Pyrrolidines; Random Allocation; Seizures; Thiadiazoles; Valproic Acid

Imidazoline I2 receptors are involved in pain modulation and psychiatric disorders and its ligands may represent a new therapeutic strategy against pain and depression. In particular, 2-BFI and BU224 are the two most widely studied I2 receptor ligands and have antinociceptive and antidepressant-like activities in rodents. However, little is known of the toxicological effects and potential gender differences of these I2 receptor ligands. This study examined the epileptogenic activities of 2-BFI and BU224 in male and female mice and also examined their underlying receptor mechanisms. 2-BFI (10-40 mg/kg, i.p.) and BU224 (10-40 mg/kg) produced epileptic seizures in a dose-related manner, as did the epileptogenic agent, pentylenetetrazole (PTZ, 15-60 mg/kg). However, female mice were significantly more sensitive than male mice in all the measures. The commonly used I2 receptor antagonist, idazoxan (10mg/kg), did not block the onset and magnitude of the epileptic seizures or lethality induced by 2-BFI and BU224. When studied in combination, PTZ potentiated the epileptogenic effect of 2-BFI and BU224. The lack of antagonism by idazoxan of the epileptogenic activities of 2-BFI and BU224 suggests that the epileptogenic effects of 2-BFI and BU224 are mediated by non-imidazoline I2 receptors and that I2 receptors remain a viable therapeutic target for neurological disorders such as pain.

Topics: Animals; Benzofurans; Female; Imidazoles; Imidazoline Receptors; Male; Mice; Mice, Inbred C57BL; Seizures; Sex Characteristics

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.

Topics: Animals; Anticonvulsants; Benzofurans; Convulsants; Drug Design; Electroshock; Indicators and Reagents; Mice; Nervous System Diseases; Pentylenetetrazole; Piperazines; Rats; Seizures

Seizures occur in the basal ganglia (BG) of epileptic patients and in animal models of epilepsy, but there is relatively little known about how these events are gated and/or propagated through this structure. Here, we present and characterize a model of in vitro seizure-like events (SLEs) in the striatum by applying chemostimulants to brain slices from young rat pups. We found that bath perfusion of artificial cerebral spinal fluid (aCSF) containing 0.25 mM MgCl(2), 5mM KCl and 100 μM 4-aminopyridine (LM/HK/4AP) elicited recurrent hyper-excitability in striatal medium spiny neurons (MSNs) in the form of paroxysmal depolarization shifts (PDSs) with an amplitude of 27.8 ± 2.1 mV and a duration of 29.4 ± 3.7s. PDSs coincided with SLEs in the striatal network with an amplitude of 106.5 ± 11.3 μV, duration of 23.6 ± 3.2 s, and a spiking frequency of 7.9 ± 1.3 Hz. Notably, chemostimulant-induced MSN PDSs were predominantly observed at earlier ages (P7-11), whereas occurrence of MSN PDSs declined to 50% by P12 and were no longer noted after P14; antagonism of the cannabinoid receptor (CB1) with 10 μM LY 320135 along with perfusion of LM/HK/4AP in older animals (P14-15) was unable to elicit MSN PDSs and SLEs. PDSs and SLEs were blocked with 60 μM 2-amino-5-phosphonopentanoate (APV), an N-methyl-d-aspartate receptor (NMDAR) blocker, or with traditional anticonvulsants such as 100 μM phenytoin or 50 μM carbamazepine. Conversely, blockade of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptors (AMPARs) with 10 μM CNQX or T- and L-type Ca(2+) channels with 50 μM NiCl(2) or 50 μM nimodipine, respectively, did not significantly change MSN PDS and SLE amplitudes, durations and frequencies seen with LM/HK/4AP treatment alone. Striatal SLEs were driven by MSN hyper-excitability and synchrony since neither the presence of 1μM scopolamine, a muscarinic acetylcholine (ACh) receptor inhibitor, nor selective inhibition of fast-spiking interneurons (FSIs) with 50μM IEM1460 had any significant effect on MSN PDSs and SLEs. Next, we physically isolated the striatum from cortical and thalamic input and found that the striatum was intrinsically capable of manifesting NMDAR-dependent SLEs. Altogether, the present study is the first to deconstruct how SLEs can form in the striatum by examining how MSN activity coincides with SLEs. It also highlights a previously unrecognized potential for the striatum to manifest SLEs in vitro, without involving the cortex and thalamus.

Topics: Action Potentials; Animals; Anticonvulsants; Benzofurans; Cannabinoid Receptor Antagonists; Carbamazepine; Corpus Striatum; Nerve Net; Neurons; Phenytoin; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Seizures

Four new N-1',N-3'-disubstituted-2'H,3H,5'H-spiro-(2-benzofuran-1,4'-imidazolidine)-2',3,5'-triones bearing a chiral N-3' substituent were synthesized, resolved and their anticonvulsant activity was obtained and determined that the activity was not stereoselective.

