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[PMID]:28816437
[Au] Autor:Mascarenhas R; Le HV; Clevenger KD; Lehrer HJ; Ringe D; Kelleher NL; Silverman RB; Liu D
[Ad] Endereço:Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
[Ti] Título:Selective Targeting by a Mechanism-Based Inactivator against Pyridoxal 5'-Phosphate-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover.
[So] Source:Biochemistry;56(37):4951-4961, 2017 Sep 19.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Potent mechanism-based inactivators can be rationally designed against pyridoxal 5'-phosphate (PLP)-dependent drug targets, such as ornithine aminotransferase (OAT) or γ-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity toward other PLP-dependent, off-target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation, similar to that reported for GABA-AT. However, the crystal structure of an off-target, PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggests that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. Amid existing difficulties in achieving selectivity of inactivation among a large number of PLP-dependent enzymes, the obtained results provide evidence that a desirable selectivity could be achieved, taking advantage of subtle structural and mechanistic differences between a drug-target enzyme and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/antagonistas & inibidores
Aspartato Aminotransferases/antagonistas & inibidores
Cicloleucina/análogos & derivados
Inibidores Enzimáticos/farmacologia
Modelos Moleculares
Ornitina-Oxo-Ácido Transaminase/antagonistas & inibidores
Fosfato de Piridoxal/metabolismo
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/química
4-Aminobutirato Transaminase/metabolismo
Aspartato Aminotransferases/química
Aspartato Aminotransferases/genética
Aspartato Aminotransferases/metabolismo
Sítios de Ligação
Domínio Catalítico
Cristalografia por Raios X
Cicloleucina/química
Cicloleucina/metabolismo
Cicloleucina/farmacologia
Bases de Dados de Compostos Químicos
Bases de Dados de Proteínas
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Proteínas de Escherichia coli/antagonistas & inibidores
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Seres Humanos
Ligantes
Conformação Molecular
Ornitina-Oxo-Ácido Transaminase/química
Ornitina-Oxo-Ácido Transaminase/genética
Ornitina-Oxo-Ácido Transaminase/metabolismo
Conformação Proteica
Fosfato de Piridoxal/química
Piridoxamina/química
Piridoxamina/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Homologia Estrutural de Proteína
Especificidade por Substrato
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-amino-4-fluorocyclopentane-1-carboxylic acid); 0 (Enzyme Inhibitors); 0 (Escherichia coli Proteins); 0 (Ligands); 0 (Recombinant Proteins); 0TQU7668EI (Cycloleucine); 5V5IOJ8338 (Pyridoxal Phosphate); 6466NM3W93 (Pyridoxamine); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.13 (Ornithine-Oxo-Acid Transaminase); EC 2.6.1.19 (4-Aminobutyrate Transaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00499


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[PMID]:28806600
[Au] Autor:Sahu M; Siddiqui N; Iqbal R; Sharma V; Wakode S
[Ad] Endereço:Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research (Formerly, Faculty of Pharmacy), Jamia Hamdard, New Delhi 110062, India.
[Ti] Título:Design, synthesis and evaluation of newer 5,6-dihydropyrimidine-2(1H)-thiones as GABA-AT inhibitors for anticonvulsant potential.
