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James P Stables - One of the best experts on this subject based on the ideXlab platform.
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discovery of n 2 6 dimethylphenyl substituted semicarbazones as Anticonvulsants hybrid pharmacophore based design
Journal of Medicinal Chemistry, 2005Co-Authors: Perumal Yogeeswari, Rathinasabapathy Thirumurugan, Jegadeesan Vaigunda Raghavendran, Kannan Sudhan, Roheeth Kumar Pavana, Dharmarajan Sriram, James P StablesAbstract:Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common Anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for Anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited Anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum Anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118%...
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discovery of n 2 6 dimethylphenyl substituted semicarbazones as Anticonvulsants hybrid pharmacophore based design
Journal of Medicinal Chemistry, 2005Co-Authors: Perumal Yogeeswari, Rathinasabapathy Thirumurugan, Jegadeesan Vaigunda Raghavendran, Kannan Sudhan, Roheeth Kumar Pavana, Dharmarajan Sriram, James P StablesAbstract:Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common Anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for Anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited Anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum Anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118% and inhibited the GABA transaminase enzyme both in vitro and ex vivo.
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design synthesis and evaluation of novel hydroxyamides as orally available Anticonvulsants
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Hilary A Schenck, James P Stables, Paul W Lenkowski, Indrani Choudhurymukherjee, Manoj K Patel, Milton L BrownAbstract:Abstract Themisone, also known as Atrolactamide, was found, in the 1950s, to be a very potent Anticonvulsant. It was hypothesized that the -CF3 substitution would maintain the Anticonvulsant activity. Anticonvulsant testing of our novel compounds by the National Institute of Health's Anticonvulsant Screening Project of the Antiepileptic Drug Discovery Program identified analogue 1, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide, to have potent Anticonvulsant activity (MES ED50 of 9.9 mg/kg, ScMET ED50 of 34 mg/kg and TD50 of 100 mg/kg). Therefore, a diverse range of analogues were synthesized utilizing multiple synthetic pathways to explore the structure–activity relationship. Patch clamp electrophysiology experiments demonstrate that compound 1 is an effective T-type calcium channel blocker. Altogether, these results suggest these compounds as a class of orally available Anticonvulsants.
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Anticonvulsant activity of Schiff bases of isatin derivatives.
Acta pharmaceutica (Zagreb Croatia), 2004Co-Authors: M. Verma, Surendra N. Pandeya, Krishna Nand Singh, James P StablesAbstract:Schiff bases of N-methyl and N-acetyl isatin derivatives with different aryl amines have been synthesized and screened for Anticonvulsant activities against maximal electroshock (MES) and subcutaneous metrazole (ScMet). N-methyl-5-bromo-3-(p-chlorophenylimino) isatin (2) exhibited Anticonvulsant activity in MES and ScMet with LD50 > 600 mg kg(-1), showing better activity than the standard drugs phenytoin, carbamazepine and valproic acid. Thus, compound 2 may be chosen as a prototype for development of new Anticonvulsants.
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Anticonvulsant properties of various acetylhydrazones oxamoylhydrazones and semicarbazones derived from aromatic and unsaturated carbonyl compounds
European Journal of Medicinal Chemistry, 2000Co-Authors: J R Dimmock, Sarvesh C Vashishtha, James P StablesAbstract:Various acetylhydrazones, oxamoylhydrazones and semicarbazones were prepared as candidate Anticonvulsants with a view to examining the viability of a putative binding site hypothesis. Atomic charge calculations were undertaken to determine the hydrogen bonding capacities of various molecules. The biological results obtained revealed that in general the acetylhydrazones and semicarbazones afforded good protection against convulsions while the oxamoylhydrazones were significantly less active. These data suggest that terminal electron-donating groups enhanced the hydrogen bonding capabilities and Anticonvulsant properties of these molecules.
Perumal Yogeeswari - One of the best experts on this subject based on the ideXlab platform.
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discovery of n 2 6 dimethylphenyl substituted semicarbazones as Anticonvulsants hybrid pharmacophore based design
Journal of Medicinal Chemistry, 2005Co-Authors: Perumal Yogeeswari, Rathinasabapathy Thirumurugan, Jegadeesan Vaigunda Raghavendran, Kannan Sudhan, Roheeth Kumar Pavana, Dharmarajan Sriram, James P StablesAbstract:Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common Anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for Anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited Anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum Anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118%...
