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[PMID]:28373066
[Au] Autor:Banks ML; Snyder RW; Fennell TR; Negus SS
[Ad] Endereço:Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: matthew.banks@vcuhealth.org.
[Ti] Título:Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: Evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys.
[So] Source:Pharmacol Biochem Behav;156:30-38, 2017 May.
[Is] ISSN:1873-5177
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10-18mg/kg, intramuscular (IM)) and d-amphetamine (0.032-0.32mg/kg, IM) in monkeys (n=3-4) trained to discriminate IM cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥90% cocaine-appropriate responding, in all monkeys without altering response rates. The time course of d-amphetamine's cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100min) and d-amphetamine (peak at 24h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment.
[Mh] Termos MeSH primário: Benzfetamina/farmacologia
Dextroanfetamina/farmacologia
Metanfetamina/farmacologia
[Mh] Termos MeSH secundário: Animais
Comportamento Animal/efeitos dos fármacos
Benzfetamina/farmacocinética
Dextroanfetamina/farmacocinética
Macaca mulatta
Masculino
Metanfetamina/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0M3S43XK27 (Benzphetamine); 44RAL3456C (Methamphetamine); TZ47U051FI (Dextroamphetamine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE


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[PMID]:23904614
[Au] Autor:Ménard C; Tse YC; Cavanagh C; Chabot JG; Herzog H; Schwarzer C; Wong TP; Quirion R
[Ad] Endereço:Douglas Mental Health University Institute, McGill University, Montreal, Quebec H4H 1R3, Canada.
[Ti] Título:Knockdown of prodynorphin gene prevents cognitive decline, reduces anxiety, and rescues loss of group 1 metabotropic glutamate receptor function in aging.
[So] Source:J Neurosci;33(31):12792-804, 2013 Jul 31.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.
[Mh] Termos MeSH primário: Envelhecimento/fisiologia
Ansiedade/metabolismo
Encefalinas/deficiência
Regulação da Expressão Gênica/genética
Precursores de Proteínas/deficiência
Receptores de Glutamato Metabotrópico/metabolismo
[Mh] Termos MeSH secundário: Animais
Ansiedade/tratamento farmacológico
Benzamidas/farmacologia
Benzamidas/uso terapêutico
Benzfetamina/análogos & derivados
Benzfetamina/farmacologia
Estimulantes do Sistema Nervoso Central/farmacologia
Córtex Cerebral/efeitos dos fármacos
Córtex Cerebral/metabolismo
Transtornos Cognitivos/tratamento farmacológico
Modelos Animais de Doenças
Antagonistas de Aminoácidos Excitatórios/farmacologia
Antagonistas de Aminoácidos Excitatórios/uso terapêutico
Comportamento Exploratório/efeitos dos fármacos
Comportamento Exploratório/fisiologia
Regulação da Expressão Gênica/efeitos dos fármacos
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Técnicas In Vitro
Depressão Sináptica de Longo Prazo/efeitos dos fármacos
Depressão Sináptica de Longo Prazo/genética
Transtornos da Memória/tratamento farmacológico
Transtornos da Memória/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Pirazóis/farmacologia
Pirazóis/uso terapêutico
Piridinas/farmacologia
Piridinas/uso terapêutico
Receptores de Glutamato Metabotrópico/antagonistas & inibidores
Recognição (Psicologia)/efeitos dos fármacos
Recognição (Psicologia)/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide); 0 (Benzamides); 0 (Central Nervous System Stimulants); 0 (Enkephalins); 0 (Excitatory Amino Acid Antagonists); 0 (Protein Precursors); 0 (Pyrazoles); 0 (Pyridines); 0 (Receptors, Metabotropic Glutamate); 0 (metabotropic glutamate receptor type 1); 0M3S43XK27 (Benzphetamine); 1085-42-3 (norbenzphetamine); 7VC0YVI27Y (6-methyl-2-(phenylethynyl)pyridine); 93443-35-7 (preproenkephalin)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130802
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0290-13.2013


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[PMID]:21497079
[Au] Autor:Carrara S; Cavallini A; Erokhin V; De Micheli G
[Ad] Endereço:Integrated Systems Laboratory - EPFL - École Polytechnique Fédérale de Lausanne, Switzerland.
[Ti] Título:Multi-panel drugs detection in human serum for personalized therapy.
[So] Source:Biosens Bioelectron;26(9):3914-9, 2011 May 15.
[Is] ISSN:1873-4235
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This work focuses on P450 biosensors based on multiwalled carbon nanotubes (MWCNT) and different cytochrome isoforms: 3A4, 2B4, 2C9. The proposed biosensors exhibit enhanced sensitivities and decreased detection limits thanks to carbon nanotubes. The MWCNT structuring improves the sensitivity from 5.1 to 20.5 nA/mM mm(2) in case of CYP2B4-mediated Benzphetamine detection, from 0.26 to 0.63 nA/µM mm(2) in case of CYP3A4-mediated Cyclophosphamide detection, and from 0.11 to 0.25 nA/µM mm(2) in case of CYP2C9-mediated Naproxen detection. By using MWCNT, the limit of detection was enhanced from 59 to 12 µM in case of Cyclophosphamide and from to 187 to 82 µM in case of Naproxen. This makes possible the drug detection in human serum within the pharmacological range. In the paper, a new mathematical model is also proposed to succeed in discriminating different drug contributions in a mixture containing both Cyclophosphamide and Dextromethorphan or combining Naproxen and Flurbiprofen. Data analysis shows variations in reduction peaks that are dependent on the drug ratio, and that are consistent with competitive kinetics of substrates. This new approach enables multiple drug detection and opens the way to possible applications in personalized therapy.
[Mh] Termos MeSH primário: Benzfetamina/isolamento & purificação
Técnicas Biossensoriais
Ciclofosfamida/isolamento & purificação
Naproxeno/isolamento & purificação
[Mh] Termos MeSH secundário: Hidrocarboneto de Aril Hidroxilases/química
Benzfetamina/química
Ciclofosfamida/química
Citocromo P-450 CYP2C9/química
Citocromo P-450 CYP3A/química
Família 2 do Citocromo P450
Seres Humanos
Limite de Detecção
Nanotubos de Carbono/química
Naproxeno/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nanotubes, Carbon); 0M3S43XK27 (Benzphetamine); 57Y76R9ATQ (Naproxen); 8N3DW7272P (Cyclophosphamide); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.14.1 (cytochrome P-450 CYP2B4 (rabbit))
[Em] Mês de entrada:1607
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110419
[St] Status:MEDLINE
[do] DOI:10.1016/j.bios.2011.03.009


