Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:4432-31-9 (MES)
 1,294 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study focused on the evaluation of anticonvulsant properties of isonicotinic acid benzylamide (iso-Nic-BZA) in numerous experimental seizure models (maximal electroshock [MES]-, bicuculline [BIC]-, pentylenetetrazole [PTZ]-, pilocarpine [PILO]-, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]-, kainic acid [KA]- and N-methyl-d-aspartic acid [NMDA]-induced seizures). Moreover, acute adverse-effect profile of the agent with respect to impairment of motor coordination was assessed in animals subjected to the chimney test. The evaluation of time-course and dose-response relationships for iso-Nic-BZA provided evidence that the compound produced the peak to maximum antielectroshock action and acute adverse effects at 5min after its systemic (i.p.) administration. Iso-Nic-BZA exerted a clear-cut anticonvulsant action against maximal electroshock-induced seizures in mice and its ED(50) value was 70.6 (56.4-88.4)mg/kg. The assessment of acute adverse effects in the chimney test revealed that the agent produced acute neurotoxic effects and its TD(50) value was 135.6 (108.8-169.0)mg/kg. Additionally, iso-Nic-BZA showed the anticonvulsant activity in numerous chemically-induced seizures (AMPA-, BIC-, KA-, and PTZ-evoked clonic convulsions), remaining virtually ineffective (at doses up to 200mg/kg) in PILO- and NMDA-induced seizures in mice. Based on this study, one can conclude that iso-Nic-BZA due to the short time to peak of its maximum anticonvulsant effects (5min after its i.p. administration), deserves more attention as a potential antiepileptic drug for patients in status epilepticus.
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PMID:Characterization of the anticonvulsant profile of isonicotinic acid benzylamide in various experimental seizure models in mice. 1754 62

Glutamate uptake into synaptic vesicles is a vital step for glutamatergic neurotransmission. Quinolinic acid (QA) is an endogenous glutamate analog that may be involved in the etiology of epilepsy and is related to disturbances on glutamate release and uptake. Guanine-based purines (GBPs) guanosine 5'-monophosphate (GMP and guanosine) have been shown to exert anticonvulsant effects against QA-induced seizures. The aims of this study were to investigate the effects of in vivo administration of several convulsant agents on glutamate uptake into synaptic vesicles and investigate the role of MK-801, guanosine or GMP (anticonvulsants) on glutamate uptake into synaptic vesicles from rats presenting QA-induced seizures. Animals were treated with vehicle (saline 0.9%), QA 239.2 nmoles, kainate 30 mg/kg, picrotoxin 6 mg/kg, PTZ (pentylenetetrazole) 60 mg/kg, caffeine 150 mg/kg or MES (maximal transcorneal electroshock) 80 mA. All convulsant agents induced seizures in 80-100% of animals, but only QA stimulated glutamate uptake into synaptic vesicle. Guanosine or GMP prevented seizures induced by QA (up to 52% of protection), an effect similar to the NMDA antagonist MK-801 (60% of protection). Both GBPs and MK-801 prevented QA-induced glutamate uptake stimulation. This study provided additional evidence on the role of QA and GBPs on glutamatergic system in rat brain, and point to new perspectives on seizures treatment.
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PMID:Quinolinic acid-induced seizures stimulate glutamate uptake into synaptic vesicles from rat brain: effects prevented by guanine-based purines. 1768 41

