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)

In this study, we evaluated whether beta-adrenoceptor antagonists may modify the protective efficacy of dizocilpine (MK-801), a NMDA receptor antagonist, and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a non-NMDA (AMPA/kainate) receptor antagonist, against maximal electroshock-induced seizures in mice. Propranolol, acebutolol, metoprolol and atenolol were used in doses that did not alter the electroconvulsive threshold. Propranolol potentiated the anticonvulsant activity of MK-801 and GYKI 52466, significantly lowering their ED(50) values from 0.38 and 15.0 to 0.15 (P<0.001) and 8.4 mg/kg (P<0.001), respectively. Similarly, metoprolol lowered the ED(50) of MK-801 and GYKI 52466 from 0.38 and 15.0 to 0.17 (P<0.05) and 11.2 mg/kg (P<0.05). Acebutolol enhanced the protective action of GYKI 52466, lowering its ED(50) value from 15.0 to 12.2 mg/kg (P<0.05), but not that of MK-801. Atenolol, not penetrating the blood-brain barrier, did not affect the anticonvulsive efficacy of MK-801 and GYKI 52466. In conclusion, beta-adrenoceptor antagonists may act synergistically with excitatory amino acid receptor antagonists to inhibit generalised tonic-clonic seizures.
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PMID:beta-Adrenoceptor blockade enhances the anticonvulsant effect of glutamate receptor antagonists against maximal electroshock. 1172 27

GYKI 52466 [1,4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine], a non-competitive AMPA/kainate receptor antagonist, administered i.p. at the dose of 5 mg/kg, exerted a significant anticonvulsant effect, as it decreased seizure and afterdischarge durations, being ineffective at 2 mg/kg. Subsequently, GYKI 52466 (2 mg/kg) was combined with antiepileptic drugs at doses ineffective in fully kindled rats. Co-administration of GYKI 52466 with clonazepam (0.003 mg/kg i.p.) resulted in a significant reduction of seizure severity (by 20%), seizure duration (by 31%) and afterdischarge duration (by 24%). Co-injection of GYKI 52466 with valproate (75 mg/kg i.p.) also resulted in the respective 8%, 16%, and 17% reductions of the three studied seizure parameters. No protection was observed when GYKI 52466 was co-administered with carbamazepine (20 mg/kg i.p.), phenobarbital (20 mg/kg i.p.), or diphenylhydantoin (40 mg/kg i.p.). Combinations of GYKI 524662 with antiepileptic drugs did not cause any significant motor (rotarod test) or long-term memory deficits (passive avoidance task). Only GYKI 52466 administered alone at 5 mg/kg, caused a significant impairment of retention in amygdala-kindled rats. The interaction at a pharmacokinetic level, at least in case of the combination of GYKI 52466 with valproate, can be excluded because GYKI 52466 did not interfere with the free plasma level of valproate. These results give further support to the idea of a potential clinical benefits of the combined treatment of AMPA/kainate receptor antagonists with some antiepileptic drugs.
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PMID:Interaction of GYKI 52466, a selective non-competitive antagonist of AMPA/kainate receptors, with conventional antiepileptic drugs in amygdala-kindled seizures in rats. 1178 48

In this paper we describe the synthesis of a series of novel 2-[(4-alkylsemicarbazono)-(4-aminophenyl)-methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters (10-19) carrying an alkylsemicarbazono moiety at a benzylic site. The influence of this group on the biological activity was evaluated by testing the corresponding derivatives 20-22 in which the 4-alkylsemicarbazono moiety was removed (compound 20) or its alkylureido portion shifted at position 1 (compounds 21-22). Furthermore, the involvement of the 4-aminobenzyl moiety in the anticonvulsant activity was evaluated by testing derivative 23. The anticonvulsant activity of all compounds was assayed against audiogenic seizures induced in DBA/2 mice. Within this series of derivatives, 2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester (10) proved to be the most active compound. It displayed a potency 5-fold higher than that shown by 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonist. Compound 10 was also effective in suppressing seizures induced in Swiss mice by maximal electroshock (MES) or pentylenetetrazole (PTZ). Furthermore, it antagonized in vivo seizures induced by icv administration of AMPA or kainate (KA). Using the patch-clamp technique in primary cultures of granule neurons we tested compounds 10 and 21 for their ability to modulate currents evoked by KA and 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid (ATPA). These two derivatives reduced KA and ATPA currents to a larger extent than that shown by reference compound 1. Compounds 10 and 21 were also able to reduce neuronal cell death induced by the application of KA (100 microM).
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PMID:Novel potent AMPA/kainate receptor antagonists: synthesis and anticonvulsant activity of a series of 2-[(4-alkylsemicarbazono)-(4-amino-phenyl)methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters. 1223 23

