Base de dados : MEDLINE
Pesquisa : D02.886.092 [Categoria DeCS]
Referências encontradas : 144 [refinar]
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[PMID]:28699511
[Au] Autor:Kulikova E; Kulikov A
[Ad] Endereço:Federal Research Center, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090, Novosibirsk. Russian Federation.
[Ti] Título:Striatal-enriched Tyrosine Protein Phosphatase (STEP) in the Mechanisms of Depressive Disorders.
[So] Source:Curr Protein Pept Sci;18(11):1152-1162, 2017 Aug 30.
[Is] ISSN:1875-5550
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Striatal-enriched tyrosine protein phosphatase (STEP) is expressed mainly in the brain. Its dysregulation is associated with Alzheimer's and Huntington's diseases, schizophrenia, fragile X syndrome, drug abuse and stroke/ischemia. However, an association between STEP and depressive disorders is still obscure. The review discusses the theoretical foundations and experimental facts concerning possible relationship between STEP dysregulation and depression risk. STEP dephosphorylates and inactivates several key neuronal signaling proteins such as extracellular signal-regulating kinase 1 and 2 (ERK1/2), stress activated protein kinases p38, the Src family tyrosine kinases Fyn, Pyk2, NMDA and AMPA glutamate receptors. The inactivation of these proteins decreases the expression of brain derived neurotrophic factor (BDNF) necessary for neurogenesis and neuronal survival. The deficit of BDNF results in progressive degeneration of neurons in the hippocampus and cortex and increases depression risk. At the same time, a STEP inhibitor, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), increases BDNF expression in the hippocampus and attenuated the depressivelike behavior in mice. Thus, STEP is involved in the mechanism of depressive disorders and it is a promising molecular target for atypical antidepressant drugs of new generation.
[Mh] Termos MeSH primário: Encéfalo/enzimologia
Depressão/genética
Neurônios/enzimologia
Proteínas Tirosina Fosfatases não Receptoras/genética
[Mh] Termos MeSH secundário: Animais
Benzotiepinas/farmacologia
Encéfalo/efeitos dos fármacos
Encéfalo/patologia
Fator Neurotrófico Derivado do Encéfalo/genética
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Depressão/tratamento farmacológico
Depressão/enzimologia
Depressão/fisiopatologia
Modelos Animais de Doenças
Regulação da Expressão Gênica
Seres Humanos
Camundongos
Neurônios/efeitos dos fármacos
Neurônios/patologia
Fosforilação
Proteínas Quinases/genética
Proteínas Quinases/metabolismo
Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores
Proteínas Tirosina Fosfatases não Receptoras/metabolismo
Proteínas Proto-Oncogênicas c-fyn/genética
Proteínas Proto-Oncogênicas c-fyn/metabolismo
Receptores de AMPA/genética
Receptores de AMPA/metabolismo
Receptores de N-Metil-D-Aspartato/genética
Receptores de N-Metil-D-Aspartato/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Benzothiepins); 0 (Brain-Derived Neurotrophic Factor); 0 (Receptors, AMPA); 0 (Receptors, N-Methyl-D-Aspartate); 0 (brain-derived neurotrophic factor, human); EC 2.7.- (Protein Kinases); EC 2.7.10.2 (FYN protein, human); EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn); EC 3.1.3.48 (PTPN5 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
[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:170713
[St] Status:MEDLINE
[do] DOI:10.2174/1389203718666170710121532


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[PMID]:27316378
[Au] Autor:Bozinovic N; Segan S; Vojnovic S; Pavic A; Solaja BA; Nikodinovic-Runic J; Opsenica IM
[Ad] Endereço:Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
[Ti] Título:Synthesis and anti-Candida activity of novel benzothiepino[3,2-c]pyridine derivatives.
