Potential Anticonvulsants Research Articles

Antiepileptic drug development program: a cooperative effort of government and industry.

The most important step in antiepileptic drug discovery is the choice of an appropriate animal model for the initial screening as well as for the more complex procedures that elucidate mechanisms of action. The currently available models fall short in their inability to identify all drugs for all types of seizures in a mechanism-independent manner. Nevertheless, spontaneous models of epilepsy are the most commonly used, and chemically or electrically induced seizures in rodents can also identify potential anticonvulsants. In the latter models, the intensity of the seizure stimulus is of paramount importance. The Antiepileptic Drug Development Program evaluates approximately 800 compounds each year, using two models for preliminary screening. One model assesses the ability of a compound to prevent seizure spread; the other weighs the ability to raise seizure threshold. In vivo tests, featuring amygdala- and corneal-kindled seizures, and in vitro assays, employing gamma-aminobutyric acid (GABA) receptors and synaptosomal uptake of adenosine, define drug-drug interactions and elucidate the pharmacological profiles of potential anticonvulsants.

Impaired motor coordination in mice induced by 2-amino-7-phosphonoheptanoic acid (APH), glutamic acid diethyl ester (GDEE), and other compounds

Impairment of motor coordination by the excitatory amino acid antagonists 2-amino-7-phosphonoheptanoic acid (APH) and glutamic acid diethyl ester (GDEE) was measured and compared to GABA agonists and anticonvulsants and other compounds by the Coughenour inverted screen test. The GABA agonists muscimol and imidazole acetic acid, and the GABA analogue gamma-hydroxybutyric acid were found to produce a marked impairment of motor coordination. The dosages of phenytoin and valproarte which impaired motor coordination, on the other hand, were considerably above the dosages which have been reported to inhibit seizures. APH caused motor incoordination at a dosage of 125 mg/kg, and a prolonged motor impairment was present after administration of APH, 250 mg/kg. GDEE did not significantly impair motor coordination in any dosage tested up to 1920 mg/kg. These results further encourage development of more potent GDEE-like compounds as potential anticonvulsants.

ChemInform Abstract: Cycloheximide Analogues as Potential Anticonvulsants.

AbstractDargestellt und auf antikonvulsive Wirkung untersucht werden die Cycloimide (I) und (II).

Spirosuccinimides as Potential Anticonvulsants

A series of spirosuccinimides was synthesized and evaluated for anticonvulsant activity. The study was designed to apply the Topliss approach to structure–activity correlations in this novel series of 2-substituted-2-azaspiro[4.4]nonane-1,3-diones and 2,4-disubstituted-2-azaspiro[4.4]nonane-1,3-diones. While no correlation was noted with the 2-substituted derivatives, a good correlation was obtained in the 2,4-disubstituted series, indicating that anticonvulsant activity was related to increasing π values. The results of these anticonvulsant tests are presented and a rational approach to the structure–activity relationships of spirosuccinimides is provided.

Potential anticonvulsants. X. (Reissert compounds studies. LI.) 1‐methyl‐4‐(1‐isoquinolinyl)piperidin‐4‐ol and related compounds

AbstractThe anion of isoquinoline Reissert Compounds has been condensed with 4‐piperidones and pyridinecarb‐oxaldehydes to give esters which are easily hydrolyzed to alcohols. The anticonvulsants activity of these alcohols is reported and several are active in the maximal electroshock seizure test.

Synthesis of 3‐amino‐3,4‐dihydro‐2(1H)‐quinazolinones as potential anticonvulsants

AbstractThirteen 3‐amino‐3,4‐dihydro‐2(1H)‐quinazolinones have been synthesized from ethyl chloroformate and o‐aminobenzylhydrazines. The latter compounds were obtained from the metal hydride reduction of either o‐aminobenzhydrazides or o‐acylaniline hydrazones. All compounds were evaluated in mice in the maximal electroshock (MES) seizure and pentylenetetrazole (sc Met) seizure threshold tests for anticonvulsant activity and in the rotorod test to determine neurotoxicity. Five of the compounds showed activity in one or both tests at a dose of 300 mg/kg or lower. The most active compound is 3‐dimethylamino‐3,4‐dihydro‐2(1H)‐quinazolinone.

