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)

The objective of this study was to determine whether electroconvulsions lead to excessive lipid peroxidation. The concentrations of the conjugated dienes (CD) and malonyl dialdehyde (MDA) in the homogenates of the brains after seizures induced with 25 mA current (MES) measured immediately after seizures were significantly higher in comparison with the control brains. There were no significant differences between control group and animals treated with multiple MES. Significant rise in CD concentrations was also observed at 1 h following MES. The results indicate that electroconvulsions may lead to the increased formation of lipid peroxidation products.
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PMID:Electroconvulsions elevate the levels of lipid peroxidation products in mice. 1259 41

Elucidation of the metabolism and pharmacology of 1,2,3-triazolines (TRs) led to the identification of the triazoline pharmacophore and the evolution of the aminoalkylpyridines (AAPs). The AAPs have no activity in the scMet test but are highly effective in the MES seizure test by the oral route. The AAPs bind to the sigma(1) receptor with low affinity, but high selectivity. They impair Glu release to the same extent as the triazolines and afforded a high degree of protection in the kindled rat. They show no affinity for the NMDA/PCP receptor sites; thus the toxic side effects of NMDA antagonists are absent in the sigma selective AAPs. Variations of the heterocyclic unit, the alkyl chain and the amino group in the AAP leads, indicated that the 4-pyridyl substituent along with a methyl (alkyl) group, and a 4-C1, 3-C1 or 3,4-C1(2) substitution on the N-phenyl group, afforded the most active compounds. Amino group modification by acylation did not improve activity. The hydrazone compounds were the most active. Although the AAPs are very effective in the MES and the kindling models of epilepsy, they showed only low to moderate activity in protecting neuronal cells in stroke-induced cerebral ischemia. In the case of the TR compounds, even the least effective TR afforded 47% protection from neuronal injury. It is not known at this point, whether activity in both the MES and scMet tests, which would imply a role for both Glu and GABA, is a prerequisite for antiischemic activity.
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PMID:Aminoalkylpyridines (AAPs), triazoline metabolite analogues, as anticonvulsants highly effective in the MES test. 1287 Oct 88

The synthesis and pharmacological evaluation of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones (4a--l, 5a--j) as potential anticonvulsant agents are described. The compounds were tested in vivo for the anticonvulsant activity. The compound which have maximum protection against MES induced seizures is 1-[3-(2-aminophenylamino)-2-hydroxypropyl)-1,2-dihydro-pyridazine-3,6-dione 4h (ED(50)=44.7 mg x kg(-1) i.p.) 1-[2-hydroxy-3-piperazin1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4c (ED(50)=72 mg x kg(-1) i.p.) and 1-[2-hydroxy-3-imidazol-1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4d (ED(50)=79 mg x kg(-1) i.p.) were also found to have maximum protection against MES induced seizures. Whereas all these compounds failed to protect the animals from subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met).
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PMID:Synthesis and anticonvulsant activity of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones. 1451 45

The present study will summarize our findings concerning the anticonvulsant properties of the Ca2+ channel blocker flunarizine in a variety of experimental models of epilepsy. Flunarizine exhibits anticonvulsant effects against tonic seizures induced by electroshock or various chemoconvulsants in mice, however, did not protect against pentylenetetrazol-induced clonic seizures. In the MES test, the efficacy of clinically established antiepileptics was increased by co-medication. In the rotarod test, a minimal "neurotoxic" dose (TD50) of 18.0 mg/kg intraperitoneally was determined. In models of complex partial seizures like the hippocampal stimulation and the amygdala kindling in rats, flunarizine showed only a moderate activity. Thus, it can be suggested that the anticonvulsant potency of flunarizine in various screening tests is lower than that of standard antiepileptics such as carbamazepine and phenytoin. Concerning the possible mode of action, whole-cell patch-clamp experiments with cultured neonatal rat cardiomyocytes showed that flunarizine depressed the fast inward Na+ current in a concentration- and frequency-dependent manner well comparable with the action of phenytoin. It is concluded that the use-dependent inhibition of voltage-dependent Na+ channels may essentially contribute to the anticonvulsant activity of flunarizine in models for generalized tonic-clonic seizures. The clinical efficacy as add-on therapy is critically discussed in view of the present data.
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PMID:Anticonvulsant profile of flunarizine and relation to Na(+) channel blocking effects. 1474 51

Ocimum gratissimum L. (Lamiaceae) and other species of the same genus are used as medicines to treat central nervous system (CNS) diseases, commonly encountered in warm regions of the world. The chemical composition of Ocimum gratissimum essential oil varies according to their chemotypes: timol, eugenol or geraniol. In this study, the essential oil type eugenol was extracted by hydrodistillation in each of the four seasons of the year. Activity upon CNS was evaluated in the open-field and rota-rod tests; sleeping time induced by sodium pentobarbital (PBS, 40 mg/kg, intra-peritoneally, i.p.) and anticonvulsant activity against seizures induced by both pentylenetetrazole (PTZ; 85 mg/kg, s.c.) and maximal electroshock (MES, 50 mA, 0.11 s) were determined. Essential oils obtained in each season were effective in increasing the sleeping duration and a preparation obtained in Spring was able to protect animals against tonic seizures induced by electroshock. In each season, eugenol and 1,8-cineole were the most abundant compounds, and in Spring the essential oil presented the greatest relative percentage of sesquiterpenes, suggesting that these compounds could explain the differences observed in the biological activity in essential oils obtained in different seasons of the year.
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PMID:Effects of seasonal variation on the central nervous system activity of Ocimum gratissimum L. essential oil. 1630 72

