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[PMID]:27452335
[Au] Autor:Rodriguez CR; Alvarez LD; Dansey MV; Paolo LS; Veleiro AS; Pecci A; Burton G
[Ad] Endereço:Universidad de Buenos Aires, CONICET. UMYMFOR and Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Pabellón 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
[Ti] Título:Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRß activity.
[So] Source:J Steroid Biochem Mol Biol;165(Pt B):268-276, 2017 Jan.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293T cells co-transfected with full length human LXRß expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3ß,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the case of the difluoroalcohol, the fluorine atoms actively participated in the interaction with several residues in the ligand binding pocket leading to a stabilization of the active receptor conformation.
[Mh] Termos MeSH primário: Colestenos/química
Flúor/química
Hidroxicolesteróis/química
Receptores X do Fígado/agonistas
Noresteroides/química
Oxisteróis/química
[Mh] Termos MeSH secundário: Álcoois/química
Benzoatos/química
Benzilaminas/química
Colesterol/química
Células HEK293
Seres Humanos
Ligações de Hidrogênio
Ligantes
Receptores X do Fígado/antagonistas & inibidores
Espectroscopia de Ressonância Magnética
Simulação de Dinâmica Molecular
Ligação Proteica
Transdução de Sinais
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (25,25-difluoro-27-nor-26-hydroxycholesterol); 0 (25,25-difluoro-27-norcholestenoic acid); 0 (Alcohols); 0 (Benzoates); 0 (Benzylamines); 0 (Cholestenes); 0 (GW 3965); 0 (Hydroxycholesterols); 0 (Ligands); 0 (Liver X Receptors); 0 (Norsteroids); 0 (Oxysterols); 0 (cholestenoic acid); 284SYP0193 (Fluorine); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170706
[Lr] Data última revisão:
170706
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160726
[St] Status:MEDLINE


  2 / 303 MEDLINE  
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[PMID]:27623548
[Au] Autor:Whuang TY; Tsai WC; Chen NF; Chen ZC; Tsui KH; Wen ZH; Su YD; Chang YC; Chen YH; Lu MC; Fang LS; Chen JJ; Wu TY; Wu YC; Sung PJ
[Ad] Endereço:Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan; National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan.
[Ti] Título:Columnaristerol A, a novel 19-norsterol from the Formosan octocoral Nephthea columnaris.
[So] Source:Bioorg Med Chem Lett;26(20):4966-4969, 2016 10 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Columnaristerol A (1), a rare natural 19-norsterol possessing a 10ß-hydroxy group was isolated from the Formosan octocoral Nephthea columnaris, and its structure was elucidated by spectroscopic methods. Sterol 1 was found to be a cytotoxic agent that exhibited in vitro moderate cytotoxic activity against MOLT-4 and SUP-T1 human leukemia-lymphoma cell lines.
[Mh] Termos MeSH primário: Antozoários/metabolismo
Noresteroides/química
Noresteroides/farmacologia
Esteróis/química
Esteróis/farmacologia
[Mh] Termos MeSH secundário: Animais
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13
Linhagem Celular Tumoral
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Espectroscopia de Prótons por Ressonância Magnética
Relação Estrutura-Atividade
Taiwan
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Norsteroids); 0 (Sterols); 0 (columnaristerol A)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160914
[St] Status:MEDLINE


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[PMID]:25377730
[Au] Autor:Emnett CM; Eisenman LN; Mohan J; Taylor AA; Doherty JJ; Paul SM; Zorumski CF; Mennerick S
[Ad] Endereço:Graduate Program in Neuroscience, Washington University, St Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
[Ti] Título:Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel.
[So] Source:Br J Pharmacol;172(5):1333-47, 2015 Mar.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers. EXPERIMENTAL APPROACH: We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques. KEY RESULTS: SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks - measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection. CONCLUSIONS AND IMPLICATIONS: Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour.
[Mh] Termos MeSH primário: Regulação Alostérica/efeitos dos fármacos
Hidroxicolesteróis/farmacologia
Noresteroides/farmacologia
Pregnenolona/farmacologia
Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Relação Dose-Resposta a Droga
Feminino
Hidroxicolesteróis/química
Noresteroides/química
Pregnenolona/química
Ratos
Receptores de N-Metil-D-Aspartato/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 ((delta5,6-3-oxynorcholenyl)dimethylcarbinol); 0 (Hydroxycholesterols); 0 (Norsteroids); 0 (Receptors, N-Methyl-D-Aspartate); 04Y4D91RG0 (pregnenolone sulfate); 73R90F7MQ8 (Pregnenolone)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141108
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13007