Potential anticonvulsants. IX. Some isatin hydrazones and related compounds

AbstractA number of hydrazines, hydrazides, and related compounds have been condensed with isatin and substituted isatins. The anticonvulsant activity of these compounds is reported.

Synthesis of previously inaccessible quinazolines and 1,4-benzodiazepines as potential anticonvulsants.

A series of 4,6,7,8- tetrasubstituted 3,4- dihydroquinazolines , quinazolines, quinazolin -2-ones, 1,2,3,4- tetrahydroquinazolin -2-ones, and 5,7,8,9- tetrasubstituted 1,4-benzodiazepines have been synthesized by utilizing the Diels -Alder reaction between furan o-amino nitriles and various alkyl or aryl vinyl ketone dienophiles to obtain the anthranilic acid precursors. All of the newly synthesized target compounds were evaluated in mice for anticonvulsant activity. Pro- and anticonvulsant action was quantified by the timed intravenous pentylenetetrazol seizure threshold method. Selected compounds were also evaluated for benzodiazepine receptor binding properties and in vivo antagonist potential. Although the compounds lack potency, the data suggest that previously inaccessible substituted analogues may be useful to segregate the proconvulsant , anticonvulsant, and antagonist actions of benzodiazepines and quinazolines.

Synthesis of 3,4-dihydro-4-oxoquinazoline derivatives as potential anticonvulsants.

Twenty-three substituted 3,4-dihydro-4-oxoquinazolines or 3,4-dihydro-4-oxoazaquinazolines have been synthesized utilizing 2-amino-3-cyano-4,5-dimethylfuran and methyl acrylate as precursors for synthesis of the required substituted anthranilates. Six additional azaquinazolones were synthesized from 2-aminonicotinic or 3-aminopicolinic acid for comparison studies. All compounds were evaluated in mice with the maximal electroshock (MES) seizure and pentylenetetrazol (sc Met) seizure threshold tests for potential anticonvulsant activity and in the rotorod test to evaluate neurotoxicity. Nine of the twenty-nine compounds in the series demonstrated anticonvulsant action. The azaquinazolones were found to possess the most significant activity.

Potential Anticonvulsants VI: Condensation of Isatins with Cyclohexanone and other Cyclic Ketones

□ Cyclohexanone, substituted cyclohexanones, and other cycloalkanones have been condensed with isatin and substituted isatins to give a series of new 3-hydroxy-3-substituted oxindoles. A number of these 3-hydroxyoxindoles possess anticonvulsant activity.

Esters of Nipecotic and Isonipecotic Acids as Potential Anticonvulsants

A variety of esters of nipecotic and isonipecotic acids were synthesized and evaluated for anticonvulsant activity. The ester group was varied in terms of lipophilicity and reactivity toward hydrolysis. The esters were screened against seizures induced by electroshock, pentylenetetrazol, and the putative 7-aminobutyric acid antagonist, bicuculline. The most significant activity was demonstrated by the p-nitrophenyl esters of nipecotic and isonipecotic acids against bicuculline-induced seizures. Esters of nipecotic acid were tested for in vitro inhibition of 7-aminobutyric acid and L-proline uptakes into mouse whole brain mi-nislices. The p-nitrophenyl, ra-octyl, and succinimidyl esters were the most potent inhibitors of 7-aminobutyric acid uptake. The uptake of 7-aminobutyric acid by the ester derivatives appeared to involve specific and nonspecific mechanisms.

Potential Anticonvulsants IV: Condensation of Isatin with Benzoylacetone and Isopropyl Methyl Ketone

A series of new 3-hydroxy-3-substituted oxindoles were prepared and screened for anticonvulsant activity. A number of these 3-hydroxyoxindoles had activity in the maximal electroshock seizure test.

Potential anticonvulsants. V. The condensation of isatins with C‐acetyl heterocyclic compounds

AbstractA number of C‐acetyl heterocyclic compounds were condensed with isatin and substituted isatins to give a series of 3‐hydroxy‐3‐substituted oxindoles. The products from 2‐acetylfuran and isatin, 2‐acetylthiophene and isatin, and 2‐acetylpyridine and 1‐methylisatin were active at 100 mg/Kg in the maximal electroshock seizure test.