[So] Source:Chem Biol Drug Des;88(6):795-806, 2016 Dec.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi Candida albicans (ATCC 10231), C. parapsilosis (clinical isolate), Gram-negative bacterium Pseudomonas aeruginosa (ATCC 44752), and Gram-positive bacterium Staphylococcus aureus (ATCC 25923). Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Selected thiepines efficiently inhibited Candida hyphae formation, a trait necessary for their pathogenicity. Thiepine 8-phenyl[1]benzothiepino[3,2-c]pyridine (16) efficiently killed Candida albicans at 15.6 µg/mL and showed no embryotoxicity at 75 µg/mL. Derivative 8-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl][1]benzothiepino[3,2-c]pyridine (23) caused significant hemolysis and in vitro DNA interaction. The position of the phenyl ring was essential for the antifungal activity, while the electronic effects of the substituents did not significantly influence activity. Results obtained from in vivo embryotoxicity on zebrafish (Danio rerio) encourage further structure optimizations.
[Mh] Termos MeSH primário: Antifúngicos/síntese química
Antifúngicos/farmacologia
Benzotiepinas/química
Candida/efeitos dos fármacos
Piridinas/química
[Mh] Termos MeSH secundário: Animais
Testes de Sensibilidade Microbiana
Pseudomonas aeruginosa/efeitos dos fármacos
Análise Espectral/métodos
Staphylococcus aureus/efeitos dos fármacos
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Benzothiepins); 0 (Pyridines)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160619
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.12809


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[PMID]:26450419
[Au] Autor:Xu J; Kurup P; Baguley TD; Foscue E; Ellman JA; Nairn AC; Lombroso PJ
[Ad] Endereço:Child Study Center, Yale University, 230 S Frontage Rd., New Haven, CT, 06520, USA.
[Ti] Título:Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice.
[So] Source:Cell Mol Life Sci;73(7):1503-14, 2016 Apr.
[Is] ISSN:1420-9071
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.
[Mh] Termos MeSH primário: Fator Neurotrófico Derivado do Encéfalo/metabolismo
Transtornos Cognitivos/tratamento farmacológico
Fenciclidina/uso terapêutico
Proteínas Tirosina Fosfatases/metabolismo
[Mh] Termos MeSH secundário: Animais
Benzotiepinas/farmacologia
Fator Neurotrófico Derivado do Encéfalo/análise
Proteína de Ligação a CREB/antagonistas & inibidores
Proteína de Ligação a CREB/genética
Proteína de Ligação a CREB/metabolismo
Células Cultivadas
Transtornos Cognitivos/metabolismo
Transtornos Cognitivos/patologia
Regulação para Baixo/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Atividade Motora/efeitos dos fármacos
Neurônios/citologia
Neurônios/metabolismo
Fenciclidina/farmacologia
Fosforilação/efeitos dos fármacos
Proteínas Tirosina Fosfatases/antagonistas & inibidores
Proteínas Tirosina Fosfatases/genética
Interferência de RNA
Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
Receptores de N-Metil-D-Aspartato/metabolismo
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Benzothiepins); 0 (Brain-Derived Neurotrophic Factor); 0 (Receptors, N-Methyl-D-Aspartate); EC 2.3.1.48 (CREB-Binding Protein); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3); EC 3.1.3.48 (Protein Tyrosine Phosphatases); EC 3.1.3.48 (striatal-enriched tyrosine phosphatase 61, mouse); J1DOI7UV76 (Phencyclidine)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151010
[St] Status:MEDLINE
[do] DOI:10.1007/s00018-015-2057-1


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[PMID]:26316048
[Au] Autor:Xu J; Kurup P; Azkona G; Baguley TD; Saavedra A; Nairn AC; Ellman JA; Pérez-Navarro E; Lombroso PJ
[Ad] Endereço:Yale University School of Medicine, New Haven, Connecticut, USA.
[Ti] Título:Down-regulation of BDNF in cell and animal models increases striatal-enriched protein tyrosine phosphatase 61 (STEP61 ) levels.