Topics: Animals; Anticonvulsants; Benzofurans; Humans; Imidazolidines; Mice; Pentylenetetrazole; Seizures; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship

Topics: Antidepressive Agents; Benzofurans; Emergency Service, Hospital; Female; Humans; Indoles; Infant; Piperazines; Seizures; Status Epilepticus; Vilazodone Hydrochloride

This technique proposes a new approach to correlate intra- and extracellular variations of the ionic concentrations in vivo by means of tapered optical waveguides coupled to standard electrophysiological electrodes to monitor in vivo simultaneously the intracellular and extracellular K(+) concentration as well as the neighboring field potential. The optical fibers were tapered to a final diameter of approximately 10 μm and were used to guide the excitation light deep into the tissue and to collect the fluorescence emanating from the intracellular milieu. This fiber was coupled to a double barrel ion-sensitive electrode forming a micro-optrode with a final diameter around 15 μm. The method was successfully used to record the intracellular K(+) evolution with the fluorescent indicator PBFI during three states: normal sleep-like patterns, paroxysmal seizures, and coma. While we could not disclose any phasic fluctuations of the intracellular K(+) during normal sleep patterns, they were clearly present during seizures and coma. In the majority of cases (58%), paroxysmal discharges were associated with positive variations of the intracellular fluorescence of 62±5% corresponding to extracellular K(+) increases of 2.04±0.4 mM. In the remaining cases (42%) intracellular K(+) dropped by 44.4±12% for an extracellular K(+) increase of 2.62±0.47 mM. We suggest that this differential behavior might reflect different cellular populations (glia vs. neurons, respectively). Comatose states were accompanied by an extracellular drop of K(+) of 1.31±0.13 mM, which was reflected, in all cases, by an intracellular K(+) increase of 39±4%.

Topics: Animals; Benzofurans; Brain; Cats; Coma; Databases, Factual; Electroencephalography; Ethers, Cyclic; Extracellular Fluid; Fiber Optic Technology; Glial Fibrillary Acidic Protein; Intracellular Fluid; Ion-Selective Electrodes; Neurons; Potassium; Reproducibility of Results; Seizures; Sleep

Synthesis of furochromone, 2-phenylchromone (flavone) and benzofuran derivatives substituted with thiosemicarbazide or thiazolidin-4-one moieties were accomplished. All the newly synthesized compounds were tested for their anticonvulsant activity in both subcutaneous pentylenetetrazole induced seizures (scPTZ) and maximal electric shock induced seizures (MES) tests using valproic acid and phenytoin respectively as reference standards. The most active compounds in scPTZ model were 1c, 2b, 5a and 7e showing 100% protection at 300 mg/kg upon intraperitoneal administration. Also, the effect of pre-treatment of three of the most active compounds (1c, 2b, 5a) on 4-amino pyridine-induced lethality in mice was investigated. Pre-treatment with these compounds significantly increased the latency for clonic and tonic seizures and prevented 4-amino pyridine induced death. Hence, this provides evidence for anticonvulsant activity of these compounds, and a neuroprotective activity for them. The structure-activity relationship was studied based on the obtained data.

Topics: Animals; Anticonvulsants; Benzofurans; Chromones; Electroshock; Female; Flavones; Male; Mice; Molecular Structure; Seizures; Structure-Activity Relationship

Thirteen new N-1',N-3'-disubstituted-2'H,3H,5'H-spiro-(2-benzofuran-1,4'-imidazolidine)-2',3,5'-triones were synthesized and their pharmacological activity determined with the objective to better understand their SAR for anticonvulsant activity. The anticonvulsant effects of these compounds were evaluated by standard pentylenetetrazol (scPTZ test) and maximum electroshock seizure (MES test) models in mice. Most of the compounds showed ability to protect against the pentylenetetrazol-induced convulsions. Compound 3o (the N-1'-p-nitrophenyl, N-3'-ethyl derivative) in the N-1'-aryl, N-3'-alkyl disubstituted series exhibited maximum activity with ED(50) of 41.8 mg/kg in scPTZ convulsion model.