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discovery of n 2 6 dimethylphenyl substituted semicarbazones as Anticonvulsants hybrid pharmacophore based design
Journal of Medicinal Chemistry, 2005Co-Authors: Perumal Yogeeswari, Rathinasabapathy Thirumurugan, Jegadeesan Vaigunda Raghavendran, Kannan Sudhan, Roheeth Kumar Pavana, Dharmarajan Sriram, James P StablesAbstract:Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common Anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for Anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited Anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum Anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118% and inhibited the GABA transaminase enzyme both in vitro and ex vivo.
Giovambattista De Sarro - One of the best experts on this subject based on the ideXlab platform.
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influence of carbenoxolone on the Anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in dba 2 mice
European Journal of Pharmacology, 2004Co-Authors: Pietro Gareri, Guido Ferreri, Eugenio Donato Di Paola, Santo Gratteri, Natale Belluardo, Daniele Filippo Condorelli, Giovambattista De SarroAbstract:Abstract Carbenoxolone, the succinyl ester of glycyrrhetinic acid, is an inhibitor of 11β-hydroxy steroid dehydrogenase and gap junctional intercellular communication. It is currently used in clinical treatment of ulcer diseases. Systemic administration of carbenoxolone (1–40 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. Glycyrrhizin, an analogue of carbenoxolone inactive at the gap-junction level, was unable to affect audiogenic seizures at doses up to 30 mg/kg. In combination with conventional antiepileptic drugs, carbenoxolone, 0.5 mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the Anticonvulsant activity of carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. This effect was not observed after the combination of glycyrrhizin (10 mg/kg, i.p.) with some conventional antiepileptic drugs. The degree of potentiation induced by carbenoxolone was greater for diazepam, felbamate, gabapentin, phenobarbital and valproate, less for lamotrigine, phenytoin and carbamazepine. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with carbenoxolone was more favourable than the combination with glycyrrhizin or saline. Since carbenoxolone did not significantly influence the total and free plasma levels of diazepam, felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital, valproate and carbamazepine, pharmacokinetic interactions are not likely. However, the possibility that carbenoxolone can modify the brain clearance of the Anticonvulsant drugs studied may not be excluded. In addition, carbenoxolone did not significantly affect the hypothermic effects of the Anticonvulsants tested. In conclusion, carbenoxolone showed an additive Anticonvulsant effect when administered in combination with some classical Anticonvulsants, most notably diazepam, felbamate, gabapentin, phenobarbital, and valproate, implicating a possible therapeutic relevance of such drug combinations.
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7 nitroindazole potentiates the antiseizure activity of some Anticonvulsants in dba 2 mice
European Journal of Pharmacology, 2000Co-Authors: Giovambattista De Sarro, Pietro Gareri, Umberto Falconi, Angela De SarroAbstract:Abstract 7-Nitroindazole, a selective neuronal nitric oxide synthase inhibitor (25–200 mg kg −1 , intraperitoneally (i.p.)) antagonized audiogenic seizures in DBA/2 mice in a dose-dependent manner. We investigated the effects of 7-nitroindazole at a dose of 25 mg kg −1 i.p., which per se did not show Anticonvulsant activity against audiogenic seizures in DBA/2 mice, on the antiseizure activity of some conventional antiepileptic drugs. 7-Nitroindazole sometimes potentiated the Anticonvulsant activity of carbamazepine, diazepam, lamotrigine, phenytoin, phenobarbital and valproate against audiogenic seizures in DBA/2 mice. The degree of potentiation by 7-nitroindazole was greatest for phenobarbital and diazepam, less for valproate and least for carbamazepine, lamotrigine and phenytoin. The increase in Anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment with diazepam+7-nitroindazole, phenobarbital+7-nitroindazole or valproate+7-nitroindazole was more favourable than that of the diazepam+vehicle, phenobarbital+vehicle or valproate+vehicle treatment. The results indicate that 7-nitroindazole is able to increase the protective activity of some conventional antiepileptics and this effect appears not to result only from the impaired synthesis of nitric oxide. In fact, mice receiving 7-nitroindazole (25 mg kg −1 , i.p.) and l -arginine (30 μg/mouse, intracerebroventricularly (i.c.v.) did not show significant changes of ED 50 values in comparison to those of related groups of animals treated with 7-nitroindazole and Anticonvulsants. 