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)

A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.
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PMID:Synthesis and anticonvulsant activity of some new 2-substituted 3-aryl-4(3H)-quinazolinones. 229 16

Anticonvulsants are neuronal stabilizing compounds that exhibit multiple clinical effects, including anticonvulsant, anxiolytic, sedative, and muscle-relaxant properties. This complex therapeutic picture complicates the treatment of seizure disorders in individuals with mental and developmental disorders, and frequently impairs the routine integration into society for these individuals. In order to improve the therapeutic effectiveness of these compounds, it is necessary to identify their precise molecular actions on the neuronal membrane and their effects on neuronal function. We have identified two major classes of low-affinity BZ binding sites that seem to function as generalized anticonvulsant receptors and that may mediate the anticonvulsant and sedative effects produced by these compounds. The identification of these binding sites and their anticonvulsant binding profile may clarify the complex picture of anticonvulsant mechanisms and elucidate the site(s) at which anticonvulsants produce their inhibition of MES-induced seizures and sedative effects. We will continue to examine the physiological changes induced by anticonvulsant binding at these BZ binding sites that may be a foundation for understanding the molecular basis of sedation and MES-induced seizure inhibition. Specifically, we will investigate the specific membrane components associated with the inhibition of Ca2+ channels, Na+ channel rectification, and CaM kinase II. If these goals can be achieved, then model systems could be developed to screen potential anticonvulsant or sedative compounds in the search for more effective therapeutic drugs.
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PMID:A molecular approach to the development of anticonvulsants. 243 83

(+/-) Propranolol (1-50 mg/kg), (+) propranolol (50 mg/kg) and pindolol (10-50 mg/kg) exhibited significant protective effects against MES (maximum electroshock seizures), whereas, timolol (1 mg/kg), the propranolol analog, UM-272 (1 and 10 mg/kg), and the beta-agonist, terbutaline (1 and 10 mg/kg) were ineffective. Cholinergic agents, physostigmine (0.01-1.0 mg/kg), and atropine (1 and 10 mg/kg), the serotonin antagonist, cyproheptadine (0.05 mg/kg), and the prostaglandin synthesis inhibitor, indomethacin (10 mg/kg), were also without effect on the MES extensor phase. Further, pretreatment of mice with terbutaline, atropine, cyproheptadine or indomethacin did not influence the anti-MES effect of propranolol to any significant extent. The results indicate that the observed anticonvulsant effects of beta-adrenoceptor antagonists are unrelated to noradrenergic or other central neurotransmitter systems and that a non-specific mechanism, probably a membrane stabilizing effect is involved.
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PMID:Effect of beta-adrenoceptor antagonists and some related drugs on maximal electroshock seizures in mice. 257 45

A number of new 1,2-diphenylethane derivatives were synthesized and tested for anticonvulsant activity. Their structure was designed on the basis of the potential metabolic degradation of the imidazole ring present in denzimol ( ( +/- )-N-[2-[4-(beta-phenylethyl)phenyl]-2-hydroxethyl]imidazole), a potent anticonvulsant. The compounds which inhibited the electroshock-induced seizures (MES) in mice, namely N-[4-(beta-phenylethyl)phenacyl]formamide (VII) and N-[2-[4-(beta-phenylethyl)phenyl]-2-hydroxyethyl]formamide (IX), proved active also as inhibitors of the pentylenetetrazole-induced tonic seizures. The results of the pharmacological screening were evaluated in relation to the lipophilicity of the compounds.
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PMID:Synthesis and anticonvulsant evaluation of 1,2-diphenylethane derivatives, potential metabolites of denzimol. 280 48

The interaction of two tranquilizers, the 1,5-benzodiazepine clobazam (CBZ, Frisium) and the non-benzodiazepine etifoxin (Hoe-36,801) hydrochloride (EFX, 6-chloro-2-ethylamino-4-methyl-4-phenyl-4H-3,1-benzoxazine HCl) was investigated for anticonvulsant activity in mice. Corresponding experiments were performed with the antiepileptic drug sodium valproate (VPA). Tonic-clonic (maximal) seizures were induced by maximal electroshock (MES; 12 mA, 200 ms) and clonic (threshold) seizures by pentetrazol (PTZ; 85 mg/kg s.c.). The addition of an anticonvulsant threshold dose of EFX (50 mg/kg p.o.) led to an increase of CBZ's potency against both MES- and PTZ-seizures by 410 or 450%, respectively. Under the same conditions, EFX enhanced the potency of VPA only by 20 or 80% and a threshold dose of VPA (100 mg/kg p.o.) enhanced the potency of CBZ by 110 or 0%, respectively. It is concluded that this potentiation of CBZ's anticonvulsant activity by EFX may be beneficially used in epileptic patients either to increase CBZ's antiepileptic effects or to reduce CBZ's therapeutic doses in order to prevent or delay the development of resistance.
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PMID:Potentiation of clobazam's anticonvulsant activity by etifoxine, a non-benzodiazepine tranquilizer, in mice. Comparison studies with sodium valproate. 309 54