[So] Source:J Neurochem;136(2):285-94, 2016 Jan.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Brain-derived neurotrophic factor (BDNF) regulates synaptic strengthening and memory consolidation, and altered BDNF expression is implicated in a number of neuropsychiatric and neurodegenerative disorders. BDNF potentiates N-methyl-D-aspartate receptor function through activation of Fyn and ERK1/2. STriatal-Enriched protein tyrosine Phosphatase (STEP) is also implicated in many of the same disorders as BDNF but, in contrast to BDNF, STEP opposes the development of synaptic strengthening. STEP-mediated dephosphorylation of the NMDA receptor subunit GluN2B promotes internalization of GluN2B-containing NMDA receptors, while dephosphorylation of the kinases Fyn, Pyk2, and ERK1/2 leads to their inactivation. Thus, STEP and BDNF have opposing functions. In this study, we demonstrate that manipulation of BDNF expression has a reciprocal effect on STEP61 levels. Reduced BDNF signaling leads to elevation of STEP61 both in BDNF(+/-) mice and after acute BDNF knockdown in cortical cultures. Moreover, a newly identified STEP inhibitor reverses the biochemical and motor abnormalities in BDNF(+/-) mice. In contrast, increased BDNF signaling upon treatment with a tropomyosin receptor kinase B agonist results in degradation of STEP61 and a subsequent increase in the tyrosine phosphorylation of STEP substrates in cultured neurons and in mouse frontal cortex. These findings indicate that BDNF-tropomyosin receptor kinase B signaling leads to degradation of STEP61 , while decreased BDNF expression results in increased STEP61 activity. A better understanding of the opposing interaction between STEP and BDNF in normal cognitive functions and in neuropsychiatric disorders will hopefully lead to better therapeutic strategies. Altered expression of BDNF and STEP61 has been implicated in several neurological disorders. BDNF and STEP61 are known to regulate synaptic strengthening, but in opposite directions. Here, we report that reduced BDNF signaling leads to elevation of STEP61 both in BDNF(+/-) mice and after acute BDNF knockdown in cortical cultures. In contrast, activation of TrkB receptor results in the degradation of STEP61 and reverses hyperlocomotor activity in BDNF(+/-) mice. Moreover, inhibition of STEP61 by TC-2153 is sufficient to enhance the Tyr phosphorylation of STEP substrates and also reverses hyperlocomotion in BDNF(+/-) mice. These findings give us a better understanding of the regulation of STEP61 by BDNF in normal cognitive functions and in neuropsychiatric disorders.
[Mh] Termos MeSH primário: Fator Neurotrófico Derivado do Encéfalo/metabolismo
Regulação para Baixo/fisiologia
Neurônios/metabolismo
Proteínas Tirosina Fosfatases/metabolismo
[Mh] Termos MeSH secundário: Animais
Benzotiepinas/farmacologia
Encéfalo/citologia
Fator Neurotrófico Derivado do Encéfalo/genética
Células Cultivadas
Inibidores de Cisteína Proteinase/farmacologia
Regulação para Baixo/efeitos dos fármacos
Regulação para Baixo/genética
Embrião de Mamíferos
Feminino
Flavonas/farmacologia
Leupeptinas/farmacologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Atividade Motora/efeitos dos fármacos
Atividade Motora/genética
Neurônios/efeitos dos fármacos
Proteínas Tirosina Fosfatases/genética
RNA Interferente Pequeno/farmacologia
Ratos
Ratos Sprague-Dawley
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (6,7-dihydroxyflavone); 0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Benzothiepins); 0 (Brain-Derived Neurotrophic Factor); 0 (Cysteine Proteinase Inhibitors); 0 (Flavones); 0 (Leupeptins); 0 (RNA, Small Interfering); EC 3.1.3.48 (Protein Tyrosine Phosphatases); EC 3.1.3.48 (striatal-enriched tyrosine phosphatase 61, mouse); RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150829
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.13295


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[PMID]:26270590
[Au] Autor:Azkona G; Saavedra A; Aira Z; Aluja D; Xifró X; Baguley T; Alberch J; Ellman JA; Lombroso PJ; Azkue JJ; Pérez-Navarro E
[Ad] Endereço:aDepartament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain bInstitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain cCentro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain dDepartment of Neurosciences, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Bizkaia, Spain eDepartament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Catalonia, Spain fDepartment of Chemistry, Yale University, New Haven, CT, USA gChild Study Center, Yale School of Medicine, Yale University, New Haven, CT, USA.