GABA is the major inhibitory neurotransmitter in the central nervous system, and its concentration in the brain in associated with a variety of neurological disorders, including seizures, convulsions, and epilepsy. The concentration of GABA is modulated by the pyridoxal-5'-phosphate (PLP)-dependent enzymes, GAD and GABA-T. In this study, we generated pyridoxyl-gamma-aminobutyrate (PL-GABA), a novel GABA analogue composed of pyridoxyl and GABA, and have also characterized its anticonvulsant and pharmacological functions in vitro. The results of biodistribution studies revealed that PL-GABA is capable of crossing the blood-brain barrier. PL-GABA evidenced anticonvulsant activity in a wide range of epilepsy models, some of which were electrically-based (MES seizures) and some chemically-based (bicuculline, pentylenetetrazol (PTZ), picrotoxine, 3-mercaptopropionic acid). Following a timed subcutaneous administration of PTZ to mice, PL-GABA consistently increased the latencies to first twitch and clonus. In addition, PL-GABA displayed no signs of tolerance after subchronic (10 day) treatment. PL-GABA appears to exert its anticonvulsant effects by influencing seizure spread and by raising the seizure threshold. Therefore, our results indicate that PL-GABA exerts a broad-spectrum anticonvulsant effect, and identify the potential for reduced PL-GABA tolerance as an additional positive profile for novel antiepileptic drugs.
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PMID:Anticonvulsant characteristics of pyridoxyl-gamma-aminobutyrate, PL-GABA. 1834 62

Sulfamides are promising functions for the design of new antiepileptic drugs ( Bioorg. Med. Chem. 2007, 15, 1556-1567; 5604-5614 ). Following previous research in this line, a set of amino acid-derived sulfamides has been designed, synthesized, and tested as new anticonvulsant compounds. The experimental data confirmed the ability of some of the structures to suppress the convulsions originated by the electrical seizure (MES test) at low doses (100 mg/kg).
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PMID:Synthesis and anticonvulsant activity of amino acid-derived sulfamides. 1924 53

The synthesis and characterization of the binary complex of copper(II) with the antiepileptic drug valproic acid sodium salt (Valp) and the related ternary complex with 1,10-phenanthroline (phen) are reported, as well as the anticonvulsant properties of the latter. The characterization was carried out by means of elemental analyses, infrared (IR), UV-visible (UV-vis) spectrophotometry and Electron Paramagnetic Resonance (EPR). The X-ray crystal structure of the mononuclear complex bis(2-propylpentanoate)(1,10-phenanthroline)copper(II) [Cu(Valp)(2)phen] is showed for the first time. It crystallized in C2/c space group with unit cell dimensions of a = 14.939(1) A, b = 19.280(1) A, c = 9.726(1) A, beta = 97.27(2) degrees , V = 2778.8(4) A(3) and Z = 8. The carboxylates bond in an asymmetric chelating mode and the copper atom adopts a highly distorted octahedral coordination, characterized by the sum of the angles of 365.9 degrees around Cu(II) and its nearest atoms in the CuN(2)O(2) + O(2) chromophore instead of the expected 360 degrees for a basal square planar geometry found in most Cu(II) complexes. Molecules assemble three by three through slipped pi-pi stacking of the aromatic phen with respectively 3.519 and 3.527 A distances, in a head-to-tail arrangement. Studies of the anticonvulsant properties of this bioligand chelate evidenced its lack of efficacy in preventing MES-induced seizures. Interestingly, complex 4 protected mice against the Minimal Clonic seizures at doses that do not cause Rotorod toxicity, with an ED(50) documenting very potent anticonvulsant activity in this model of seizure, a particularly useful pharmacological profile of activity for the treatment of Petit Mal seizures.
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PMID:Synthesis, structural analysis and anticonvulsant activity of a ternary Cu(II) mononuclear complex containing 1,10-phenanthroline and the leading antiepileptic drug valproic acid. 1956 61

In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g., acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo neuroprotective activity, using the mouse maximal electroshock-induced seizure model (MES test). 7-Isopentenyloxycoumarin and (2E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic acid, administered ip at a dose of 300 mg/kg, suppressed MES-induced seizures in mice in a time- and dose-dependent manner.
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PMID:Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents. 1967 72