Pioneering studies in our laboratories have led to the emergence of the delta 2-1,2,3-triazolines (4,5-dihydro-1H-1,2,3-triazoles) and the closely related 1H-1,2,3-triazoles as a unique family of anticonvulsant agents hitherto unknown. Unlike the traditional anticonvulsants, the dicarboximide moiety is absent from the traiazoline ring system. This paper examines the results of evaluation of several groups of 1-aryl-5-pyridyl-substituted triazolines and triazoles with particular reference to structure-activity relationships in each compound group as well as between compounds in the different groups and the 1,5-diaryl compounds. The Topliss manual approach for application fo the Hansch method is employed for the rational design of triazoline/triazole anticonvulsants. Anticonvulsant activity was determined, after intraperitoneal administration, in two standard seizure models in the mouse, the MES and scMet tests. Central nervous system toxicity was evaluated in the rotorod ataxia test. Analysis of structure-activity relationships using the Topliss scheme indicated a clear pi + sigma dependency in the 1-aryl-5-(4-pyridyl)triazolines while an adverse steric effect (Es) from 4-substitution appeared to be present in the 1-aryl-5-(3-pyridyl) compounds. A similar but strong steric effect dominated the structure-activity pattern of the 1-aryl-5-(4-pyridyl)triazoles, although a sigma dependency was more evident in the 1-aryl-5-(3-pyridyl)- and the 1,5-diaryltriazole series. No significant activity was observed among the 1-aryl-5-(2-pyridyl)triazolines, and although the respective triazoles were active, the parameter dependency was not clearly defined. Similarly, the 1,5-diaryltriazolines, as a group, showed no pronounced anticonvulsant activity. However, replacement of the 5-aryl with a pyridyl group, particularly a 4-pyridyl, led to highly enhanced anticonvulsant activity. In addition, oxidation of triazolines with no anticonvulsant activity yielded, as a rule, triazoles that were active, which could be linked to their chemistry or structural conformation. The triazolines and triazoles evince anticonvulsant activity as a class and compare very well with the prototype antiepileptic drugs--ethosuximide, phenytoin, phenobarbital, valproate--in their anticonvulsant potency and minimal neurotoxicity. They have emerged as a new generation of anticonvulsant agents that show great promise as potentially useful antiepileptic drugs.
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PMID:Triazolines. 14. 1,2,3-Triazolines and triazoles, a new class of anticonvulsants. Drug design and structure-activity relationships. 333 19

The major metabolite of the non-opioid anticonvulsant/antitussive dextromethorphan is dextrorphan. In the present study, the effects of dextrorphan were determined in an experimental model of seizure activity (maximal electroshock convulsions) (MES). Subcutaneous administration of dextrorphan produced dose-related blockade of tonic hindlimb extension (THE) and a decrease in the duration of tonic forelimb extension (TFE). The anticonvulsant effect of dextrorphan was linear and maximally efficacious. Compared to the prototypical anticonvulsant drug diphenylhydantoin, dextrorphan was 2.5 times more potent (ED50's = 30 mumol/kg and 12 mumol/kg, respectively). Pretreatment with naloxone failed to antagonize dextrorphan-induced blockade of THE. Moreover, pretreatment with dextrophan failed to significantly enhance the anticonvulsant potency of diphenylhydantoin. It is likely that the anticonvulsant effects of dextrorphan are related to its actions at the phencyclidine/N-methyl-D-aspartate receptor complex, whereas the anticonvulsant effects of dextromethorphan have been attributed to binding to a specific dextromethorphan site in the brain. Therefore, we suggest that while metabolism to dextrorphan could possibly contribute to the anticonvulsant effects of dextromethorphan, it is probably through an unrelated receptor mechanism.
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PMID:Anticonvulsant effects of dextrorphan in rats: possible involvement in dextromethorphan-induced seizure protection. 337 69