[So] Source:Bioorg Chem;74:166-178, 2017 Oct.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Several new 5,6-dihydropyrimidine-2(1H)-thione derivatives have been prepared and investigated for their potencies for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) test in mice. The acute neurotoxicity was measured by rotarod test. Compounds 3c and 3l were found active in both of the animal models. Further, in vitro GABA-AT enzyme activity assay was carried out to investigate the possible mechanism of action through GABA-AT inhibition. The most potent compounds 3c and 3l showed inhibitory potency (IC ) of 18.42µM and 19.23µM, respectively. The molecular modeling was performed for all the synthesized compounds. The docking results were found in concordant with the observed animal studies.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/antagonistas & inibidores
Anticonvulsivantes/farmacologia
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Pirimidinas/farmacologia
Convulsões/tratamento farmacológico
Tionas/farmacologia
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/metabolismo
Animais
Anticonvulsivantes/síntese química
Anticonvulsivantes/química
Relação Dose-Resposta a Droga
Eletrochoque
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Camundongos
Modelos Moleculares
Estrutura Molecular
Pentilenotetrazol
Pirimidinas/síntese química
Pirimidinas/química
Relação Estrutura-Atividade
Tionas/síntese química
Tionas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5,6-dihydropyrimidine-2(1H)-thione); 0 (Anticonvulsants); 0 (Enzyme Inhibitors); 0 (Pyrimidines); 0 (Thiones); EC 2.6.1.19 (4-Aminobutyrate Transaminase); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


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[PMID]:28411234
[Au] Autor:Koenig MK; Hodgeman R; Riviello JJ; Chung W; Bain J; Chiriboga CA; Ichikawa K; Osaka H; Tsuji M; Gibson KM; Bonnen PE; Pearl PL
[Ad] Endereço:From Child and Adolescent Neurology (M.K.K.), University of Texas Medical School, Houston; Neurology (R.H., P.L.P.), Boston Children's Hospital, Harvard Medical School, MA; Child Neurology (J.J.R., W.C., J.B., C.A.C.), Columbia University School of Medicine, New York, NY; Neurology (K.I., M.T.), Kan
[Ti] Título:Phenotype of GABA-transaminase deficiency.
[So] Source:Neurology;88(20):1919-1924, 2017 May 16.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype. METHODS: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil. RESULTS: All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued. CONCLUSIONS: GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/deficiência
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia
[Mh] Termos MeSH secundário: Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico
Erros Inatos do Metabolismo dos Aminoácidos/mortalidade
Encéfalo/diagnóstico por imagem
Encéfalo/fisiopatologia
Criança
Pré-Escolar
Diagnóstico Diferencial
Feminino
Flumazenil/uso terapêutico
Seguimentos
Moduladores GABAérgicos/uso terapêutico
Seres Humanos
Lactente
Masculino
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GABA Modulators); 40P7XK9392 (Flumazenil); EC 2.6.1.19 (4-Aminobutyrate Transaminase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170416
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000003936


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[PMID]:27596361
[Au] Autor:Nagappa M; Bindu PS; Chiplunkar S; Govindaraj P; Narayanappa G; Krishnan A; Bharath MM; Swaminathan A; Saini J; Arvinda HR; Sinha S; Mathuranath PS; Taly AB
[Ad] Endereço:Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore 560029, India; Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore 560029, India.
[Ti] Título:Hypersomnolence-hyperkinetic movement disorder in a child with compound heterozygous mutation in 4-aminobutyrate aminotransferase (ABAT) gene.
[So] Source:Brain Dev;39(2):161-165, 2017 Feb.
[Is] ISSN:1872-7131
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Deficiency of gamma-amino-butyrate aminotransferase (ABAT) is a rare inherited disorder. A six-month-old girl presented with hyper-somnolence, hyperkinetic movements of distal extremities during wakefulness, hypotonia, bi-pyramidal signs, and impaired response to sound and visual stimuli. Brain MRI at five months showed restricted diffusion along the internal capsule and genu of corpus callosum. A follow up MRI at 18months, showed hyperintensities in brainstem, external and internal capsule, 'trilaminated' appearance of posterior limb of internal capsule and dysmyelination of sub-cortical white matter. MRS showed a peak between 2.2ppm and 2.4ppm, corresponding to glutamine, glutamate and GABA. EEG was normal at six months but showed multifocal epileptiform discharges at 18months. Targeted exome sequencing revealed compound heterozygous missense variations in ABAT resulting in its reduced function. We report the novel association of hypersomnolence and hyperkinetic movement disorder with ABAT variations thus expanding the clinical spectrum of this uncommon neuro-metabolic disorder and discuss the emerging role of GABA in pathways regulating sleep-wake cycle and movement disorders.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/genética
Distúrbios do Sono por Sonolência Excessiva/genética
Heterozigoto
Hipercinese/genética
Mutação de Sentido Incorreto
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/deficiência
Encéfalo/diagnóstico por imagem
Encéfalo/fisiopatologia
Deficiências do Desenvolvimento/diagnóstico por imagem
Deficiências do Desenvolvimento/genética
Deficiências do Desenvolvimento/fisiopatologia
Diagnóstico Diferencial
Distúrbios do Sono por Sonolência Excessiva/diagnóstico por imagem
Distúrbios do Sono por Sonolência Excessiva/fisiopatologia
Feminino
Seguimentos
Seres Humanos
Hipercinese/diagnóstico por imagem
Hipercinese/fisiopatologia
Lactente
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.6.1.19 (4-Aminobutyrate Transaminase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170214
[Lr] Data última revisão:
170214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160907
[St] Status:MEDLINE


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[PMID]:27918244
[Au] Autor:Li X; Zhang J; Wu X; Yan H; Zhang Y; He RH; Tang YJ; He YJ; Tan D; Mao XY; Yin JY; Liu ZQ; Zhou HH; Liu J
[Ad] Endereço:Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China.
