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)

Several 2-[(2-methylimidazo[1,2-a]pyridine-3-yl)carbonyl]hydrazono- 3-nonsubstituted/substituted-4-phenyl-4-thiazolines (3a-d, 3f-h) and 3-(2-methylimidazo[1,2-a]pyridine-3-yl)-4-nonsubstituted/substitut ed-5- mercapto-4H-1,2,4-triazoles (4a-f, 4i) were synthesized, characterized and evaluated for anticonvulsant activity. Only 3g showed significant activity against MES induced seizures.
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PMID:Synthesis of some 4-thiazoline and 4H-1,2,4-triazole derivatives of imidazo[1,2-a]pyridine as possible anticonvulsants. 782 78

1. GYKI 52466 is a benzodiazepine derivative that has muscle relaxant and anticonvulsant properties thought to be mediated by highly selective, noncompetitive antagonism of non-NMDA receptors. However, recent electrophysiological data showed that, in addition to non-NMDA receptors, the GABAA-receptor associated benzodiazepine site is involved in the depressant effect of GYKI 52466 on spinal reflex transmission. In view of the structural similarities between the 2,3 benzodiazepine derivative GYKI 52466 and 1,4-benzodiazepines such as diazepam, the benzodiazepine site of GABAA receptor complex could also be involved in the anticonvulsant activity of GYKI 52466, which has not yet been proven. This prompted us to study the effect of the benzodiazepine receptor antagonist, flumazenil, on anticonvulsant and adverse effects of GYKI 52466 in different seizure models in mice. The non-NMDA antagonist, NBQX and diazepam were used for comparison. 2. Seizure threshold models for different types of generalized seizures were used. The threshold for maximal (tonic) electroshock seizures (MES) was significantly increased by GYKI 52466 (10-20 mg kg-1), NBQX (80-120 mg kg-1) and diazepam (5 mg kg-1) shortly after i.p. drug administration. The same dose-range of the non-NMDA antagonists also significantly increased the threshold for myoclonic and clonic seizures induced by i.v. infusion of pentylenetetrazol (PTZ), although the magnitude of threshold increases obtained with the respective drugs, differed, at least in part, from that seen in the MES experiments. GYKI 52466 was clearly less potent in increasing PTZ thresholds for myoclonic and clonic seizures than on the MES threshold, while NBQX exerted about the same potency in both models. In contrast to the non-NMDA antagonists, diazepam was capable of increasing themyoclonic and clonic PTZ seizure threshold at much lower doses than the MES threshold. The PTZ threshold for tonic seizures was markedly increased by GYKI 52466, while NBQX and diazepam were clearly less potent in this respect.3. With respect to adverse effects, GYKI 52466 and NBQX induced significant seizure threshold increases in the different seizure models only at doses which caused sedation and ataxia, while diazepam increased the myoclonic and clonic PTZ seizure threshold at doses below those inducing motor impairment.4. Flumazenil (5-20 mg kg-1) antagonized the anticonvulsant and adverse effects of diazepam but not GYKI 52466. Instead, the anticonvulsant effect of GYKI 52466 was potentiated by flumazenil in some experiments. The anticonvulsant activity of NBQX was slightly reduced by flumazenil in the MES model but not in the PTZ test.5. The data indicate that the GABAA receptor-associated benzodiazepine site is not critically involved in anticonvulsant or adverse effects of GYKI 52466. However, both GYKI 52466 and NBQX were unable to increase seizure thresholds at doses below those inducing sedation and motor impairment,thus demonstrating that non-NMDA antagonists lack a selective anticonvulsant action in standard models of generalized seizures.
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PMID:Effects of the non-NMDA antagonists NBQX and the 2,3-benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil. 788 91

A series of fifteen N-phenylphthalimides including 12 4-amino-N-phenylphthalimides and three N-(3-amino-2-methylphenyl)phthalimides was prepared and evaluated for anticonvulsant properties. The compounds were tested against seizures induced by electroshock (MES) and pentylenetetrazol (scPTZ) in mice dosed intraperitoneally. Their neurologic toxicity was assessed using the rotorod assay procedure. The most potent 4-amino-N-phenylphthalimides against MES were those possessing small lipophilic groups in either 2 or 2 and 6 positions of the N-phenyl ring. They also exhibited some activity against scPTZ and were the most toxic of the series. By contrast, no activity against scPTZ or neurotoxicity could be observed up to 300 mg/kg for members of the N-(3-amino-2- methylphenyl)phthalimide series. In this series, the order of anti-MES activity appears to correspond to the phthalimide ring substitution pattern of 4-amino > H > 4-methyl. Quantitation of anticonvulsant properties and toxicity of 4-amino-N-(2,6-dimethylphenyl)phthalimide (ADD 213063) previously initiated in rats has been, here, extended to mice dosed intraperitoneally but also orally. The confrontation of the two modes of administration in mice suggests that ADD 213063 presents with a good bioavailability.
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PMID:Anticonvulsant activity of some 4-amino-N-phenylphthalimides and N-(3-amino-2-methylphenyl)phthalimides. 791 12

A number of 2-(2-furoylhydrazono)-3-substituted 4-thiazolidone and 2-(2-furoylhydrazono)-3,4-disubstituted 4-thiazoline derivatives were synthesized and evaluated for anticonvulsant activity. Most of the tested compounds showed significant activity against MES induced seizures.
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PMID:Synthesis and anticonvulsant activity of new 4- thiazolidone and 4-thiazoline derivatives. 800 82