The anticonvulsant activity of propranolol was investigated in mice and rats using the electroshock seizure test (MES) and in special cases the electrically evoked hippocampal afterdischarges as a model. The results show that racemic propranolol as well as the two enantiomers were effective against MES. (+)-propranolol, the isomer with negligible beta-adrenoceptor blocking capacity revealed the stronger effect, its efficacy was comparable with the potency of phenobarbital, an overadditive synergism could be demonstrated. Subchronic administration of the two enantiomers led to a significantly reduced ED50 value of (-)-propranolol 24 h after the last application, the (-)-isomer became more effective. The (+)-propranolol did not reveal significant differences. In unrestrained rats with chronically implanted electrodes propranolol increased the stimulation threshold and reduced the duration of electrically evoked hippocampal afterdischarges. Investigations with drugs affecting monoaminergic systems in the CNS demonstrated that the noradrenergic system might play a predominant role in modulating the anticonvulsant effectiveness of propranolol. Pharmacological suppression (6-hydroxydopamine, reserpine, phenoxybenzamine) or stimulation (maprotiline, yohimbine, clenbuterol) reduced or enhanced the activity of propranolol against MES. On the other hand, manipulation of the serotonergic or dopaminergic system seemed to be less effective. In general, the findings confirm the results of previous studies that the membrane stabilizing property and not the blocking action on beta adrenergic (or serotonergic) receptors accounts for the anticonvulsant activity of propranolol.
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PMID:Anticonvulsant effects of propranolol and their pharmacological modulation. 384 95

Postictal immobility (IP) following chemically (pictrotoxin, metrazol) and electrically-induced (maximal electroshock, MES) convulsions has behavioral features close to neuroleptic-type catalepsy. EEG, monitored postictally, showed that catalepsy is accompanied by a variety of EEG patterns. Cataleptic behavior extended beyond the period of "postictal EEG depression". During PI rats had vivid righting and corneal reflexes. Like haloperidol-pretreated rats they were able to maintain uncomfortable postures on the vertical grid or horizontal bar; although signs of rigidity were noticed, the rats would fail to remain self-supporting when placed across metal bookends ("bridge" test). All rats reacted to the tail-pinch immediately when the seizure would halt. However, 10-15 min later when PI was minimal or not detectable, animals became totally unresponsive to pressure applied to the tail ("delayed analgesia"). Examination of VEP recovery after MES showed that the secondary slow negativity and sensory after discharge were well developed irrespective of the score of the tail-pinch test. Pharmacological profile of PI suggests that the endogenous opiate system might contribute to this syndrome. Similar to morphine-induced catalepsy/catatonia: (1) PI is insensitive to atropine and scopolamine; (2) neither haloperidol nor alpha-methyl-p-tyrosine was able to potentiate it; (3) PI is reduced by apomorphine, naloxone, and physostigmine. Also, drugs acting via GABA system (gamma-vinyl GABA, diazepam, sodium valproate) reduce PI intensity. It is hypothesized that PI system (1) is controlled by GABA carrying fibers and (2) uses neuropeptide with neuroleptic properties.
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PMID:Pharmacologic analysis of the postictal immobility syndrome in the rat. 729 Dec 36

Recent studies have demonstrated that C(alpha)-substituted alpha-acetamido-N-benzylacetamides displayed excellent anticonvulsant activities in mice. Analysis of the structure-activity relationship for this series of compounds has shown that placement of small, electron-rich aromatic and heteroaromatic groups at the C(alpha) site led to pronounced protection against MES-induced seizures. In this note, synthetic protocols are reported for the preparation of three novel nonnaturally occurring electron-deficient C(alpha)-aza aromatic alpha-acetamido-N-benzylacetamides (i.e., pyrid-2-yl (11), pyrazin-2-yl (12), pyrimid-2-yl (13)). Expedient syntheses for 12 and 13 were developed using a phase-transfer, nucleophilic aromatic substitution process. All three adducts exhibited potencies comparable to or greater than phenytoin in the MES test (mice, ip). These findings required us to modify in part the previously proposed structure-activity relationship for this class of anticonvulsants.
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PMID:Synthesis and anticonvulsant activities of alpha-acetamido-N-benzylacetamide derivatives containing an electron-deficient alpha-heteroaromatic substituent. 779 8


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