[Ti] Título:Striatal-enriched protein tyrosine phosphatase modulates nociception: evidence from genetic deletion and pharmacological inhibition.
[So] Source:Pain;157(2):377-86, 2016 Feb.
[Is] ISSN:1872-6623
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The information from nociceptors is processed in the dorsal horn of the spinal cord by complex circuits involving excitatory and inhibitory interneurons. It is well documented that GluN2B and ERK1/2 phosphorylation contributes to central sensitization. Striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates GluN2B and ERK1/2, promoting internalization of GluN2B and inactivation of ERK1/2. The activity of STEP was modulated by genetic (STEP knockout mice) and pharmacological (recently synthesized STEP inhibitor, TC-2153) approaches. STEP(61) protein levels in the lumbar spinal cord were determined in male and female mice of different ages. Inflammatory pain was induced by complete Freund's adjuvant injection. Behavioral tests, immunoblotting, and electrophysiology were used to analyze the effect of STEP on nociception. Our results show that both genetic deletion and pharmacological inhibition of STEP induced thermal hyperalgesia and mechanical allodynia, which were accompanied by increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Striatal-enriched protein tyrosine phosphatase heterozygous and knockout mice presented a similar phenotype. Furthermore, electrophysiological experiments showed that TC-2153 increased C fiber-evoked spinal field potentials. Interestingly, we found that STEP(61) protein levels in the lumbar spinal cord inversely correlated with thermal hyperalgesia associated with age and female gender in mice. Consistently, STEP knockout mice failed to show age-related thermal hyperalgesia, although gender-related differences were preserved. Moreover, in a model of inflammatory pain, hyperalgesia was associated with increased phosphorylation-mediated STEP(61) inactivation and increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Collectively, the present results underscore an important role of spinal STEP activity in the modulation of nociception.
[Mh] Termos MeSH primário: Nociceptividade/fisiologia
Limiar da Dor/efeitos dos fármacos
Dor/patologia
Dor/fisiopatologia
Proteínas Tirosina Fosfatases não Receptoras/deficiência
[Mh] Termos MeSH secundário: Animais
Benzotiepinas/farmacologia
Benzotiepinas/uso terapêutico
Modelos Animais de Doenças
Inibidores Enzimáticos/farmacologia
Inibidores Enzimáticos/uso terapêutico
Potenciais Evocados/efeitos dos fármacos
Potenciais Evocados/genética
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/genética
Hiperalgesia/tratamento farmacológico
Hiperalgesia/genética
Hiperalgesia/metabolismo
Hiperalgesia/patologia
Inflamação/induzido quimicamente
Inflamação/complicações
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Sistema de Sinalização das MAP Quinases/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Fibras Nervosas Amielínicas/efeitos dos fármacos
Fibras Nervosas Amielínicas/fisiologia
Nociceptividade/efeitos dos fármacos
Dor/etiologia
Proteínas Tirosina Fosfatases não Receptoras/genética
Ratos
Ratos Sprague-Dawley
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Benzothiepins); 0 (Enzyme Inhibitors); EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor); EC 3.1.3.48 (Ptpn5 protein, mouse)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170201
[Lr] Data última revisão:
170201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150814
[St] Status:MEDLINE
[do] DOI:10.1097/j.pain.0000000000000329


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[PMID]:26369372
[Au] Autor:AL-Shuaeeb RA; Galvani G; Bernadat G; Brion JD; Alami M; Messaoudi S
[Ad] Endereço:Univ. Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Equipe Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France. samir.messaoudi@u-psud.fr mouad.alami@u-psud.fr.
[Ti] Título:Diversity-oriented synthesis of fused thioglycosyl benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-5(2H)-ones by a sequence of palladium-catalyzed glycosyl thiol arylation and deprotection-lactonization reactions.