Various N-(5-chloro-6-substituted-benzothiazol-2-yl)-N'-(substituted phenyl)-[1,3,4]thiadiazole-2,5-diamines (5a-t) were designed and synthesized starting from substituted acetophenones. Structures of all the compounds were confirmed on the basis of spectral and elemental analyses. All the newly synthesized compounds were screened for their anticonvulsant activity and were compared with the standard drug phenytoin sodium. Interestingly, all the compounds showed protections against seizures in the range 50-100% indicative of the promising nature of the compounds against seizure spread. Compounds 5b and 5c showed complete protection against MES induced seizures.
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PMID:Synthesis and preliminary screening of benzothiazol-2-yl thiadiazole derivatives for anticonvulsant activity. 1991 33

A series of 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives were synthesized. In initial screening and quantitative evaluation, compound 2r was among the most active agents, exhibiting in the same time the lowest toxicity. In the anti-maximal electroshock test, it showed median effective dose (ED50) of 17.3 mg/kg and median toxicity dose (TD50) of 380.3 mg/kg, and the protective index (PI) of 22.0, which is much better than PI of the reference drugs. In a subsequent test, compound 2r had median hypnotic dose (HD50) of 746.6 mg/kg, thus demonstrating much better margin of safety compared to reference drugs. Compound 2r also showed oral activity against MES-induced seizures and lower oral neurotoxicity. For explanation of the putative mechanism of action, compound 2r was tested in chemical induced models.
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PMID:Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine. 2011 41

We have advanced a novel strategy to search for lacosamide ((R)-1) targets in the brain proteome where protein binding is expected to be modest. Our approach used lacosamide agents containing affinity bait (AB) and chemical reporter (CR) units. The affinity bait moiety is designed to irreversibly react with the target, and the CR group permits protein detection and capture. In this study, we report the preparation and evaluation of (R)-N-(4-azido)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-3) and show that this compound exhibits potent anticonvulsant activities in the MES seizure model in rodents. We compared the utility of (R)-3 with its isostere, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-2), in proteomic studies designed to identify potential (R)-1 targets. We showed that despite the two-fold improved anticonvulsant activity of (R)-3 compared with (R)-2, (R)-2 was superior in revealing potential binding targets in the mouse brain soluble proteome. The difference in these agents utility has been attributed to the reactivity of the affinity baits (i.e., (R)-2: aryl isothiocyanate moiety; (R)-3: photoactivated aryl azide intermediates) in the irreversible protein modification step, and we conclude that this factor is a critical determinant of successful target detection where ligand (drug) binding is modest. The utility of (R)-2 and (R)-3 in in situ proteome studies is explored.
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PMID:Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group. 2040 68

2,4(1H)-Diarylimidazoles have been previously shown to inhibit hNa(V)1.2 sodium (Na) channel currents. Since many of the clinically used anticonvulsants are known to inhibit Na channels as an important mechanism of their action, these compounds were tested in two acute rodent seizure models for anticonvulsant activity (MES and scMet) and for sedative and ataxic side effects. Compounds exhibiting antiepileptic activity were further tested to establish a dose response curve (ED(50)). The experimental data identified four compounds with anticonvulsant activity in the MES acute seizure rodent model (compound 10, ED(50)=61.7mg/kg; compound 13, ED(50)=46.8mg/kg, compound 17, ED(50)=129.5mg/kg and compound 20, ED(50)=136.7mg/kg). Protective indexes (PI=TD(50)/ED(50)) ranged from 2.1 (compound 10) to greater than 3.6 (compounds 13, 17 and 20). All four compounds were shown to inhibit hNa(V)1.2 in a dose dependant manner. Even if a correlation between sodium channel inhibition and anticonvulsant activity was unclear, these studies identify four Na channel antagonists with anticonvulsant activity, providing evidence that these derivatives could be potential drug candidates for development as safe, new and effective antiepileptic drugs (AEDs).
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PMID:Anticonvulsant activity of 2,4(1H)-diarylimidazoles in mice and rats acute seizure models. 2094 96


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