2,3-Benzodiazepines represent a family of specific, noncompetitive AMPA receptor antagonists with anticonvulsant and neuroprotective properties. In this study, the antiexcitotoxic potency of the clinical antiepileptic drug candidate, talampanel (4 x 2 mg/kg), and that of two related 2,3-benzodiazepines, 5-(4-aminophenyl)-8-methyl-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (GYKI 52466) (4 x 10 mg/kg) and GYKI 53784 (4 x 2 mg/kg), was investigated in 7-day-old rats. The AMPA antagonists were applied in four consecutive i.p. injections at 1-h intervals, the first dosage was given shortly after the intrastriatal injection of (S)-alpha-amino-3-hydroxy-5,7-methylisoxazole-4-propionic acid (AMPA) (2.5 nmol). All tested compounds protected animals from brain damage induced by AMPA as assessed 5 days later by using a tissue volume determination method based on computer-aided serial section reconstruction. GYKI 53784 (56.1 +/- 5.0% protection) and talampanel (42.5 +/- 5.3% protection) were more potent neuroprotective agents than GYKI 52466 (21.8 +/- 2.8% protection). Furthermore, the three compounds attenuated the unilateral AMPA injection-induced turning behavior and seizure-like events.Our present findings are in agreement with those of other investigators who found talampanel neuroprotective in various in vivo experimental models. These data indicate that besides being a promising antiepileptic drug candidate talampanel may have a value in the pharmacotherapy of acute and chronic neurodegenerative diseases, including perinatal ischemia/hypoxia-induced brain injuries, as well.
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PMID:Protective effect of the antiepileptic drug candidate talampanel against AMPA-induced striatal neurotoxicity in neonatal rats. 1237 46

A series of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines was synthesized starting from the corresponding bicyclic 1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (CFMs), previously described as noncompetitive AMPA-type glutamate receptor antagonists, more potent than GYKI 52466. New synthesized compounds proved to be able to protect against seizures induced by means of auditory stimulation in DBA/2 mice and compound 8f the most active of the series showed anticonvulsant properties comparable to GYKI 52466.
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PMID:Synthesis and pharmacological properties of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines. 1238 27

Glutamatergic ionotropic and metabotropic receptor modulators have been shown to produce anticonvulsant activity in a number of animal seizure models, e.g. maximal electroshock (MES) and DBA/2 sensory-induced seizures. The 6 Hz model of partial seizures is an alternative low frequency, long duration stimulation paradigm resulting in a seizure characterized by jaw and forelimb clonus, immobility, and an elevated tail (Straub-tail). A unique aspect of this model is that it is the only acute electrically-induced seizure model in which levetiracetam has displayed anticonvulsant activity, suggesting that the 6 Hz seizure model may be useful in identifying compounds with unique anticonvulsant profiles. The purpose of the present study was to examine the role of glutamate receptors in the MES and 6 Hz seizure models using a number of NMDA, AMPA/KA, and mGlu receptor modulators. The pharmacological profile of the 6 Hz seizure model was compared to that of the MES model using eight ionotropic glutamate receptor antagonists and eight mGlu receptor modulators. The ionotropic receptor antagonists MK-801, LY235959, NBQX, LY293558, GYKI 52466, LY300168, and LY377770 produced complete protection from tonic extension in the MES model. Furthermore, the noncompetitive mGlu1 (LY456236) and mGlu5 (MPEP) metabotropic receptor antagonists and the mGlu8 metabotropic receptor agonist (PPG) were also effective in the MES model whereas the competitive mGlu1 (LY367385) receptor antagonist, the mGlu2/3 (LY379268 and LY389795) and Group III (L-AP4) metabotropic receptor agonists were ineffective. In contrast, all of the compounds tested, produced dose-dependent protection in the 6 Hz model with an increase in potency as compared to the MES model. The largest protective indices (P.I.=TD50/ED50) observed were associated with the iGlu5 antagonist LY382884 and the mGlu2/3 receptor agonists LY379268 and LY389795 (P.I.=>14, 14, and 4.9, respectively) in the 6 Hz model. The results from the present study support the continued search for glutamate receptor modulators as potential antiepileptic agents. Furthermore these results illustrate the importance of using several different animal seizure models in the search for novel AEDs and the potential utility of the 6 Hz seizure model in identifying novel AEDs.
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PMID:Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models. 1452 50