7-Nitroindazole was able to increase the brain levels of dopamine and noradrenaline and its Anticonvulsant effects and changes in catecholamine content were antagonized by pretreatment with α-methyl-paratyrosine, an agent inhibiting the synthesis of catecholamines. The fact that α-methyl-paratyrosine reverses concomitantly both the increase in brain levels of dopamine and noradrenaline and the Anticonvulsant properties of 7-nitroindazole strongly suggests an important role of catecholamines in the antiseizure activity of 7-nitroindazole. Since 7-nitroindazole did not significantly influence the total and free plasma levels of the Anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. 7-Nitroindazole did not significantly affect the hypothermic effects of the Anticonvulsant compounds studied. 7-Nitroindazole showed an additive effect when administered in combination with some classical Anticonvulsants, most notably diazepam, phenobarbital and valproate and its activity could be, in part, due to an increase of monoamine levels.
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gabapentin potentiates the antiseizure activity of certain Anticonvulsants in dba 2 mice
European Journal of Pharmacology, 1998Co-Authors: Giovambattista De Sarro, Pietro Gareri, C Spagnolo, Luca Gallelli, Angela De SarroAbstract:Gabapentin (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in Dilute Brown Agouti DBA2J (DBA/2) mice in a dose-dependent manner. Gabapentin at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the Anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The potentiation induced by gabapentin was greatest for diazepam, phenobarbital and valproate, less for felbamate and phenytoin and least for carbamazepine and lamotrigine. The increase in Anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment of the above drugs + gabapentin was more favourable than that of the same drugs + saline. Since gabapentin did not significantly influence the total and free plasma levels of the Anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that gabapentin can modify the clearance from the brain of the Anticonvulsant drugs studied can not be excluded. In addition, gabapentin did not significantly affect the hypothermic effects of the Anticonvulsants tested. In conclusion, gabapentin showed an additive effect when administered in combination with certain classical Anticonvulsants, most notably diazepam, phenobarbital, felbamate, phenytoin and valproate.
Angela De Sarro - One of the best experts on this subject based on the ideXlab platform.
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7 nitroindazole potentiates the antiseizure activity of some Anticonvulsants in dba 2 mice
European Journal of Pharmacology, 2000Co-Authors: Giovambattista De Sarro, Pietro Gareri, Umberto Falconi, Angela De SarroAbstract:Abstract 7-Nitroindazole, a selective neuronal nitric oxide synthase inhibitor (25–200 mg kg −1 , intraperitoneally (i.p.)) antagonized audiogenic seizures in DBA/2 mice in a dose-dependent manner. We investigated the effects of 7-nitroindazole at a dose of 25 mg kg −1 i.p., which per se did not show Anticonvulsant activity against audiogenic seizures in DBA/2 mice, on the antiseizure activity of some conventional antiepileptic drugs. 7-Nitroindazole sometimes potentiated the Anticonvulsant activity of carbamazepine, diazepam, lamotrigine, phenytoin, phenobarbital and valproate against audiogenic seizures in DBA/2 mice. The degree of potentiation by 7-nitroindazole was greatest for phenobarbital and diazepam, less for valproate and least for carbamazepine, lamotrigine and phenytoin. The increase in Anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment with diazepam+7-nitroindazole, phenobarbital+7-nitroindazole or valproate+7-nitroindazole was more favourable than that of the diazepam+vehicle, phenobarbital+vehicle or valproate+vehicle treatment. The results indicate that 7-nitroindazole is able to increase the protective activity of some conventional antiepileptics and this effect appears not to result only from the impaired synthesis of nitric oxide. In fact, mice receiving 7-nitroindazole (25 mg kg −1 , i.p.) and l -arginine (30 μg/mouse, intracerebroventricularly (i.c.v.) did not show significant changes of ED 50 values in comparison to those of related groups of animals treated with 7-nitroindazole and Anticonvulsants. 7-Nitroindazole was able to increase the brain levels of dopamine and noradrenaline and its Anticonvulsant effects and changes in catecholamine content were antagonized by pretreatment with α-methyl-paratyrosine, an agent inhibiting the synthesis of catecholamines. The fact that α-methyl-paratyrosine reverses concomitantly both the increase in brain levels of dopamine and noradrenaline and the Anticonvulsant properties of 7-nitroindazole strongly suggests an important role of catecholamines in the antiseizure activity of 7-nitroindazole. Since 7-nitroindazole did not significantly influence the total and free plasma levels of the Anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. 7-Nitroindazole did not significantly affect the hypothermic effects of the Anticonvulsant compounds studied. 7-Nitroindazole showed an additive effect when administered in combination with some classical Anticonvulsants, most notably diazepam, phenobarbital and valproate and its activity could be, in part, due to an increase of monoamine levels.
