Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that 1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (3) possess marked anticonvulsant properties and antagonize seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) in analogy to the structurally related 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA/kainate receptor antagonist. We now report the synthesis of 3-(N-alkylcarbamoyl)-1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (4a-h) and 1-aryl-3, 5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepine-4-thiones (5a-c). The activity of all compounds, intraperitoneally (ip) injected, was evaluated against audiogenic seizures in DBA/2 mice and against seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in Swiss mice. Some of the new compounds 4 and 5 showed remarkable anticonvulsant activity, and their toxicity, as evidenced by the rotarod test, is lower than that of 1. The time course of anticonvulsant activity of derivatives 4b and 5b,c was studied and compared to that of 1 and 3b,c. Compounds 4a,b and 5a-c antagonize seizures induced by AMPA and kainate (KA) and their anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 3c, 4b, and 5c to antagonize KA-evoked currents in primary cultures of granule neurons was tested and compared with that of the parent compounds 1 and 1-(4-aminophenyl)-3, 4-dihydro-4-methyl-3-methylcarbamoyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine (2, GYKI 53655).
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PMID:Synthesis and anticonvulsant activity of novel and potent 2,3-benzodiazepine AMPA/kainate receptor antagonists. 1054 85

The effect of GYKI 52466, a selective, non-competitive antagonist of the AMPA glutamate receptor subtype was investigated on the development, expression and propagation of 3-aminopyridine-induced cortical ictal activity, both in the primary and secondary focus. In one group of animals GYKI 52466 was administered intraperitoneally, 20 minutes prior to the local application of the convulsant the surface of the cortex of anaesthetized rats. Control animals were injected by physiological solution. Different parameters of electrographic ictal discharges were measured under the influence of the antagonist and compared to control values. The results demonstrate that GYKI 52466 exerts anticonvulsive effects on both the induction and the expression of primary and secondary electrical ictal activity, by delaying the onset of the first ictal period, shortening the duration of ictal activity and decreasing the amplitudes of epileptiform discharges. However, the seizure propagation was not influenced significantly. It is suggested that the initiation, maintenance and the propagation of spontaneous seizures may be controlled by separate mechanisms and that changes can occur in one of the procedures without parallel changes in others. The observations of the present study extend those reported previously by others, namely that activation of non-NMDA receptors is significantly involved in the initiation and maintenance of cortical epileptiform activity.
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PMID:The anticonvulsive effect of non-NMDA antagonist GYKI 52466 on 3-aminopyridine-induced primary and secondary cortical ictal activity in rat. 1057 45

The effect of GYKI-52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine), a selective antagonist of AMPA receptor was investigated on the generation and manifestation of 4-aminopyridine-induced cortical epileptiform activity. In vivo experiments were carried out on pentobarbital-anaesthetised adult rats. Ictal epileptiform activity was induced by local application of 4-aminopyridine (4-Ap) to the surface of somatosensory cortex. In one group of animals, GYKI 52466 was administered intraperitoneally before 4-Ap application, in another group, the already active primary focus was treated locally by GYKI 52466. Different parameters of epileptic activity were measured and compared in GYKI 52466-treated and control animals. The results demonstrate that GYKI 52466 exerts anticonvulsive effects on both the induction and the expression of epileptiform activity, by delaying the onset of the first ictal event, decreasing the numbers and duration of ictal periods, as well as the amplitudes of epileptiform discharges both in the primary and mirror foci. However, seizure propagation to other cortical areas seemed to be facilitated. The anticonvulsive effect of GYKI 52466 was stronger in pretreatment than in treatment of ongoing epileptiform activity. As a conclusion, it is supposed that AMPA receptors are probably more dominant in the induction of epileptiform activity than in the maintenance of it, mainly through the activation of corticothalamo-cortical networks. It is also supposed that the cortical inhibition which blocks the propagation of epileptiform process might be activated mainly through non-N-methyl-D-aspartate receptors.
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PMID:Anticonvulsive effect of AMPA receptor antagonist GYKI 52466 on 4-aminopyridine-induced cortical ictal activity in rat. 1071 16

Our previous studies have shown a local decrease in glutamate and aspartate levels during seizures, induced by picrotoxin microdialysis in the hippocampus of chronic freely moving rats. In this paper, we study the effect of continuous hippocampal microperfusion of the NMDA, AMPA and kainate glutamate receptor inhibitors 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801); 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466). We also examine the action of L(-)-threo-3-hydroxyaspartic acid (THA), a glutamate and aspartate reuptake blocker, on the modification of extracellular glutamate and aspartate levels induced by picrotoxin, using the microdialysis method in freely moving rats. We found that changes in extracellular hippocampal concentrations in both amino acids are prevented by NMDA, AMPA and kainate receptor inhibitors. Seizures elicited under DNQX also induce a transient increase in aspartate extracellular levels coincident with seizure time. L(-)-threo-3-hydroxyaspartic acid increased the basal extracellular concentrations of both amino acids, but did not prevent the seizure-related decrease. Our results suggest that glutamate, the major neurotransmitter at the synaptic level, may also play an important role in non-synaptic transmission during seizures.
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PMID:Effect of ionotropic glutamate receptors antagonists on the modifications in extracellular glutamate and aspartate levels during picrotoxin seizures: a microdialysis study in freely moving rats. 1082 78

In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.
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PMID:Synthesis and anticonvulsant activity of novel and potent 6,7-methylenedioxyphthalazin-1(2H)-ones. 1095 93