[So] Source:Org Biomol Chem;13(44):10904-16, 2015 Nov 28.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:An efficient synthesis of thioglycosylated benzo[e][1,4]oxathiepin-5-one and benzothiazepinone derivatives by a sequence of palladium-catalyzed glycosyl thiol arylation followed by deprotection-lactonization reactions has been reported. This diversity-oriented strategy enabled access to unknown complex cyclic scaffolds with polyhydroxylated appendages of biological interest.
[Mh] Termos MeSH primário: Benzotiepinas/química
Lactonas/química
Paládio/química
Compostos de Sulfidrila/química
Tiazepinas/química
[Mh] Termos MeSH secundário: Catálise
Glicosilação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzothiepins); 0 (Lactones); 0 (Sulfhydryl Compounds); 0 (Thiazepines); 5TWQ1V240M (Palladium)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:151104
[Lr] Data última revisão:
151104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150916
[St] Status:MEDLINE
[do] DOI:10.1039/c5ob01603g


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[PMID]:25966577
[Au] Autor:Kulikova EA; Tikhonova MA; Volcho KP; Khomenko TM; Salakhutdinov NF; Kulikov AV; Popova NK
[Ti] Título:[Comparison of behavioral effects of fluoxetine, imipramine and new psychotropic drug TC-2153 on mice with hereditary predisposition to catalepsy].
[So] Source:Zh Vyssh Nerv Deiat Im I P Pavlova;65(1):105-12, 2015 Jan-Feb.
[Is] ISSN:0044-4677
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Behavioral effects of classic antidepressants, fluoxetine and imipramine, and new psychotropic benzopentathiepin TC-2153 (20 mg/kg, per os) were studied on mice differing in the predisposition to catalepsy-noncataleptic AKR strain and cataleptic strains CBA and AKR.CBA-D13Mit76 (D13). Mice of D13 strain was created by transferring the CBA-allele of major locus of catalepsy to AKR genome. In the forced swim test (FST) fluoxetine showed antidepressant effect on mice of all three strains, imipramine was effective only in D13 mice, while TC-2153 produced antidepressant effect on AKR and D13 mice. Unlike to imipramine and fluoxetine, TC-2153 did not produce negative side effects in the open field and elevated plus-maze tests. Thus, TC-2153 produces antidepressant effects similar to imipramine and fluoxetine, without any visible negative side effect on locomotory activity and anxiety. The D13 mice in the FST showed high sensitivity to the studied drugs in comparison to the parent strains and can be used as new genetic model for investigation of the mechanism of antidepressant effects.
[Mh] Termos MeSH primário: Antidepressivos/administração & dosagem
Ansiedade/tratamento farmacológico
Catalepsia/tratamento farmacológico
Predisposição Genética para Doença
[Mh] Termos MeSH secundário: Animais
Ansiedade/genética
Ansiedade/fisiopatologia
Benzotiepinas/administração & dosagem
Catalepsia/genética
Catalepsia/fisiopatologia
Fluoxetina/administração & dosagem
Genótipo
Seres Humanos
Imipramina/administração & dosagem
Camundongos
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Antidepressive Agents); 0 (Benzothiepins); 01K63SUP8D (Fluoxetine); OGG85SX4E4 (Imipramine)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:150513
[Lr] Data última revisão:
150513
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150514
[St] Status:MEDLINE


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[PMID]:25666825
[Au] Autor:Baguley TD; Nairn AC; Lombroso PJ; Ellman JA
[Ad] Endereço:Department of Chemistry, Yale University, New Haven, CT 06520, United States.
[Ti] Título:Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP.