[Ti] Título:Polymorphisms of ABAT, SCN2A and ALDH5A1 may affect valproic acid responses in the treatment of epilepsy in Chinese.
[So] Source:Pharmacogenomics;17(18):2007-2014, 2016 Dec.
[Is] ISSN:1744-8042
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: The clinical efficacy of valproic acid (VPA) varies greatly among epileptic patients. To find the potential genetic factors related to VPA responses, the pharmacogenetics study was conducted. METHODS: Two hundred and one Chinese Han epileptic patients who were treated by VPA for at least 1 year were recruited. Up to 24 SNPs in 11 candidate genes that correlate with the metabolism, transport or target of VPA were genotyped. RESULTS: Three SNPs, rs1731017 (ABAT), rs2304016 (SCN2A) and rs1054899 (ALDH5A1) were found associated with VPA responses with the p-values of 0.003, 0.007 and 0.048, respectively. Further interaction analysis showed that the interaction between rs17183814 (ABAT) and rs1641022 (SCN2A) was also correlated with the response of VPA (p = 0.006). CONCLUSION: This study found three SNPs and one interaction among ABAT, SCN2A and ALDH5A1 were significantly associated with VPA response, which indicated that these genes may play important roles in the pharmacological mechanism of VPA.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/genética
Anticonvulsivantes/uso terapêutico
Epilepsia/tratamento farmacológico
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Polimorfismo de Nucleotídeo Único
Succinato-Semialdeído Desidrogenase/genética
Ácido Valproico/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Epilepsia/genética
Feminino
Seres Humanos
Masculino
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (SCN2A protein, human); 614OI1Z5WI (Valproic Acid); EC 1.2.1.24 (ALDH5A1 protein, human); EC 1.2.1.24 (Succinate-Semialdehyde Dehydrogenase); EC 2.6.1.19 (4-Aminobutyrate Transaminase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161206
[St] Status:MEDLINE


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[PMID]:27903293
[Au] Autor:Besse A; Petersen AK; Hunter JV; Appadurai V; Lalani SR; Bonnen PE
[Ad] Endereço:Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
[Ti] Título:Personalized medicine approach confirms a milder case of ABAT deficiency.
[So] Source:Mol Brain;9(1):93, 2016 12 01.
[Is] ISSN:1756-6606
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ABAT deficiency (OMIM 613163) is a rare inborn error of metabolism caused by recessive variants in the gene 4-aminobutyric acid transaminase (ABAT), which is responsible for both the catalysis of GABA and maintenance of nucleoside pools in the mitochondria. To date, only a few patients have been reported worldwide. Their clinical presentation has been remarkably consistent with primary features of severe psychomotor retardation, encephalopathy, hypotonia, and infantile-onset refractory epilepsy. We report a new case of ABAT deficiency that marks an important departure from previous clinical findings. The patient presented at age 6 months with global developmental delay, hypotonia, hypersomnolence and mild choreiform movements. At age 18 months, the subject's clinical presentation was still milder than all previously reported patients and, most notably, did not include seizures. Clinical whole exome sequencing revealed two heterozygous ABAT missense variants that are rare and predicted damaging, but never before reported in a patient and were reported as variants of unknown significance. To test the potential pathogenicity of the variants identified in this patient we developed a cell-based system to test both functions of the ABAT protein via GABA transaminase enzyme activity and mtDNA copy number assays. This systematic approach was validated using vigabatrin, the irreversible inhibitor of ABAT, and leveraged to test the functionality of all ABAT variants in previously reported patients plus the variants in this new case. This work confirmed