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[PMID]:29407641
[Au] Autor:Kaizer J; Aoyama M; Kumamoto Y; Molnár M; Palcsu L; Povinec PP
[Ad] Endereço:Faculty of Mathematics, Physics and Informatics, Comenius University, 84248 Bratislava, Slovakia. Electronic address: kaizer@fmph.uniba.sk.
[Ti] Título:Tritium and radiocarbon in the western North Pacific waters: post-Fukushima situation.
[So] Source:J Environ Radioact;184-185:83-94, 2018 Apr.
[Is] ISSN:1879-1700
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Impact of the Fukushima Dai-ichi Nuclear Power Plant (FNPP1) accident on tritium ( H) and radiocarbon ( C) levels in the water column of the western North Pacific Ocean in winter 2012 is evaluated and compared with radiocesium ( Cs) data collected for the same region. Tritium concentrations in surface seawater, varying between 0.4 and 2.0 TU (47.2-236 Bq m ), follow the Fukushima radiocesium trend, however, some differences in the vertical profiles were observed, namely in depths of 50-400 m. No correlation was visible in the case of C, whose surface Δ C levels raised from negative values (about -40‰) in the northern part of transect, to positive values (∼68‰) near the equator. Homogenously mixed C levels in the subsurface layers were observed at all stations. Sixteen surface (from 30 in total) and 6 water profile (from 7) stations were affected by the Fukushima tritium. Surface and vertical profile data together with the calculated water column inventories indicate that the total amount of the FNPP1-derived tritium deposited to the western North Pacific Ocean was 0.7 ±â€¯0.3 PBq. No clear impact of the Fukushima accident on C levels in the western North Pacific was observed.
[Mh] Termos MeSH primário: Radioisótopos de Césio/análise
Acidente Nuclear de Fukushima
Monitoramento de Radiação
Trítio/análise
Poluentes Radioativos da Água/análise
[Mh] Termos MeSH secundário: Oceano Pacífico
Água do Mar/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cesium Radioisotopes); 0 (Water Pollutants, Radioactive); 10028-17-8 (Tritium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE


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[PMID]:29221756
[Au] Autor:Lesniak A; Aarnio M; Diwakarla S; Norberg T; Nyberg F; Gordh T
[Ad] Endereço:Uppsala University, Department of Pharmaceutical Biosciences, SE 751 24 Uppsala, Sweden; Medical University of Warsaw, Department of Pharmacodynamics, Centre for Preclinical Research and Technology, 02-097 Warsaw, Poland. Electronic address: anna.lesniak@wum.edu.pl.
[Ti] Título:Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
[So] Source:Life Sci;194:26-33, 2018 Feb 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: d-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for d-deprenyl in synovial membrane explants from arthritic patients. MAIN METHODS: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [ H]d-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation. KEY FINDINGS: The [ H]d-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [ H]d-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [ H]d-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [ H]d-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation. SIGNIFICANCE: Our study was the first to show the biochemical characteristics of the [ H]d-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.
[Mh] Termos MeSH primário: Artrite/diagnóstico
Inibidores da Monoaminoxidase/metabolismo
Monoaminoxidase/análise
Selegilina/metabolismo
Membrana Sinovial/patologia
Sinovite/diagnóstico
[Mh] Termos MeSH secundário: Idoso
Artrite/metabolismo
Sítios de Ligação
Feminino
Seres Humanos
Masculino
Meia-Idade
Monoaminoxidase/metabolismo
Tomografia por Emissão de Pósitrons
Ensaio Radioligante
Membrana Sinovial/metabolismo
Sinovite/metabolismo
Trítio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Monoamine Oxidase Inhibitors); 10028-17-8 (Tritium); 2K1V7GP655 (Selegiline); EC 1.4.3.4 (Monoamine Oxidase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171210
[St] Status:MEDLINE


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[PMID]:28455390
[Au] Autor:Christian WV; Hinkle PM
[Ad] Endereço:Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, U.S.A.
[Ti] Título:Global functions of extracellular, transmembrane and cytoplasmic domains of organic solute transporter ß-subunit.