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.
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PMID:New non competitive AMPA antagonists. 1100 58

The aim of this study was to evaluate the contribution of ionotropic glutamate receptors to kindled seizure-evoked somatostatin release in the hippocampus, using a microdialysis approach. Basal and amygdala stimulation-evoked somatostatin-like immunoreactivity (-LI) release was significantly greater in kindled compared to naive rats. In naive rats, neither hippocampal perfusion with the selective AMPA/kainate receptor antagonist GYKI 52466 nor with the selective NMDA receptor antagonist MK-801 affected behavior, EEG, or somatostatin-LI release. In kindled rats, GYKI 52466 was still devoid of any effect, while MK-801 significantly decreased stimulus-evoked (but not basal) somatostatin-LI efflux. MK-801 produced identical effects when injected i.p. This study provides the first direct evidence that kindled seizure-evoked somatostatin release in the hippocampus is partly NMDA receptor dependent.
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PMID:Kindled seizure-evoked somatostatin release in the hippocampus: inhibition by MK-801. 1104 50

The role of AMPA and GluR5-containing kainate receptors in the development and expression of amygdala kindling was examined using the selective 2,3-benzodiazepine AMPA receptor antagonist GYKI 52466 [(1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine] and the decahydroisoquinoline mixed AMPA receptor and GluR5 kainate receptor antagonist LY293558 {(3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline- 3-carboxy lic acid)}. Administration of GYKI 52466 (5-40 mg/kg, intraperitoneally) and LY293558 (10-40 mg/kg, intraperitoneally) prior to daily kindling stimulation in mice produced a dose-dependent suppression of the rate of development of behavioral kindled seizure activity and reduced the duration of the stimulation-induced electrographic afterdischarge. In drug-free stimulation sessions after the initial drug-treatment sessions, there was an acceleration in the rate of kindling development compared with the rate during the preceding drug-administration period; the "rebound" rate was also greater than the kindling rate in saline-treated control animals. In fully kindled animals, both GYKI 52466 and LY293558 produced a dose-dependent suppression of evoked seizures (ED(50), 19.3 and 16.7 mg/kg, respectively). Although AMPA receptors appear to be critical to the expression of kindled seizures, since kindling development progressed despite the suppression of behavioral seizure activity, AMPA receptors are less important to the kindling process. LY293558 was modestly less effective at suppressing behavioral seizures during kindling and was not superior to GYKI 52466 in retarding the overall extent of kindling development, indicating that GluR5 kainate receptors do not contribute to epileptogenesis in this model.
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PMID:Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse. 1107 68

The 2,3-benzodiazepine GYKI 52466, administered intracerebrally or systemically, was assessed for its ability to protect against the neuronal death in the brain caused by intra-hippocampal injections of the non-N-methyl-D-aspartate (NMDA) receptor agonists, kainate and L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). In contrast to a previous report, a low intra-hippocampal dose of GYKI 52466 (25 nmol) did not protect against kainate toxicity. In order to achieve higher doses of GYKI 52466, solubilization in 2-hydroxypropyl-beta-cyclodextrin was used, and limited protection against AMPA, but not kainate toxicity was found. There was a commensurate reduction in seizure-related neuronal loss in the limbic regions of the brain. When diazepam was used to prevent seizures, GYKI 52466 had no effect on hippocampal neuronal loss caused by the direct toxicity of AMPA and kainate on hippocampal neurons. Systemic administration of GYKI 52466 had only a minimal effect on preventing neuronal death caused by AMPA. In vivo, GYKI 52466 is only weakly effective as a neuroprotective agent.
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PMID:In vivo, the direct and seizure-induced neuronal cytotoxicity of kainate and AMPA is modified by the non-competitive antagonist, GYKI 52466. 1116 69

GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine], a non-competitive AMPA [alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate] and kainate receptor antagonist and its two analogues, GYKI 53405 [1-(4-aminophenyl)-3-acetyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] and GYKI 53655 [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] were investigated in two seizure models and in MgCl2 induced global cerebral ischaemia, as an acute neuroprotective model. The ED(50) values of GYKI 52466 for suppression of the tonic and clonic phases of sound-induced seizures were 3.6 and 4.3 mg/kg, respectively. The corresponding data for GYKI 53405 were 1.1 and 3.1 mg/kg, while ED(50) values of GYKI 53655 were 1.3 and 2.0 mg/kg, respectively. The inhibition of seizure evoked by maximal electroshock was also found to be remarkable: the ED(50) values of GYKI 52466 and its two analogues were 6.9, 2.6, and 2.2 mg/kg, respectively. All compounds prolonged the survival times in MgCl2 induced global cerebral ischaemia test in a dose-dependent fashion, with PD(50) (dose of 50% prolongation) values of 24.1, 8.3, and 8.2 mg/kg intraperitoneal, respectively. In audiogenic seizure model the duration of anticonvulsant action of 10 mg/kg GYKI 52466 and 5 mg/kg GYKI 53405, GYKI 53655 were examined, too. The effect of GYKI 52466 decreased to 50% after 2 h, while the analogues showed more than 80% seizure suppression 3 h after treatment. After 6 h the effect of GYKI 53655 decreased to zero, while the effect of GYKI 52466, remained on the 50% level.
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PMID:Comparison of anticonvulsive and acute neuroprotective activity of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655. 1148 46


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