[So] Source:Bioorg Med Chem Lett;25(5):1044-6, 2015 Mar 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Striatal-enriched protein tyrosine phosphatase (STEP) is a brain specific protein tyrosine phosphatase that has been implicated in many neurodegenerative diseases, such as Alzheimer's disease. We recently reported the benzopentathiepin TC-2153 as a potent inhibitor of STEP in vitro, cells and animals. Herein, we report the synthesis and evaluation of TC-2153 analogs in order to define what structural features are important for inhibition and to identify positions tolerant of substitution for further study. The trifluoromethyl substitution is beneficial for inhibitor potency, and the amine is tolerant of acylation, and thus provides a convenient handle for introducing additional functionality such as reporter groups.
[Mh] Termos MeSH primário: Benzotiepinas/química
Benzotiepinas/farmacologia
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Proteínas Tirosina Fosfatases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/enzimologia
Animais
Benzotiepinas/síntese química
Corpo Estriado/efeitos dos fármacos
Corpo Estriado/enzimologia
Inibidores Enzimáticos/síntese química
Halogenação
Metilação
Camundongos
Proteínas Tirosina Fosfatases/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Benzothiepins); 0 (Enzyme Inhibitors); EC 3.1.3.48 (Protein Tyrosine Phosphatases)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150211
[St] Status:MEDLINE


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[PMID]:25093574
[Au] Autor:Robinson R
[Ad] Endereço:Freelance Science Writer, Sherborn, Massachusetts, United States of America.
[Ti] Título:A novel phosphatase inhibitor may be a STEP toward ameliorating cognitive dysfunction.
[So] Source:PLoS Biol;12(8):e1001924, 2014 Aug.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Transtornos Cognitivos/tratamento farmacológico
Transtornos Cognitivos/enzimologia
Inibidores Enzimáticos/uso terapêutico
Proteínas Tirosina Fosfatases não Receptoras/metabolismo
[Mh] Termos MeSH secundário: Animais
Benzotiepinas/química
Benzotiepinas/farmacologia
Benzotiepinas/uso terapêutico
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Ensaios de Triagem em Larga Escala
Seres Humanos
Camundongos
Fosforilação/efeitos dos fármacos
Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Benzothiepins); 0 (Enzyme Inhibitors); EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:170224
[Lr] Data última revisão:
170224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140806
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.1001924


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[PMID]:25093460
[Au] Autor:Xu J; Chatterjee M; Baguley TD; Brouillette J; Kurup P; Ghosh D; Kanyo J; Zhang Y; Seyb K; Ononenyi C; Foscue E; Anderson GM; Gresack J; Cuny GD; Glicksman MA; Greengard P; Lam TT; Tautz L; Nairn AC; Ellman JA; Lombroso PJ
[Ad] Endereço:Child Study Center, Yale University, New Haven, Connecticut, United States of America.
[Ti] Título:Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.
[So] Source:PLoS Biol;12(8):e1001923, 2014 Aug.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/enzimologia
Transtornos Cognitivos/tratamento farmacológico
Transtornos Cognitivos/enzimologia
Inibidores Enzimáticos/uso terapêutico
Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores
[Mh] Termos MeSH secundário: Doença de Alzheimer/complicações
Doença de Alzheimer/patologia
Sequência de Aminoácidos
Animais
Benzotiepinas/farmacologia
Benzotiepinas/uso terapêutico
Domínio Catalítico
Morte Celular/efeitos dos fármacos
Córtex Cerebral/patologia
Transtornos Cognitivos/complicações
Transtornos Cognitivos/patologia
Cisteína/metabolismo
Modelos Animais de Doenças
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Ensaios de Triagem em Larga Escala
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Dados de Sequência Molecular
Neurônios/efeitos dos fármacos
Neurônios/patologia
Fosforilação/efeitos dos fármacos
Fosfotirosina/metabolismo
Proteínas Tirosina Fosfatases não Receptoras/química
Proteínas Tirosina Fosfatases não Receptoras/metabolismo
Especificidade por Substrato/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine); 0 (Benzothiepins); 0 (Enzyme Inhibitors); 21820-51-9 (Phosphotyrosine); EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor); EC 3.1.3.48 (Ptpn5 protein, mouse); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:170224
[Lr] Data última revisão:
170224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140806
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.1001923



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