[So] Source:Biochem J;474(12):1981-1992, 2017 05 25.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Transport of bile acids across the basolateral membrane of the intestinal enterocyte is carried out by the organic solute transporter (Ost) composed of a seven-transmembrane domain (TMD) subunit (Ostα) and an ancillary single TMD subunit (Ostß). Although previous investigations have demonstrated the importance of the TMD of Ostß for its activity, further studies were conducted to assess the contributions of other regions of the Ostß subunit. Transport activity was retained when Ostß was truncated to contain only the TMD with 15 additional residues on each side and co-expressed with Ostα, whereas shorter fragments were inactive. To probe the broader functions of Ostß segments, chimeric proteins were constructed in which N-terminal, TMD or C-terminal regions of Ostß were fused to corresponding regions of receptor activity-modifying protein (RAMP1), a single TMD protein required by several seven-TMD G-protein-coupled receptors including the calcitonin receptor-like receptor (CLR). Ostß/RAMP1 chimeras were expressed with Ostα and CLR. As expected, replacing the Ostß TMD abolished transport activity; however, replacing either the entire N-terminal or entire C-terminal domain of Ostß with RAMP1 sequences did not prevent plasma membrane localization or the ability to support [ H]taurocholate uptake. Co-immunoprecipitation experiments revealed that the C-terminus of Ostß is a previously unrecognized site of interaction with Ostα. All chimeras containing N-terminal RAMP1 segments allowed co-expressed CLR to respond to agonists with strong increases in cyclic AMP. These results provide new insights into the structure and function of the heteromeric Ost transporter complex.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
[Mh] Termos MeSH secundário: Absorção Fisiológica/efeitos dos fármacos
Animais
Transporte Biológico/efeitos dos fármacos
Peptídeo Relacionado com Gene de Calcitonina/genética
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Proteína Semelhante a Receptor de Calcitonina/agonistas
Proteína Semelhante a Receptor de Calcitonina/genética
Proteína Semelhante a Receptor de Calcitonina/metabolismo
AMP Cíclico/metabolismo
Células HEK293
Seres Humanos
Imunoprecipitação
Proteínas de Membrana Transportadoras/química
Proteínas de Membrana Transportadoras/genética
Camundongos
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Transporte Proteico
Proteína 1 Modificadora da Atividade de Receptores/química
Proteína 1 Modificadora da Atividade de Receptores/genética
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Sistemas do Segundo Mensageiro/efeitos dos fármacos
Homologia Estrutural de Proteína
Ácido Taurocólico/metabolismo
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (CALCA protein, human); 0 (CALCRL protein, human); 0 (Calcitonin Receptor-Like Protein); 0 (Membrane Transport Proteins); 0 (Peptide Fragments); 0 (Ramp1 protein, mouse); 0 (Receptor Activity-Modifying Protein 1); 0 (Recombinant Fusion Proteins); 0 (organic solute transporter alpha, mouse); 0 (organic solute transporter beta, mouse); 10028-17-8 (Tritium); 5E090O0G3Z (Taurocholic Acid); 83652-28-2 (Calcitonin Gene-Related Peptide); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171217
[Lr] Data última revisão:
171217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20161093


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[PMID]:28910625
[Au] Autor:Ota M; Kwamena NA; Mihok S; Korolevych V
[Ad] Endereço:Research Group for Environmental Science, Japan Atomic Energy Agency, Tokai, Ibaraki 319-1195 Japan. Electronic address: ohta.masakazu@jaea.go.jp.
[Ti] Título:Role of soil-to-leaf tritium transfer in controlling leaf tritium dynamics: Comparison of experimental garden and tritium-transfer model results.
[So] Source:J Environ Radioact;178-179:212-231, 2017 Nov.