the novel variants compromised ABAT function to similar levels as variants in previously characterized cases with more severe clinical presentation, thereby confirming the molecular diagnosis of this patient. Additionally, functional studies conducted in cells from both mild and severe patient fibroblasts showed similar levels of compromise in mitochondrial membrane potential, respiratory capacity, ATP production and mtDNA depletion. These results illustrate how cell-based functional studies can aid in the diagnosis of a rare, neurological disorder. Importantly, this patient marks an expansion in the clinical phenotype for ABAT deficiency to a milder presentation that is more commonly seen in pediatric genetics and neurology clinics.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/deficiência
Erros Inatos do Metabolismo dos Aminoácidos/terapia
Medicina de Precisão
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/genética
4-Aminobutirato Transaminase/metabolismo
Erros Inatos do Metabolismo dos Aminoácidos/enzimologia
Erros Inatos do Metabolismo dos Aminoácidos/genética
Erros Inatos do Metabolismo dos Aminoácidos/patologia
Linhagem Celular Tumoral
Criança
Pré-Escolar
DNA Mitocondrial/genética
Metabolismo Energético
Feminino
Dosagem de Genes
Seres Humanos
Lactente
Imagem por Ressonância Magnética
Masculino
Mitocôndrias/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); EC 2.6.1.19 (4-Aminobutyrate Transaminase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161202
[St] Status:MEDLINE


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[PMID]:27638539
[Au] Autor:Budczies J
[Ad] Endereço:Institut für Pathologie, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland. jan.budczies@charite.de.
[Ti] Título:[Metabolome analysis of solid tumors].
[Ti] Título:Metabolomanalyse solider Tumoren..
[So] Source:Pathologe;37(Suppl 2):204-209, 2016 Nov.
[Is] ISSN:1432-1963
[Cp] País de publicação:Germany
[La] Idioma:ger
[Ab] Resumo:Metabolomics, the newest of the omics sciences that also include genomics, transcriptomics and proteomics, has matured into a reliable high-throughput technology. Gas chromatography combined with time-of-flight mass spectrometry (GC-TOFMS) is a suitable method to analyze the central metabolism in fresh frozen tumor tissue samples. Bioinformatics methods, including the PROFILE clustering developed by us, permit integrated analysis and fast interpretation of metabolomics data in the context of enzymatic reactions and metabolic pathways. The metabolome analyses of three solid tumor types presented here, together with the results of other authors, show that metabolites are suitable as biomarkers and provide diverse options for translation into the clinical setting.
[Mh] Termos MeSH primário: Biomarcadores Tumorais
Metaboloma/fisiologia
Neoplasias/patologia
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/metabolismo
Mama/patologia
Neoplasias da Mama/patologia
Neoplasias do Colo/tratamento farmacológico
Neoplasias do Colo/patologia
Feminino
Cromatografia Gasosa-Espectrometria de Massas
Ácido Glutâmico/metabolismo
Glutaminase/antagonistas & inibidores
Glutamina/metabolismo
Seres Humanos
Metaboloma/efeitos dos fármacos
Neoplasias/tratamento farmacológico
Neoplasias Hormônio-Dependentes/tratamento farmacológico
Neoplasias Hormônio-Dependentes/patologia
Neoplasias Ovarianas/patologia
Ovário/patologia
beta-Alanina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0RH81L854J (Glutamine); 11P2JDE17B (beta-Alanine); 3KX376GY7L (Glutamic Acid); EC 2.6.1.19 (4-Aminobutyrate Transaminase); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE


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[PMID]:27383885
[Au] Autor:Shakya AK; Kamal M; Balaramnavar VM; Bardaweel SK; Naik RR; Saxena AK; Siddiqui HH
[Ti] Título:Design, synthesis and evaluation of benzofuran-acetamide scaffold as potential anticonvulsant agent.
[So] Source:Acta Pharm;66(3):353-72, 2016 Sep 01.