A number of 2-(2-furoylhydrazono)-3-substituted 4-thiazolidone and 2-(2-furoylhydrazono)-3,4-disubstituted 4-thiazoline derivatives were synthesized and evaluated for anticonvulsant activity. Most of the tested compounds showed significant activity against MES induced seizures.
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PMID:Synthesis and anticonvulsant activity of new 4-thiazolidone and 4-thiazoline derivatives. 807 88

Continuing structure-activity studies on the anticonvulsant activity of analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective index (TD50/ED50) of > 4.5 are reported. An in-depth analysis of this moiety was studied employing the Topliss structure activity and the Craig plot analytical approaches as well as a semiempirical method. CLOG P analysis was also applied to this series after experimentally determining the NOR fragment. All compounds were minimized and these physicochemical parameters correlated to anticonvulsant activity. Several interesting substituted benzyloxy compounds emerged from this study: the 2',4'-dichloro (2b), 4'-(trifluoromethyl) (2c), 2'-bromo (2d), 3'-chloro (2o), 2'-chloro (2r), 2'-fluoro (2p), and 3'-fluoro (2w) analogs, all of which had comparable, or better activity than the parent unsubstituted analog (2a). X-ray crystal analysis of the active 2a versus inactive N-benzyl-2-azaspiro[4.4]nonane-1,3-dione (10) is discussed.
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PMID:Synthesis and CLOGP correlation of imidooxy anticonvulsants. 824 20

Synthesis and physicochemical properties of new derivatives of alpha-substituted gamma-phthalimidobutyric acid are described. N-substituted amides of alpha-(4-phenylpiperazine)-gamma- phthalimidobutyric acid were prepared by condensation of the acid with the corresponding derivatives of benzylamine in the presence of BOP reagent. 2-(4-Phenylpiperazine)- or 2-(4-benzylpiperidine)-4-phthalimidobutyric acid were esterified with alkyl bromide in the presence of DBU or tetrabutylammonium bromide as catalyst. The obtained compounds were evaluated for anticonvulsant activity. 2-(4-Phenylpiperazine)-4-phthalimidobutyric acid and three N-substituted amides of this acid displaced protection against MES and scMet-induced seizures.
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PMID:Search for new anticonvulsant compounds. Part 1: Synthesis, physicochemical and anticonvulsant properties of new derivatives of alpha-amino-gamma-phthalimidobutyric acid. 857 Jun 69

A number of 1-(3-phenyl-4(3H)-quinazolinone-2-ylmercaptoacetyl)-4-substituted thiosemicarbazide and 2-(3-phenyl-4(3H)-quinazolinone-2-ylmercaptoacetylhydrazono)-3-sub stituted 4-thiazolidone derivatives were synthesized and evaluated for anticonvulsant activity. Some of the tested compounds showed significant activity against MES and ScMet induced seizures.
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PMID:Synthesis and anticonvulsant activity of new acylthiosemicarbazides and thiazolidones. 863 77

A series of N-(phenylacetyl)trifluoromethanesulfonamides (3a-g) was prepared according to the Topliss scheme in order to determine if aryl substituents would influence anticonvulsant activity. In initial (phase I) screening and quantitative (phase II) evaluation, all seven compounds exhibited significant activity against MES- and scMet-induced seizures. N-(Phenylacetyl)trifluoromethanesulfonamide (3a) was then advanced through five additional testing phases (phases III-VII). Compound 3a displayed good oral bioavailability, low toxicity, and a larger protective index in mice than the prototype drugs, phenytoin, phenobarbital, valproate, and ethosuximide. Additionally, 3a exhibited a longer time to peak effect in all tests and a greater 24-h margin of safety (HD(50)/ED(50)) than the prototypes. Compound 3a blocked picrotoxin-induced seizures but was ineffective against seizures induced by bicuculline or strychnine. In vitro receptor binding studies revealed that 3a did not displace [(3)H]-labeled gamma-aminobutyric acid or [(3)H]-labeled flunitrazepam, and tolerance did not develop during a 5-day chronic administration.
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PMID:Synthesis and evaluation of N-(phenylacetyl)trifluoromethanesulfonamides as anticonvulsant agents. 869 81

The anticonvulsant activity of the novel drug D-23129 (N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester) was evaluated in animal models of epileptic seizures. D-23129 was active after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests at nontoxic doses. The compound was active against electrically induced seizures (MES, ED50 rat p.o. = 2.87 mg/kg), against seizures induced chemically by pentylenetetrazole (s.c. PTZ, ED50 mouse p.o. = 13.5 mg/kg), picrotoxin and N-methyl-D-aspartate (NMDA) and in a genetic animal model, the DBA/2 mouse. It was not active against seizures induced by bicuculline and strychnine. Motor impairment, evaluated with the rotarod test and by observation in the open field, was minimal at doses showing anticonvulsant activity. D-23129 was very effective in elevating the threshold for electrically and chemically induced seizures. Considering the dose increasing the MES threshold by 50% (TID50 mouse i.p. = 1.6 mg/kg; TID50 rat i.p. = 0.72 mg/kg) and the TD50 obtained in the rotarod test, the protective index of D-23129 is better than that of valproate and phenytoin. During 14 days chronic oral treatment with 15 mg/kg, no development of tolerance was observed. D-23129 thus presents an orally active, safe, broad spectrum anticonvulsant agent, which is structurally unrelated to anticonvulsants currently used. We expect that D-23129 will improve the treatment of refractory seizures in humans.
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PMID:D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. 873 24


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