[Is] ISSN:1879-1700
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Environmental transfer models assume that organically-bound tritium (OBT) is formed directly from tissue-free water tritium (TFWT) in environmental compartments. Nevertheless, studies in the literature have shown that measured OBT/HTO ratios in environmental samples are variable and generally higher than expected. The importance of soil-to-leaf HTO transfer pathway in controlling the leaf tritium dynamics is not well understood. A model inter-comparison of two tritium transfer models (CTEM-CLASS-TT and SOLVEG-II) was carried out with measured environmental samples from an experimental garden plot set up next to a tritium-processing facility. The garden plot received one of three different irrigation treatments - no external irrigation, irrigation with low tritium water and irrigation with high tritium water. The contrast between the results obtained with the different irrigation treatments provided insights into the impact of soil-to-leaf HTO transfer on the leaf tritium dynamics. Concentrations of TFWT and OBT in the garden plots that were not irrigated or irrigated with low tritium water were variable, responding to the arrival of the HTO-plume from the tritium-processing facility. In contrast, for the plants irrigated with high tritium water, the TFWT concentration remained elevated during the entire experimental period due to a continuous source of high HTO in the soil. Calculated concentrations of OBT in the leaves showed an initial increase followed by quasi-equilibration with the TFWT concentration. In this quasi-equilibrium state, concentrations of OBT remained elevated and unchanged despite the arrivals of the plume. These results from the model inter-comparison demonstrate that soil-to-leaf HTO transfer significantly affects tritium dynamics in leaves and thereby OBT/HTO ratio in the leaf regardless of the atmospheric HTO concentration, only if there is elevated HTO concentrations in the soil. The results of this work indicate that assessment models should be refined to consider the importance of soil-to-leaf HTO transfer to ensure that dose estimates are accurate and conservative.
[Mh] Termos MeSH primário: Modelos Químicos
Monitoramento de Radiação
Trítio/análise
[Mh] Termos MeSH secundário: Jardins
Folhas de Planta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
10028-17-8 (Tritium)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE


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[PMID]:28898049
[Au] Autor:Hassett MR; Riegel BE; Callaghan PS; Roepe PD
[Ad] Endereço:Departments of Chemistry and of Biochemistry & Cellular & Molecular Biology, Georgetown University , 37th and O Streets NW, Washington, D.C. 20057, United States.
[Ti] Título:Analysis of Plasmodium vivax Chloroquine Resistance Transporter Mutant Isoforms.
[So] Source:Biochemistry;56(41):5615-5622, 2017 Oct 17.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum malaria is widespread and has limited the use of CQ in many regions of the globe. Malaria caused by the related human parasite P. vivax is as widespread as is P. falciparum malaria and has been treated with CQ as extensively as has P. falciparum, suggesting that P. vivax parasites have been selected with CQ as profoundly as have P. falciparum parasites. Indeed, a growing number of clinical reports have presented data suggesting increased P. vivax CQR. Cytostatic (growth inhibitory) CQR for P. falciparum is caused by Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutations, and it has been proposed that mutations in the PvCRT orthologue may simliarly cause P. vivax CQR via increasing CQ transport from the P. vivax digestive vacuole. Here we report the first quantitative analysis of drug transport mediated by all known mutant isoforms of Plasmodium vivax chloroquine resistance transporter (PvCRT) in order to test the protein's potential link to growing P. vivax CQR phenomena. Small, but statistically significant, differences in the transport of CQ and other quinoline antimalarial drugs were found for multiple PvCRT isoforms, relative to wild type PvCRT, suggesting that mutations in PvCRT can contribute to P. vivax CQR and other examples of quinoline antimalarial drug resistance.
[Mh] Termos MeSH primário: Antimaláricos/metabolismo
Cloroquina/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Modelos Moleculares
Mutação
Plasmodium vivax/metabolismo
Proteínas de Protozoários/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Antimaláricos/farmacologia
Transporte Biológico
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Cloroquina/farmacologia
Contagem de Colônia Microbiana
Resistência a Medicamentos
Seres Humanos
Malária Vivax/tratamento farmacológico
Malária Vivax/parasitologia
Proteínas de Membrana Transportadoras/química
Proteínas de Membrana Transportadoras/genética
Mutagênese Sítio-Dirigida
Plasmodium vivax/efeitos dos fármacos
Plasmodium vivax/crescimento & desenvolvimento
Plasmodium vivax/isolamento & purificação
Primaquina/metabolismo
Primaquina/farmacologia
Conformação Proteica
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Proteínas de Protozoários/química
Proteínas de Protozoários/genética
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Saccharomyces cerevisiae/efeitos dos fármacos
Saccharomyces cerevisiae/crescimento & desenvolvimento
Saccharomyces cerevisiae/metabolismo
Trítio
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Crt-o protein, Plasmodium vivax); 0 (Membrane Transport Proteins); 0 (Protein Isoforms); 0 (Protozoan Proteins); 0 (Recombinant Proteins); 10028-17-8 (Tritium); 886U3H6UFF (Chloroquine); MVR3634GX1 (Primaquine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00749


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[PMID]:28881028
[Au] Autor:Guirao V; Martí-Sistac O; DeGregorio-Rocasolano N; Ponce J; Dávalos A; Gasull T
[Ad] Endereço:Cellular and Molecular Neurobiology Research Group, Department of Neurosciences, Germans Trias i Pujol Research Institute, Badalona, Catalonia, Spain.