Topics: Animals; Anticonvulsants; Benzofurans; Imidazolidines; Mice; Molecular Structure; Pentylenetetrazole; Seizures; Structure-Activity Relationship

Brain injury was induced by intraperitoneal administration of kainic acid (KA, 10 mg/kg). Animals were randomized to receive either IRFI 042 (20 mg/kg i.p.), a lipid peroxidation inhibitor, or its vehicle (NaCl 0.9% DMSO 10% 1 ml/kg i.p.) 30 min before KA administration. A first set of animals was sacrificed 6 h after KA injection to measure malondialdehyde (MDA) content, glutathione-reduced (GSH) levels and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the hippocampus. A second set of animals was sacrificed 48 h after KA administration for histological analysis. All animals were observed for monitoring the behavioral sequelae and for evaluating latency of convulsions. Sham brain injury rats were used as controls. Intraperitoneal administration of IRFI 042 significantly decreased brain MDA (cortex: KA + vehicle = 0.285 +/- 0.04 nmol/mg protein; KA + IRFI 042 = 0.156 +/- 0.02 nmol/mg protein, P < 0.005; hippocampus: KA + vehicle = 0.350 +/- 0.03 nmol/mg protein; KA + IRFI 042 = 0.17 +/- 0.04 nmol/mg protein, P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 7.81 +/- 1 micromol/g protein; KA + IRFI 042 = 12.1 +/- 1 micromol/g protein; P < 0.005) and hippocampus (KA + vehicle = 5 +/- 0.8 micromol/g protein; KA + IRFI 042 = 9.4 +/- 1.8 micromol/g protein; P < 0.005), reduced both brain IL-1beta mRNA expression and oedema, and increased latency of convulsions. Histological analysis showed a reduction of cell damage in IRFI 042-treated samples. The present data indicate that lipid peroxidation inhibition reduces IL-1beta gene expression and protects against kainic acid-induced brain damage.

Topics: Animals; Behavior, Animal; Benzofurans; Brain Edema; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Glutathione; Hippocampus; Interleukin-1; Kainic Acid; Lipid Peroxidation; Male; Malondialdehyde; Nerve Degeneration; Neurotoxins; Oxidative Stress; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

Opioids are involved in the development of epileptic seizures. Recently, interest has been focused on the role of the kappa-opioid receptor agonists as novel approaches to the treatment of epilepsy. In the present study we investigated the effects of the kappa-opioid receptor agonist enadoline (Ena) on pentylenetetrazol (PTZ) induced seizures, PTZ kindling, shuttle-box performance and hippocampal neuromorphology. Ena injected i.c.v. in doses of 1 and 10 nmol did not affect acute PTZ seizures. In the course of PTZ kindling development, co-treatment (1 nmol) with the kappa-opioid receptor agonist suppressed seizure strength. Eight days after kindling completion the animals received a challenge dose of PTZ. In reaction to challenge, kindled animals which were pretreated with Ena reached significantly lower seizure scores. Kindling resulted in diminished shuttle-box performance. Learning performance in kindled animals pretreated with Ena was not normalised. Kindling resulted in increased glutamate binding. Interestingly, in comparison with the saline/saline group, neither in the Ena/saline nor in the Ena/PTZ treated groups changes in glutamate binding were found. That means that Ena prevented the increase in glutamate binding in the kindled group. In kindled animals significant cell loss in CA1 of the dorsal hippocampus was found and this was efficaciously counteracted by Ena. However, Ena alone did induce similar cell loss compared to kindled animals. It is hypothesised that the effects of enadoline are mainly due to interferences with glutamatergic systems.

Topics: Animals; Benzofurans; Convulsants; Glutamic Acid; Hippocampus; Kindling, Neurologic; Learning; Male; Pentylenetetrazole; Pyrrolidines; Rats; Rats, Wistar; Seizures

The selective kappa-opioid receptor agonist CI-977, stereoselectively antagonised clonic seizures induced by slow i.v. infusion of N-methyl-DL-aspartate in the mouse. It was found to be more efficacious and 10-fold more potent than the competitive N-methyl-D-aspartic acid receptor antagonist CPP (3-(+/-)-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid). The anticonvulsant action of CI-977 was antagonised by norbinaltorphimine indicating a specific interaction with the kappa-receptor. The effect of CI-977 but not that of CPP was also antagonised by the glycine/NMDA receptor agonist D-serine. These results provide evidence for a possible interaction between the kappa-receptor and the glycine/NMDA receptor.

Topics: Animals; Anticonvulsants; Benzofurans; Dizocilpine Maleate; In Vitro Techniques; Mice; Mice, Inbred Strains; Naltrexone; Piperazines; Pyrrolidines; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Stereoisomerism

Conantokin-T, a 21-amino acid peptide which induces sleep-like symptoms in young mice was purified from the venom of the fish-hunting cone snail, Conus tulipa. The amino acid sequence of the peptide was determined and verified by chemical synthesis. The peptide has 4 residues of the modified amino acid, gamma-carboxyglutamate (Gla). The sequence of the peptide is: Gly-Glu-Gla-Gla-Tyr-Gln-Lys-Met-Leu-Gla-Asn-Leu-Arg-Gla-Ala-Glu-Val-Lys- Lys-Asn-Ala-NH2. Conantokin-T inhibits N-methyl-D-aspartate (NMDA) receptor-mediated calcium influx in central nervous system neurons. This observation suggests that like conantokin-G (a homologous Conus peptide with recently identified NMDA antagonist activity) conantokin-T has NMDA antagonist activity. A sequence comparison of conantokins-T and -G identifies the 4 Gla residues and the N-terminal dipeptide sequence as potential key elements for the biological activity of this peptide.