A series of new 3-alkylcarbamoyl-1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones was synthesized starting from the corresponding 3-N-unsubstituted derivatives, previously described as noncompetitive AMPA-type glutamate receptor antagonists. The new compounds proved to protect against seizures induced by means of auditory stimulation in DBA/2 mice and some of them showed anticonvulsant properties comparable or better than those of GYKI 52466, the prototype of 2,3-benzodiazepine noncompetitive AMPA receptor antagonists.
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PMID:Synthesis and anticonvulsant activity of N-3 substituted 2,3-benzodiazepines. 1512 Mar 14

A series of 1-substituted 2-[(4-aryl)-methyl]-4,5-methylenedioxybenzene derivatives (13-25), structurally related to model compound 5 (2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester), were synthesized and tested as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds possess anticonvulsant properties lower than those of prototype 5 but, in some instances, comparable to that of GYKI 52466, a well-known noncompetitive AMPA receptor antagonist.
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PMID:Design of 1-substituted 2-arylmethyl-4,5-methylenedioxybenzene derivatives as antiseizure agents. 1518 56

A series of 2-semicarbazonomethyl-4,5-methylenedioxyphenylacetic acids (12-19) were synthesized and tested as anticonvulsant agents in DBA/2 mice against sound-induced seizures and the results compared to those previously reported for the corresponding methyl esters (4-11). The new compounds possess anticonvulsant properties lower than those of 4-11, but, in some instances, comparable to that of GYKI 52466, a well-known noncompetitive AMPA receptor antagonist.
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PMID:Synthesis of 2-semicarbazonomethyl-4,5-methylenedioxyphenylacetic acids as anticonvulsant agents. 1578 42

Hypoxia is the most common cause of perinatal seizures and can be refractory to conventional anticonvulsant drugs, suggesting an age-specific form of epileptogenesis. A model of hypoxia-induced seizures in immature rats reveals that seizures result in immediate activation of the phosphatase calcineurin (CaN) in area CA1 of hippocampus. After seizures, CA1 pyramidal neurons exhibit a downregulation of GABA(A) receptor (GABA(A)R)-mediated inhibition that was reversed by CaN inhibitors. CaN activation appears to be dependent on seizure-induced activation of Ca2+-permeable AMPA receptors (AMPARs), because the upregulation of CaN activation and GABA(A)R inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABA(A)R beta2/3 subunit protein was dephosphorylated at 1 h after seizures, suggesting this subunit as a possible substrate of CaN in this model. Finally, in vivo administration of the CaN inhibitor FK-506 significantly suppressed hypoxic seizures, and posttreatment with NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline) or FK-506 blocked the hypoxic seizure-induced increase in CaN expression. These data suggest that Ca2+-permeable AMPARs and CaN regulate inhibitory synaptic transmission in a novel plasticity pathway that may play a role in epileptogenesis in the immature brain.
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PMID:AMPA/kainate receptor-mediated downregulation of GABAergic synaptic transmission by calcineurin after seizures in the developing rat brain. 1637 59


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