[Ti] Título:Specific rescue by ortho-hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB.
[So] Source:J Neurochem;143(3):359-374, 2017 Nov.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The statin atorvastatin (ATV) given as a post-treatment has been reported beneficial in stroke, although the mechanisms involved are not well understood so far. Here, we investigated in vitro the effect of post-treatment with ATV and its main bioactive metabolite ortho-hydroxy ATV (o-ATV) on neuroprotection after oxygen and glucose deprivation (OGD), and the role of the pro-survival cAMP response element-binding protein (CREB). Post-OGD treatment of primary cultures of rat cortical neurons with o-ATV, but not ATV, provided neuroprotection to a specific subset of cortical neurons that were large and positive for glutamic acid decarboxylase (large-GAD neurons, GABAergic). Significantly, only these GABAergic neurons showed an increase in phosphorylated CREB (pCREB) early after neuronal cultures were treated post-OGD with o-ATV. We found that o-ATV, but not ATV, increased the neuronal uptake of glutamate from the medium; this provides a rationale for the specific effect of o-ATV on pCREB in large-GABAergic neurons, which have a higher ratio of synaptic (pCREB-promoting) vs extrasynaptic (pCREB-reducing) N-methyl-D-aspartate (NMDA) receptors (NMDAR) than that of small-non-GABAergic neurons. When we pharmacologically increased pCREB levels post-OGD in non-GABAergic neurons, through the selective activation of synaptic NMDAR, we observed as well long-lasting neuronal survival. We propose that the statin metabolite o-ATV given post-OGD boosts the intrinsic pro-survival factor pCREB in large-GABAergic cortical neurons in vitro, this contributing to protect them from OGD.
[Mh] Termos MeSH primário: Atorvastatina Cálcica/análogos & derivados
Hipóxia Celular/efeitos dos fármacos
Córtex Cerebral/citologia
Neurônios GABAérgicos/efeitos dos fármacos
Glucose/deficiência
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
[Mh] Termos MeSH secundário: Animais
Atorvastatina Cálcica/farmacologia
Proteína de Ligação a CREB/metabolismo
Morte Celular/efeitos dos fármacos
Células Cultivadas
Embrião de Mamíferos
Feminino
Ácido Glutâmico/farmacocinética
Masculino
Proteínas do Tecido Nervoso/metabolismo
Ratos
Ratos Sprague-Dawley
Receptores de N-Metil-D-Aspartato/metabolismo
Trítio/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-hydroxyatorvastatin); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Nerve Tissue Proteins); 0 (Receptors, N-Methyl-D-Aspartate); 10028-17-8 (Tritium); 3KX376GY7L (Glutamic Acid); 48A5M73Z4Q (Atorvastatin Calcium); EC 2.3.1.48 (CREB-Binding Protein); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14210


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[PMID]:28866099
[Au] Autor:Takano M; Kamei H; Nagahiro M; Kawami M; Yumoto R
[Ad] Endereço:Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Electronic address: takanom@hiroshima-u.ac.jp.
[Ti] Título:Nicotine transport in lung and non-lung epithelial cells.
[So] Source:Life Sci;188:76-82, 2017 Nov 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Nicotine is rapidly absorbed from the lung alveoli into systemic circulation during cigarette smoking. However, mechanism underlying nicotine transport in alveolar epithelial cells is not well understood to date. In the present study, we characterized nicotine uptake in lung epithelial cell lines A549 and NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. MATERIALS AND METHODS: Characteristics of [ H]nicotine uptake was studied using these cell lines. KEY FINDINGS: Nicotine uptake in A549 cells occurred in a time- and temperature-dependent manner and showed saturation kinetics, with a Km value of 0.31mM. Treatment with some organic cations such as diphenhydramine and pyrilamine inhibited nicotine uptake, whereas treatment with organic cations such as carnitine and tetraethylammonium did not affect nicotine uptake. Extracellular pH markedly affected nicotine uptake, with high nicotine uptake being observed at high pH up to 11.0. Modulation of intracellular pH with ammonium chloride also affected nicotine uptake. Treatment with valinomycin, a potassium ionophore, did not significantly affect nicotine uptake, indicating that nicotine uptake is an electroneutral process. For comparison, we assessed the characteristics of nicotine uptake in another lung epithelial cell line NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. Interestingly, these cell lines showed similar characteristics of nicotine uptake with respect to pH dependency and inhibition by various organic cations. SIGNIFICANCE: The present findings suggest that a similar or the same pH-dependent transport system is involved in nicotine uptake in these cell lines. A novel molecular mechanism of nicotine transport is proposed.