A set of seven novel N-substituted 2-anilinophenylacetamides were designed by pharmacophore generation and using flexible alignment module of MOE software. The novel molecules were synthesized and screened for anticonvulsant activity in Swiss albino mice by MES and ScPTZ induced seizure tests. Test compounds were found to be potent in MES test. Compounds 12 and 14 were found to be more potent with ED(50) values 24.0 and 8.0 mg kg(-1), respectively, and their activity was comparable to standard drugs (Phenytoin, Carbamazepine). Test compounds did not show significant activity in ScPTZ test. Compounds 12 and 14 also exhibited higher protective indices (20.3 and 87.5, respectively) when assessed for neurotoxicity by rotarod test as compared to the standards.
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PMID:Design, synthesis and in vivo anticonvulsant screening in mice of novel phenylacetamides. 1664 65

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.
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PMID:Synthesis and anticonvulsant activity of new N-1',N-3'-disubstituted-2'H,3H,5'H-spiro-(2-benzofuran-1,4'-imidazolidine)-2',3,5'-triones. 1679 62

To further investigate anticonvulsant activity of quinoline derivatives, a series of 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one derivatives was synthesized starting from 7-hydroxyl-3,4-dihydro-2(1H)-quinoline. In initial (phase I) screening and quantitative (phase II) evaluation, compound 7-benzyloxyl-4,5-dihydro-[1,2,4]thiazolo[4,3-a]quinoline-1(2H)-one (3f) was among the most active but also has the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 12.3 mg/kg, median toxicity dose (TD(50)) of 547.5 mg/kg, and the protective index (PI) of 44.5, which is much greater than PI of the prototype drugs phenytoin, phenobarbital, carbamazepin, and valproate. Compound 3f was chosen for further evaluation. In phase III pharmacological test, the compound had median hypnotic dose (HD(50)) and median lethal dose (LD(50)) of 1204 mg/kg and >3000 mg/kg, respectively, thus demonstrating much greater margin of safety compared to prototype drugs. The compound 3f also showed significant oral activity against MES-induced seizures and low oral neurotoxicity in mice in phase IV pharmacological test. Possible structure-activity relationship was discussed.
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PMID:Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones. 1684 67

2,2,3,3-Tetramethylcyclopropanecarbonylurea (TMCU) is an amide derivative of a tetramethylcyclopropyl analogue of valproic acid (VPA), one of the leading antiepileptic drugs. Structural considerations used in the design of TMCU aimed to enhance the anticonvulsant potency of VPA and to prevent its two life-threatening side effects; i.e., teratogenicity and hepatotoxicity. The anticonvulsant activity of TMCU was evaluated in the MES, scMet, 6-Hz, scBic and scPic tests, and also in the hippocampal kindling model of partial seizures and lamotrigine-resistant amygdala kindling model of therapy-resistant seizures. Minimal motor impairment was determined using the rotorod test in mice and the positional sense test, muscle tone test, and gait and stance test in rats. The antinociceptive effect of TMCU was evaluated in the mouse formalin model of acute-tonic pain. The molecular mechanisms of action of TMCU were investigated in electrophysiological studies using the whole-cell patch-clamp technique. Teratogenicity studies were performed in a SWV/Fnn-mouse model of VPA-induced teratogenicity. TMCU hepatotoxicity was evaluated following 1-week intraperitoneal and oral administration of 50, 250 and 500 mg/kg doses to rats. In the hepatotoxicity study the blood levels of TMCU were evaluated at day 1 and day 7 of the treatment. TMCU mutagenicity was evaluated in the Ames test.
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PMID:Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonyl-urea, a novel, second generation to valproic acid, antiepileptic drug. 1689 Feb 51

The present study was designed to investigate the central nervous system activity of terpene GABA (and piracetam) derivatives designated as BF-1, BF-2, BF-3, BF-4, BF-5, BF-6. We assessed their anticonvulsant activity in the two main mouse models of seizures (MES-test, PTZ-test), an antidepressant-like effect in the forced swim test (FST), as well as an influence on spontaneous locomotor activity. Our study demonstrated the strong anticonvulsant activity of (1S,3R,7R)-(-)-3,8,8-trimethyl-4-aza-bicyclo[5.1.0]acetate-5-one hydrochloride (compound BF-2) in the PTZ-test. Activity of BF-2 was equipotent to ethosuximide (380 mg/kg, po) in the PTZ-test, when used at a dose of 100 mg/kg, po. No neurotoxic effects were demonstrated by administration of all tested compounds. Moreover, BF-2, BF-3, BF-6 compounds significantly reduced the immobility time in FST at both doses (by 21-50%), while BF-5 induced a significant anti-immobility effect only when used at a dose of 100 mg/kg (by 39%). The compound BF-6 used at the dose of 30 mg/kg was the most active (50% reduction), and the effect was similar to the result obtained with classical antidepressant--imipramine. The motor stimulatory activity was demonstrated by BF-1 compound at the dose of 100 mg/kg with no effect at a lower (30 mg/kg) dose. On the other hand, the BF-3 at 30 mg/kg significantly decreased spontaneous activity during 30 min observation period, while no alteration in this activity during 6-min observation was detected. At present, it is not possible to indicate which mechanisms of novel, active terpene GABA derivatives are involved in the demonstrated antidepressant-like activity. Although further studies are needed to solve this issue, these data suggest a potential value of the examined terpene GABA derivatives.
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PMID:Anticonvulsant and antidepressant activity of the selected terpene GABA derivatives in experimental tests in mice. 1722 May 53


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