[Is] ISSN:1846-9558
[Cp] País de publicação:Croatia
[La] Idioma:eng
[Ab] Resumo:A series of N-(2-(benzoyl/4-chlorobenzoyl)-benzofuran- 3-yl)-2-(substituted)-acetamide derivatives (4a-l, 5a-l) was synthesized in good yield. All synthesized compounds were in agreement with elemental and spectral data. The anticonvulsant activity of all synthesized compounds was assessed against the maximal electroshock induced seizures (MES) model in mice. Neurotoxicity was evaluated using the rotarod method. The majority of compounds exhibited anticonvulsant activity at a dose of 30 mg kg-1 body mass during 0.5-4 h, indicating their ability to prevent seizure spread at low doses. Relative to phenytoin, [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(cyclohexyl( methyl) amino)-acetamide] (5i) and [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-methylpiperidin-1- yl)-acetamide] (5c) demonstrated comparable relative anticonvulsant potency of 0.74 and 0.72, respectively, whereas [(N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-(furan-2-carbonyl)-piperazin-1-yl)-acetamide] (5f) exhibited the lowest relative potency of 0.16. The ALD50 of tested compounds ranged from 1.604 to 1.675 mmol kg-1 body mass. The ED50 of synthesized compounds ranged from 0.055 to 0.259 mmol kg-1 (~23.4 to 127.6 mg kg-1) body mass. The pharmacophore mapping of the examined compounds on standard drugs (phenobarbital, phenytoin, ralitolin and carbamazepine) strongly suggests that these compounds may exert their anticonvulsant activity via the same established mechanism as that of known drugs.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/metabolismo
Anticonvulsivantes/uso terapêutico
Benzofuranos/uso terapêutico
Desenho de Drogas
Modelos Moleculares
Convulsões/prevenção & controle
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/química
Acetamidas/efeitos adversos
Acetamidas/química
Acetamidas/metabolismo
Acetamidas/uso terapêutico
Animais
Anticonvulsivantes/efeitos adversos
Anticonvulsivantes/química
Anticonvulsivantes/metabolismo
Benzofuranos/efeitos adversos
Benzofuranos/química
Benzofuranos/metabolismo
Sítios de Ligação
Cerebelo/efeitos dos fármacos
Cerebelo/metabolismo
Relação Dose-Resposta a Droga
Agonistas GABAérgicos/efeitos adversos
Agonistas GABAérgicos/química
Agonistas GABAérgicos/metabolismo
Agonistas GABAérgicos/uso terapêutico
Glicina/efeitos adversos
Glicina/análogos & derivados
Glicina/química
Glicina/metabolismo
Glicina/uso terapêutico
Dose Letal Mediana
Masculino
Bulbo/efeitos dos fármacos
Bulbo/metabolismo
Mesencéfalo/efeitos dos fármacos
Mesencéfalo/metabolismo
Camundongos
Simulação de Acoplamento Molecular
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Síndromes Neurotóxicas/etiologia
Síndromes Neurotóxicas/metabolismo
Ratos Wistar
Sus scrofa
Ácido gama-Aminobutírico/química
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Anticonvulsants); 0 (Benzofurans); 0 (GABA Agonists); 0 (N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-methylpiperidin-1-yl)acetamide); 0 (N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(cyclohexyl(methyl)amino)acetamide); 56-12-2 (gamma-Aminobutyric Acid); EC 2.6.1.19 (4-Aminobutyrate Transaminase); TE7660XO1C (Glycine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170126
[Lr] Data última revisão:
170126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160708
[St] Status:MEDLINE


  9 / 1206 MEDLINE  
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[PMID]:27261619
[Au] Autor:Piplani S; Verma PK; Kumar A
[Ad] Endereço:Toxicology & Computational Biology Group, Centre for Bioinformatics, M D University, Rohtak 124 001, India.
[Ti] Título:Neuroinformatics analyses reveal GABAt and SSADH as major proteins involved in anticonvulsant activity of valproic acid.
[So] Source:Biomed Pharmacother;81:402-10, 2016 Jul.