Topics: 1-Carboxyglutamic Acid; Amino Acid Sequence; Animals; Aspartic Acid; Benzofurans; Calcium; Cerebellum; Chromatography, Gel; Conotoxins; Fluorescent Dyes; Fura-2; Intercellular Signaling Peptides and Proteins; Mass Spectrometry; Mice; Molecular Sequence Data; Mollusk Venoms; N-Methylaspartate; Neurons; Peptides; Rats; Seizures; Sequence Homology, Nucleic Acid; Snails

Topics: Aged; Amiodarone; Ataxia; Benzofurans; Drug Interactions; Humans; Male; Myocardial Infarction; Phenytoin; Seizures

4-(Dimethylamino)- and 4-(methylamino)-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] derivatives were prepared as analogues of previously reported 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Metalation of benzanilide with n-butyllithium, addition of 4-(dimethylamino)cyclohexanone, and acidification afforded a mixture of cis- and trans-4-(dimethylamino)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-ones (1a,b), which were separated by fractional crystallization. Addition of aryllithium or aryl Grignard reagents to 1a,b and formic acid reduction afforded cis- and trans-4-(dimethylamino)-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofurans] 3a-f, which were converted to secondary amine analogues 5a-e. Tentative stereochemical assignments are based on chemical arguments and are supported by 13C NMR chemical shift data. Marked inhibition of tetrabenazine-induced ptosis is a property of most antidepressants, and significant antitetrabenazine activity is observed for several of these compounds. Optimal antitetrabenazine activity is associated with the cis-3'-phenyl series, and the cis secondary amine 5a is approximately twice as potent as the cis tertiary amine 3a. The various compounds are relatively weak with respect to potentiation of L-5-hydroxytryptophan-induced seizures.

Topics: Animals; Antidepressive Agents; Benzofurans; Chemical Phenomena; Chemistry; Drug Synergism; Magnetic Resonance Spectroscopy; Male; Rats; Seizures; Spiro Compounds; Stereoisomerism; Tetrabenazine

It was found previously that 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THbetaC) increased brain concentration of the neurotransmitter serotonin (5-HT) and decreased the concentration of its metabolite 5-hydroxyindole acetic acid (5-HIAA) at the same time the compound attenuated audiogenic seizures (AGS) in DBA/2J mice. In the present study we determined the time-course and dose-response effects of 6-MeO-THbetaC for blockade of AGS. Drugs sharing common effects with 6-MeO-THbetaC were also tested. At a dose of 100 mg/kg, 6-MeO-THbetaC blocked AGS between 10 min and 12 hr after injection, with maximal inhibition at 1 hr at which time a dose-related decrease in AGS was also demonstrated. All of the drugs tested which blocked AGS, including 6-MeO-THbetaC, THbetaC, 5-Hydroxytryptophan, chlorimipramine and pargyline, have biochemical similarities suggesting that facilitating serotonin function may be responsible for seizure-attenuating effects.

Topics: 5-Hydroxytryptophan; Acoustic Stimulation; Animals; Benzofurans; Carbolines; Citalopram; Clomipramine; Clorgyline; Fluoxetine; Harmine; Indoles; Methoxydimethyltryptamines; Mice; Mice, Inbred DBA; N,N-Dimethyltryptamine; Pargyline; Propylamines; Quipazine; Seizures; Selegiline

Nisoxetine and desipramine (inhibitors of norepinephrine reuptake) each exerted a suppressant effect on spinal cord seizures by decreasing the duration of tonic extension. In addition, desipramine increased the duration of tonic flexion and nisoxetine decreased the total duration of seizure. In contrast, citalopram (an inhibitor of 5-hydroxytryptamine reuptake) did not affect any of these seizure components. These observations support the concept that spinal cord noradrenergic, but not 5-hydroxytryptaminergic neurons act as attenuators of convulsive activity.

Topics: Animals; Benzofurans; Citalopram; Desipramine; Electric Stimulation; Female; Fluoxetine; Norepinephrine; Propylamines; Rats; Seizures; Serotonin Antagonists; Spinal Cord

Topics: Amino Acids; Ammonia; Animals; Benzofurans; Brain; Central Nervous System Stimulants; Chromatography, Paper; Electric Stimulation; Glutamates; Glutamine; Ketoglutaric Acids; Picrotoxin; Pyruvates; Rats; Seizures