[Mh] Termos MeSH primário: Transporte Biológico/efeitos dos fármacos
Células Epiteliais/metabolismo
Pulmão/metabolismo
Nicotina/farmacocinética
[Mh] Termos MeSH secundário: Carnitina/farmacologia
Células Cultivadas
Difenidramina/farmacologia
Interações Medicamentosas
Seres Humanos
Concentração de Íons de Hidrogênio
Pirilamina/farmacologia
Temperatura Ambiente
Tetraetilamônio/farmacologia
Fatores de Tempo
Trítio/metabolismo
Valinomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
10028-17-8 (Tritium); 2001-95-8 (Valinomycin); 66-40-0 (Tetraethylammonium); 6M3C89ZY6R (Nicotine); 8GTS82S83M (Diphenhydramine); HPE317O9TL (Pyrilamine); S7UI8SM58A (Carnitine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170904
[St] Status:MEDLINE


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[PMID]:28734666
[Au] Autor:Pasquinucci L; Turnaturi R; Prezzavento O; Arena E; Aricò G; Georgoussi Z; Parenti R; Cantarella G; Parenti C
[Ad] Endereço:Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
[Ti] Título:Development of novel LP1-based analogues with enhanced delta opioid receptor profile.
[So] Source:Bioorg Med Chem;25(17):4745-4752, 2017 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pain relief achieved by co-administration of drugs acting at different targets is more effective than that obtained with conventional MOR selective agonists usually associated to relevant side effects. It has been demonstrated that simultaneously targeting different opioid receptors is a more effective therapeutic strategy. Giving the promising role for DOR in pain management, novel LP1-based analogues with different N-substituents were designed and synthesized with the aim to improve DOR profile. For this purpose, we maintained the phenyl ring in the N-substituent of 6,7-benzomorphan scaffold linked to an ethyl spacer bearing a hydroxyl/methyl or methoxyl group at carbon 2 or including it in a 1,4-benzodioxane ring. LP1 analogues were tested by competition binding assays. Compounds 6 (K =2.47nM, K =9.6nM), 7 (K =0.5nM and K =0.8nM) and 9 (K =1.08nM, K =6.6nM) retained MOR affinity but displayed an improved DOR binding capacity as compared to LP1 (K =0.83nM, K =29.1nM). Moreover, GPI and MVD functional assays indicated that compounds 6 (IC =49.2 and IC =10.8nM), 7 (IC =9.9 and IC =11.8nM) and 9 (IC =21.5 and IC =4.4nM) showed a MOR/DOR agonist profile, unlike LP1 that was a MOR agonist/DOR antagonist (IC =1.9 and IC =1240nM). Measurements of their antinociceptive effect was evaluated by mice radiant tail flick test displaying for compounds 6, 7 and 9 ED values of 1.3, 1.0 and 0.9mg/kg, i.p., respectively. Moreover, the antinociceptive effect of compound 9 was longer lasting with respect to LP1. In conclusion the N-substituent nature of compounds 6, 7 and 9 shifts the DOR profile of LP1 from antagonism to agonism.