[Is] ISSN:1950-6007
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The unequivocal hypotheses about anticonvulsant activity of valproic acid (VPA) have always been a basic hurdle in designing next generation neurotherapeutics, particularly the anti-epileptic drugs. The present study reports about a comprehensive in-silico investigation into qualitative and quantitative binding of VPA and corresponding natural ligands of four major enzymes involved in neurotransmissions, namely-GABA transaminase (GABAt), α-keto glutarate dehydrogenase (α-KGDH), Succinate Semialdehyde dehydrogenase (SSADH) and Glutamate Decarboxylase (GAD), respectively. The molecular docking analyses revealed that VPA inhibits GABAt and α-KGDH through allosteric while SSADH through competitive mode of binding. There is an observed elevation in binding of glutamate over GAD in the presence of VPA. The docking inhibition constant (Ki) of VPA to all the studied enzymatic receptors were observed to be well below the therapeutic concentration of VPA in blood, except for α-KGDH, thus favouring GABAergic over glutamatergic mode of anticonvulsant activity of VPA. The report is probably the first comprehensive in-silico molecular study about VPA action.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/metabolismo
Anticonvulsivantes/farmacologia
Simulação por Computador
Succinato-Semialdeído Desidrogenase/metabolismo
Ácido Valproico/farmacologia
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/química
Anticonvulsivantes/química
Sítios de Ligação
Glutamato Descarboxilase/metabolismo
Glutamatos/metabolismo
Seres Humanos
Ligações de Hidrogênio
Complexo Cetoglutarato Desidrogenase/metabolismo
Ácidos Cetoglutáricos/metabolismo
Ligantes
Simulação de Acoplamento Molecular
Homologia Estrutural de Proteína
Succinato-Semialdeído Desidrogenase/química
Ácido Valproico/química
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Glutamates); 0 (Ketoglutaric Acids); 0 (Ligands); 56-12-2 (gamma-Aminobutyric Acid); 614OI1Z5WI (Valproic Acid); 8ID597Z82X (alpha-ketoglutaric acid); EC 1.2.1.24 (Succinate-Semialdehyde Dehydrogenase); EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex); EC 2.6.1.19 (4-Aminobutyrate Transaminase); EC 4.1.1.15 (Glutamate Decarboxylase)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170131
[Lr] Data última revisão:
170131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160605
[St] Status:MEDLINE


  10 / 1206 MEDLINE  
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Texto completo
[PMID]:27135813
[Au] Autor:Aghdam MS; Naderi R; Jannatizadeh A; Babalar M; Sarcheshmeh MA; Faradonbe MZ
[Ad] Endereço:Department of Horticultural Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran. Electronic address: aghdamm@ut.ac.ir.
[Ti] Título:Impact of exogenous GABA treatments on endogenous GABA metabolism in anthurium cut flowers in response to postharvest chilling temperature.
[So] Source:Plant Physiol Biochem;106:11-5, 2016 Sep.
[Is] ISSN:1873-2690
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Anthurium flowers are susceptible to chilling injury, and the optimum storage temperature is 12.5-20 °C. The γ-aminobutyric acid (GABA) shunt pathway may alleviate chilling stress in horticultural commodities by providing energy (ATP), reducing molecules (NADH), and minimizing accumulation of reactive oxygen species (ROS). In this experiment, the impact of a preharvest spray treatment with 1 mM GABA and postharvest treatment of 5 mM GABA stem-end dipping on GABA shunt pathway activity of anthurium cut flowers (cv. Sirion) in response to cold storage (4 °C for 21 days) was investigated. GABA treatments resulted in lower glutamate decarboxylase (GAD) and higher GABA transaminase (GABA-T) activities in flowers during cold storage, which was associated with lower GABA content and coincided with higher ATP content. GABA treatments also enhanced accumulation of endogenous glycine betaine (GB) in flowers during cold storage, as well as higher spathe relative water content (RWC). These findings suggest that GABA treatments may alleviate chilling injury of anthurium cut flowers by enhancing GABA shunt pathway activity leading to provide sufficient ATP and promoting endogenous GB accumulation.
[Mh] Termos MeSH primário: Araceae/fisiologia
Temperatura Baixa
Flores/fisiologia
Ácido gama-Aminobutírico/metabolismo
Ácido gama-Aminobutírico/farmacologia
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/metabolismo
Araceae/efeitos dos fármacos
Betaína/metabolismo
Flores/efeitos dos fármacos
Glutamato Descarboxilase/metabolismo
Água/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
059QF0KO0R (Water); 3SCV180C9W (Betaine); 56-12-2 (gamma-Aminobutyric Acid); EC 2.6.1.19 (4-Aminobutyrate Transaminase); EC 4.1.1.15 (Glutamate Decarboxylase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170327
[Lr] Data última revisão:
170327
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160503
[St] Status:MEDLINE



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