  4 / 303 MEDLINE  
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[PMID]:25231340
[Au] Autor:Mun B; Wang W; Kim H; Hahn D; Yang I; Won DH; Kim EH; Lee J; Han C; Kim H; Ekins M; Nam SJ; Choi H; Kang H
[Ad] Endereço:Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University, NS-80, Seoul, 151-747, Republic of Korea.
[Ti] Título:Cytotoxic 5α,8α-epidioxy sterols from the marine sponge Monanchora sp.
[So] Source:Arch Pharm Res;38(1):18-25, 2015 Jan.
[Is] ISSN:0253-6269
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:Three new sterols, 5α,8α-epidioxy-24-norcholesta-6,9(11),22-trien-3ß-ol (1), 5α,8α-epidioxy-cholesta-6,9(11),24-trien-3ß-ol (2), and 5α,8α-epidioxy-cholesta-6,23-dien-3ß,25-diol (3), with four known sterols (4-7) were isolated from a marine sponge Monanchora sp. Their chemical structures were elucidated by extensive spectroscopic analysis. Compounds 1 and 3-7 showed moderate cytotoxicity against several human carcinoma cell lines including renal (A-498), pancreatic (PANC-1 and MIA PaCa-2), and colorectal (HCT 116) cancer cell lines.
[Mh] Termos MeSH primário: Colestadienóis/isolamento & purificação
Colestadienóis/farmacologia
Colestenos/isolamento & purificação
Colestenos/farmacologia
Noresteroides/isolamento & purificação
Noresteroides/farmacologia
Poríferos/química
Esteróis/isolamento & purificação
Esteróis/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/isolamento & purificação
Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Esteróis/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (5,8-epidioxy-24-norcholesta-6,9(11),22-trien-3-ol); 0 (5,8-epidioxycholesta-6,23-dien-3,25-diol); 0 (Antineoplastic Agents); 0 (Cholestadienols); 0 (Cholestenes); 0 (Norsteroids); 0 (Sterols)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150106
[Lr] Data última revisão:
150106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140919
[St] Status:MEDLINE
[do] DOI:10.1007/s12272-014-0480-8


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[PMID]:25174108
[Au] Autor:Guo S; Duan JA; Zhao JL; Qian DW; Zhang WJ
[Ti] Título:[Chemical constituents from seeds of Ziziphus mauritiana].
[So] Source:Zhong Yao Cai;37(3):432-5, 2014 Mar.
[Is] ISSN:1001-4454
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: To study the chemical constituents in the seeds of Ziziphus mauritiana. METHODS: The constituents were isolated by silica column chromatography and their structures were elucidated by physico-chemical properties and spectroscopic analysis. RESULTS: Twelve compounds were isolated from the seeds of Ziziphus mauritiana and identified as betulinic aldehyde (1), betulinic acid (2), ceanothic acid (3), frangufoline (4), spinosin (5), beta-sitosterol (6), daucosterol (7), daucosterol-6'-octadecanoate (8), sucrose (9), docosanoic acid (10), stearic acid (11), palmitoleic acid (12). CONCLUSION: All the compounds are obtained from Ziziphus mauritiana seeds for the first time and compounds 4,5 and 8 are isolated from this plant for the first time.
[Mh] Termos MeSH primário: Extratos Vegetais/química
Plantas Medicinais/química
Sementes/química
Ziziphus/química
[Mh] Termos MeSH secundário: Flavonoides/química
Flavonoides/isolamento & purificação
Espectroscopia de Ressonância Magnética
Estrutura Molecular
Noresteroides/química
Noresteroides/isolamento & purificação
Extratos Vegetais/isolamento & purificação
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Flavonoids); 0 (Norsteroids); 0 (Plant Extracts); 21302-79-4 (ceanothic acid); 72063-39-9 (spinosin)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:140901
[Lr] Data última revisão:
140901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140902
[St] Status:MEDLINE