[Mh] Termos MeSH primário: Analgésicos/química
Benzomorfanos/química
Receptores Opioides delta/metabolismo
[Mh] Termos MeSH secundário: Analgésicos/metabolismo
Analgésicos/uso terapêutico
Animais
Ligação Competitiva
Concentração Inibidora 50
Cinética
Masculino
Camundongos
Dor/tratamento farmacológico
Ligação Proteica
Receptores Opioides delta/química
Receptores Opioides kappa/química
Receptores Opioides kappa/metabolismo
Receptores Opioides mu/química
Receptores Opioides mu/metabolismo
Relação Estrutura-Atividade
Trítio/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-((2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl)-N-phenylpropanamide); 0 (Analgesics); 0 (Benzomorphans); 0 (Receptors, Opioid, delta); 0 (Receptors, Opioid, kappa); 0 (Receptors, Opioid, mu); 10028-17-8 (Tritium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170724
[St] Status:MEDLINE


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[PMID]:28704052
[Au] Autor:Doornbos MLJ; Cid JM; Haubrich J; Nunes A; van de Sande JW; Vermond SC; Mulder-Krieger T; Trabanco AA; Ahnaou A; Drinkenburg WH; Lavreysen H; Heitman LH; IJzerman AP; Tresadern G
[Ad] Endereço:Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University , P.O. Box 9502, 2300RA Leiden, The Netherlands.
[Ti] Título:Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2.
[So] Source:J Med Chem;60(15):6704-6720, 2017 Aug 10.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k , k and residence time (RT) were determined. The PAMs showed various kinetic profiles; k values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu PAMs with high values for k but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.
[Mh] Termos MeSH primário: Agonistas de Aminoácidos Excitatórios/farmacologia
Piridinas/farmacologia
Receptores de Glutamato Metabotrópico/agonistas
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Regulação Alostérica
Animais
Células CHO
Cricetulus
Agonistas de Aminoácidos Excitatórios/síntese química
Cinética
Piperidinas/farmacologia
Piridinas/síntese química
Ratos Sprague-Dawley
Sono REM/efeitos dos fármacos
Relação Estrutura-Atividade
Triazóis/síntese química
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(cyclopropylmethyl)-7-((4-phenyl-1-piperidinyl)methyl)-8-(trifluoromethyl)-1,2,4-triazolo(4,3-a)pyridine); 0 (Excitatory Amino Acid Agonists); 0 (Piperidines); 0 (Pyridines); 0 (Receptors, Metabotropic Glutamate); 0 (Triazoles); 0 (metabotropic glutamate receptor 2); 10028-17-8 (Tritium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00669


  10 / 69965 MEDLINE  
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[PMID]:28699744
[Au] Autor:Xie H; Chen G; Young RN
[Ad] Endereço:Department of Chemistry, Simon Fraser University , Burnaby, British Columbia V5A 1S6, Canada.
[Ti] Título:Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis.
[So] Source:J Med Chem;60(16):7012-7028, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized conjugate 16 was designed so that esterase activity will liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K cleavable peptide-linked conjugate for targeting of bisphosphonate prodrugs to bone and slow release liberation of the active constituents in vivo. Such conjugates are potential therapies for the treatment of bone disorders such as osteoporosis.
[Mh] Termos MeSH primário: Alendronato/análogos & derivados
Alendronato/farmacologia
Conservadores da Densidade Óssea/farmacologia
Osso e Ossos/metabolismo
Dipeptídeos/farmacologia
Difosfonatos/farmacologia
Pró-Fármacos/farmacologia
[Mh] Termos MeSH secundário: Alendronato/síntese química
Alendronato/metabolismo
Animais
Conservadores da Densidade Óssea/síntese química
Conservadores da Densidade Óssea/metabolismo
Reabsorção Óssea/tratamento farmacológico
Catepsina K/metabolismo
Dipeptídeos/síntese química
Dipeptídeos/metabolismo
Difosfonatos/síntese química
Difosfonatos/metabolismo
Desenho de Drogas
Estabilidade de Medicamentos
Feminino
Seres Humanos
Osteoporose/tratamento farmacológico
Pró-Fármacos/síntese química
Pró-Fármacos/metabolismo
Ratos Sprague-Dawley
Receptores de Prostaglandina E Subtipo EP4/agonistas
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Dipeptides); 0 (Diphosphonates); 0 (PTGER4 protein, human); 0 (Prodrugs); 0 (Ptger4 protein, rat); 0 (Receptors, Prostaglandin E, EP4 Subtype); 10028-17-8 (Tritium); EC 3.4.22.38 (CTSK protein, human); EC 3.4.22.38 (Cathepsin K); EC 3.4.22.38 (Ctsk protein, rat); X1J18R4W8P (Alendronate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b00951



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