ChemInform Abstract: SUCCINIMIDES WITH OXYACETATE SIDE CHAIN AS POTENTIAL ANTICONVULSANT AGENTS

Chemischer InformationsdienstVolume 13, Issue 1 Preparative Organic Chemistry ChemInform Abstract: SUCCINIMIDES WITH OXYACETATE SIDE CHAIN AS POTENTIAL ANTICONVULSANT AGENTS J. A. OWOYALE, J. A. OWOYALESearch for more papers by this authorG. D. LAHAN, G. D. LAHANSearch for more papers by this authorG. OSUIDE, G. OSUIDESearch for more papers by this authorI. O. EDAFIOGHO, I. O. EDAFIOGHOSearch for more papers by this author J. A. OWOYALE, J. A. OWOYALESearch for more papers by this authorG. D. LAHAN, G. D. LAHANSearch for more papers by this authorG. OSUIDE, G. OSUIDESearch for more papers by this authorI. O. EDAFIOGHO, I. O. EDAFIOGHOSearch for more papers by this author First published: January 5, 1982 https://doi.org/10.1002/chin.198201156Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume13, Issue1January 5, 1982 RelatedInformation

Derivatives of 2,3,8,9‐tetrahydro‐3‐oxo‐1H‐benz[de]isoquinoline‐1,9a‐(7H)dicarboximide

AbstractThe synthesis of a series of derivatives of 2,3,8,9‐tetrahydro‐3‐oxo‐1H‐benz[de]isoquinoline‐1,9a‐(7H)dicarboximide (1) are described. Alkylations and thionations of 1 produced a variety of interesting heterocycles. In addition, triazole and triazolone rings were fused to 1 to produce novel compounds. These structures were of interest as potential anticonvulsants.

Synthesis of potential anticonvulsants: Condensation of isatins with acetone and related ketones

Substituted isatins were condensed with acetone and other ketones to give analogs of 3-hydroxy-3-acetonyloxindole. Some of these alcohols were dehydrated. Several compounds with anticonvulsant activity were obtained.

Some fused‐ring succinimides as potential anticonvulsants

AbstractThe syntheses of two compounds, which are fused‐ring succinimides, prepared as potential anticon‐vulsants, are described. The compounds are 3,4,5,6‐tetrahydro‐7‐methyl‐6‐oxoindeno[7,1‐bc]thiepin‐4a,5‐(2H)dicarboximide and 6,7,8,9‐tetrahydro‐2‐oxo‐1H‐benz[cd]azulene‐1,9a‐(2H)dicarboximide. The spirodioxolane of the latter compound was also prepared by ketalization.

Preparation of some Optically Active 5-Substituted Rhodanines as Potential Anticonvulsants

Preparation of some Optically Active 5-Substituted Rhodanines as Potential Anticonvulsants

Synthesis of Some Disubstituted Cyanoacetamides as Potential Anticonvulsants

A series of 17 cyanoacetamides was synthesized for pharmacologic evaluation. Several synthetic methods were studied: C-alkylation, acylation of amines by ester, and acylation of amines by amides. The C-alkylation of cyanoacetamides was investigated in several solvent systems using various bases, and the results are reported. This method was adopted for the alkylation of the cyanoacetamides in a pressure-reaction vessel and utilized formamide and/or dimethylsulfoxide as solvent with potassium hydroxide as the basic reagent. Several of the compounds were obtained by the pyrolytic acylation of amine by amide. A series of 17 cyanoacetamides was synthesized for pharmacologic evaluation. Several synthetic methods were studied: C-alkylation, acylation of amines by ester, and acylation of amines by amides. The C-alkylation of cyanoacetamides was investigated in several solvent systems using various bases, and the results are reported. This method was adopted for the alkylation of the cyanoacetamides in a pressure-reaction vessel and utilized formamide and/or dimethylsulfoxide as solvent with potassium hydroxide as the basic reagent. Several of the compounds were obtained by the pyrolytic acylation of amine by amide.

The Preparation of 5-Substituted 5-(2-Naphthyl)hydantoins as Potential Anticonvulsants

The Preparation of 5-Substituted 5-(2-Naphthyl)hydantoins as Potential Anticonvulsants