  6 / 303 MEDLINE  
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[PMID]:25092028
[Au] Autor:Horinouchi M; Hayashi T; Koshino H; Malon M; Hirota H; Kudo T
[Ad] Endereço:Environmental Molecular Biology Laboratory, RIKEN, Saitama, Japan masae@postman.riken.go.jp.
[Ti] Título:Identification of 9α-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid in steroid degradation by Comamonas testosteroni TA441 and its conversion to the corresponding 6-en-5-oyl coenzyme A (CoA) involving open reading frame 28 (ORF28)- and ORF30-encoded acyl-CoA dehydrogenases.
[So] Source:J Bacteriol;196(20):3598-608, 2014 Oct.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Comamonas testosteroni TA441 degrades steroids via aromatization and meta-cleavage of the A ring, followed by hydrolysis, and produces 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid as an intermediate compound. Herein, we identify a new intermediate compound, 9α-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid. Open reading frame 28 (ORF28)- and ORF30-encoded acyl coenzyme A (acyl-CoA) dehydrogenase was shown to convert the CoA ester of 9α-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid to the CoA ester of 9α-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrost-6-en-5-oic acid. A homology search of the deduced amino acid sequences suggested that the ORF30-encoded protein is a member of the acyl-CoA dehydrogenase_fadE6_17_26 family, whereas the deduced amino acid sequence of ORF28 showed no significant similarity to specific acyl-CoA dehydrogenase family proteins. Possible steroid degradation gene clusters similar to the cluster of TA441 appear in bacterial genome analysis data. In these clusters, ORFs similar to ORFs 28 and 30 are often found side by side and ordered in the same manner as ORFs 28 and 30.
[Mh] Termos MeSH primário: Comamonas testosteroni/metabolismo
Noresteroides/metabolismo
Esteroides/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Regulação Bacteriana da Expressão Gênica
Estrutura Molecular
Mutação
Noresteroides/química
Fases de Leitura Aberta
Esteroides/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Norsteroids); 0 (Steroids)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:150805
[Lr] Data última revisão:
150805
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140806
[St] Status:MEDLINE
[do] DOI:10.1128/JB.01878-14


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[PMID]:24843125
[Au] Autor:Townsend SD; Ross AG; Liu K; Danishefsky SJ
[Ad] Endereço:Laboratory of Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, New York, NY 10065; and.
[Ti] Título:Stereospecific cis- and trans-ring fusions arising from common intermediates.
[So] Source:Proc Natl Acad Sci U S A;111(22):7931-5, 2014 Jun 03.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Highly concise and stereospecific routes to cis and trans fusion, carrying various functionality at one of the bridgehead carbons, have been accomplished.
[Mh] Termos MeSH primário: Reação de Cicloadição/métodos
Ciclobutanos/química
Estrogênios/síntese química
Noresteroides/síntese química
Estereoisomerismo
[Mh] Termos MeSH secundário: Alquilação
Indústria Farmacêutica/métodos
Metilação
Modelos Moleculares
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Cyclobutanes); 0 (Estrogens); 0 (Norsteroids); 0 (cyclobutenone)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140521
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.1407613111