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gabapentin potentiates the antiseizure activity of certain Anticonvulsants in dba 2 mice
European Journal of Pharmacology, 1998Co-Authors: Giovambattista De Sarro, Pietro Gareri, C Spagnolo, Luca Gallelli, Angela De SarroAbstract:Gabapentin (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in Dilute Brown Agouti DBA2J (DBA/2) mice in a dose-dependent manner. Gabapentin at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the Anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The potentiation induced by gabapentin was greatest for diazepam, phenobarbital and valproate, less for felbamate and phenytoin and least for carbamazepine and lamotrigine. The increase in Anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment of the above drugs + gabapentin was more favourable than that of the same drugs + saline. Since gabapentin did not significantly influence the total and free plasma levels of the Anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that gabapentin can modify the clearance from the brain of the Anticonvulsant drugs studied can not be excluded. In addition, gabapentin did not significantly affect the hypothermic effects of the Anticonvulsants tested. In conclusion, gabapentin showed an additive effect when administered in combination with certain classical Anticonvulsants, most notably diazepam, phenobarbital, felbamate, phenytoin and valproate.
Dharmarajan Sriram - One of the best experts on this subject based on the ideXlab platform.
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discovery of n 2 6 dimethylphenyl substituted semicarbazones as Anticonvulsants hybrid pharmacophore based design
Journal of Medicinal Chemistry, 2005Co-Authors: Perumal Yogeeswari, Rathinasabapathy Thirumurugan, Jegadeesan Vaigunda Raghavendran, Kannan Sudhan, Roheeth Kumar Pavana, Dharmarajan Sriram, James P StablesAbstract:Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common Anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for Anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited Anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum Anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118%...
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discovery of n 2 6 dimethylphenyl substituted semicarbazones as Anticonvulsants hybrid pharmacophore based design
Journal of Medicinal Chemistry, 2005Co-Authors: Perumal Yogeeswari, Rathinasabapathy Thirumurugan, Jegadeesan Vaigunda Raghavendran, Kannan Sudhan, Roheeth Kumar Pavana, Dharmarajan Sriram, James P StablesAbstract:Epilepsy is the most common primary neurological disorder known. In the past decade, various aryl semicarbazones have been designed that were structurally dissimilar from many common Anticonvulsants containing the dicarboximide function (CONRCO), which may contribute to toxic side effects. In the present work various N4-(2,6-dimethylphenyl) semicarbazones were designed as pharmacophore hybrids between the aryl semicarbazones and ameltolide. A three-dimensional four-point pharmacophore model was developed for Anticonvulsants, and the title compounds were found to match with ralitoline. All of the compounds exhibited Anticonvulsant activity in the maximal electroshock test when administered by both intraperitoneal and oral routes. Compound N1-(2,6-dimethylphenyl)-N4-(2-hydroxybenzaldehyde) semicarbazone (9) emerged as a prototype with wide spectrum Anticonvulsant agent active in five models of seizure with no neurotoxicity and hepatotoxicity. Compound 9 increased the 4-aminobutyric acid (GABA) level by 118% and inhibited the GABA transaminase enzyme both in vitro and ex vivo.