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[PMID]:24821499
[Au] Autor:Caliph SM; Faassen FW; Porter CJ
[Ad] Endereço:Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Vic, Australia.
[Ti] Título:The influence of intestinal lymphatic transport on the systemic exposure and brain deposition of a novel highly lipophilic compound with structural similarity to cholesterol.
[So] Source:J Pharm Pharmacol;66(10):1377-87, 2014 Oct.
[Is] ISSN:2042-7158
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To assess the role of intestinal lymphatic transport in the oral bioavailability and brain deposition of a highly lipophilic, centrally acting drug candidate (Org 49209) in comparison to cholesterol, a close structural analogue. METHODS: The intestinal lymphatic transport of Org 49209 and cholesterol was assessed in lymph-cannulated anaesthetised rats and total bioavailability evaluated in non-lymph-cannulated animals. Parallel groups were employed to examine the brain deposition of Org 49209 after intraduodenal and intraperitoneal administrations. KEY FINDINGS: The contribution of intestinal lymphatic transport to total bioavailability was similar for Org 49209 and cholesterol (approximately 40% of the absorbed dose). However, the oral bioavailability of Org 49209 was significantly (fourfold) lower than cholesterol. Brain deposition of Org 49209 was similar after intraduodenal and intraperitoneal administration. Systemic exposure, however, was higher after intraduodenal administration and brain-to-plasma ratios were therefore reduced. CONCLUSION: The oral bioavailability of Org 49209 was significantly lower than that of its structural analogue cholesterol; however, intestinal lymphatic transport played a similar role in oral bioavailability for both compounds. Brain to plasma ratios were lower after intraduodenal versus intraperitoneal administration, suggesting that drug association with intestinal lymph lipoproteins may limit central nervous system access for highly lipophilic drugs.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Fármacos do Sistema Nervoso Central/farmacocinética
Colesterol/análogos & derivados
Colesterol/farmacocinética
Intestinos/metabolismo
Linfa/metabolismo
Sistema Linfático/metabolismo
Noresteroides/farmacocinética
[Mh] Termos MeSH secundário: Administração Oral
Animais
Disponibilidade Biológica
Transporte Biológico
Fármacos do Sistema Nervoso Central/metabolismo
Colesterol/metabolismo
Absorção Intestinal
Lipoproteínas/metabolismo
Masculino
Estrutura Molecular
N-Metilaspartato/metabolismo
Noresteroides/metabolismo
Ratos Sprague-Dawley
Esquizofrenia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Central Nervous System Agents); 0 (Lipoproteins); 0 (Norsteroids); 0 (Org 49209); 6384-92-5 (N-Methylaspartate); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:140912
[Lr] Data última revisão:
140912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140514
[St] Status:MEDLINE
[do] DOI:10.1111/jphp.12268


  9 / 303 MEDLINE  
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[PMID]:24174662
[Au] Autor:Paul SM; Doherty JJ; Robichaud AJ; Belfort GM; Chow BY; Hammond RS; Crawford DC; Linsenbardt AJ; Shu HJ; Izumi Y; Mennerick SJ; Zorumski CF
[Ad] Endereço:Sage Therapeutics, Cambridge, Massachusetts 02142, Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Departments of Psychiatry and Pharmacology, Weill Cornell Medical College, New York, New York 10065, and Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, Missouri 63110.
[Ti] Título:The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors.
[So] Source:J Neurosci;33(44):17290-300, 2013 Oct 30.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABAA receptors (GABA(A)Rs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations ≤10 µM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Hipocampo/metabolismo
Hidroxicolesteróis/metabolismo
Hidroxicolesteróis/farmacologia
Receptores de N-Metil-D-Aspartato/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Regulação Alostérica/efeitos dos fármacos
Regulação Alostérica/fisiologia
Animais
Feminino
Masculino
Camundongos
Noresteroides/metabolismo
Noresteroides/farmacologia
Técnicas de Cultura de Órgãos
Ratos
Ratos Long-Evans
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 ((delta5,6-3-oxynorcholenyl)dimethylcarbinol); 0 (Hydroxycholesterols); 0 (Norsteroids); 0 (Receptors, N-Methyl-D-Aspartate); 47IMW63S3F (24-hydroxycholesterol); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1312
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131101
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2619-13.2013


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[PMID]:23178256
[Au] Autor:Sánchez-Flores J; Pelayo-González VG; Romero-Ávila M; Flores-Pérez B; Flores-Álamo M; Iglesias-Arteaga MA
[Ad] Endereço:Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México DF, Mexico.
[Ti] Título:Hypervalent-iodine induced quasi-Favorskii C-ring contraction of 12-oxosteroids: a shortcut to C-norsteroids.
[So] Source:Steroids;78(2):234-40, 2013 Feb.
[Is] ISSN:1878-5867
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Treatment of 12-oxosteroids with PhI(OAc)(2) and KOH in refluxing methanol triggers a quasi-Favorskii C-ring contraction leading to the corresponding 11α-alcoxycarbonyl-C-norsteroids in moderate yields. This constitutes the first one-step synthetic alternative to C-norsteroids starting from 12-oxosteroids.
[Mh] Termos MeSH primário: Iodo/química
Cetosteroides/química
Noresteroides/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Hidrólise
Cetosteroides/síntese química
Conformação Molecular
Noresteroides/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ketosteroids); 0 (Norsteroids); 9679TC07X4 (Iodine)
[Em] Mês de entrada:1307
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121127
[St] Status:MEDLINE



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