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[PMID]:20637316
[Au] Autor:Perera R; Sono M; Kinloch R; Zhang H; Tarasev M; Im SC; Waskell L; Dawson JH
[Ad] Endereço:Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.
[Ti] Título:Stabilization and spectroscopic characterization of the dioxygen complex of wild-type cytochrome P4502B4 (CYP2B4) and its distal side E301Q, T302A and proximal side F429H mutants at subzero temperatures.
[So] Source:Biochim Biophys Acta;1814(1):69-75, 2011 Jan.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mammalian cytochrome P450 2B4 (CYP2B4) is a phenobarbital-inducible rabbit hepatic monooxygenase that catalyzes the N-demethylation of benzphetamine and metabolism of numerous other compounds. To probe the interactions of the heme environment and bound benzphetamine with the dioxygen (O2) complex of CYP2B4, homogeneous O2 complexes of the wild-type enzyme and three mutants at sites of conserved amino acids, two on the heme distal side (T302A and E301Q) and one on the proximal side (F429H), have been prepared and stabilized at ~-50°C in mixed solvents (60-70% v/v glycerol). We report that the magnetic circular dichroism and electronic absorption spectra of wild-type oxyferrous CYP2B4, in the presence and absence of substrate, are quite similar to those of the dioxygen complex of bacterial cytochrome P450-CAM (CYP101). However, the oxyferrous complexes of the T302A and E301Q CYP2B4 mutants have significantly perturbed electronic structure (~4 nm and ~3 nm red-shifted Soret features, respectively) compared to that of the wild-type oxyferrous complex. On the other hand, the heme proximal side mutant, CYP2B4 F429H, undergoes relatively facile conversion to a partially (~50%) denatured (P420) form upon reduction. The structural changes in the heme pocket environments of the CYP2B4 mutants that lead to the spectroscopic distinctions reported herein can be related to the differences in oxidation activities of wild-type CYP2B4 and its E301Q, T302A and F429H mutants.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/genética
Hidrocarboneto de Aril Hidroxilases/metabolismo
Mutação
Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Hidrocarboneto de Aril Hidroxilases/química
Benzfetamina/química
Benzfetamina/metabolismo
Domínio Catalítico
Dicroísmo Circular
Temperatura Baixa
Família 2 do Citocromo P450
Heme/química
Heme/metabolismo
Ferro/química
Ferro/metabolismo
Modelos Moleculares
Compostos Organometálicos/química
Compostos Organometálicos/metabolismo
Oxigênio/química
Ligação Proteica
Estrutura Terciária de Proteína
Coelhos
Espectrofotometria
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Organometallic Compounds); 0M3S43XK27 (Benzphetamine); 42VZT0U6YR (Heme); E1UOL152H7 (Iron); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.14.1 (cytochrome P-450 CYP2B4 (rabbit)); S88TT14065 (Oxygen)
[Em] Mês de entrada:1103
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100720
[St] Status:MEDLINE
[do] DOI:10.1016/j.bbapap.2010.07.012


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[PMID]:20673214
[Au] Autor:Myasoedova KN; Timofeev KN
[Ad] Endereço:Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow, Russia. KseniaMyasoedova@gmail.com
[Ti] Título:Conformational changes near the cytochrome P450 active site upon binding of two different ligands.
[So] Source:Biochemistry (Mosc);75(7):899-904, 2010 Jul.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It is shown that a stable nitroxyl radical, 4-cyano-2,2,6,6-tetramethylpiperidine-1-oxyl, forms a complex with cytochrome P4502B4 by analogy with the second type substrates by joining directly to pentacoordinate heme iron. The bound radical is inaccessible to water-soluble paramagnetic ions, which confirms its localization in a hydrophobic pocket near the heme. Benzphetamine and N,N-dimethylaniline, the first-type nonpolar substrates, induce conformational changes of the spin-labeled hemoprotein which are evidently accompanied by an increase in the volume of the pocket resulting in emergence of contact with aqueous phase, and the heme-bound spin label becomes accessible to water-soluble paramagnetics. In this case potassium ferricyanide broadens the spin-labeled cytochrome signal and, as a result, lowers the amplitudes of the spectral components. Similar changes were registered at non-micellar concentrations of nonionic detergent Emulgen 913, whose activating effect on hydroxylation reactions is associated, as we showed previously, with its presence in the CYP2B4 active site simultaneously with substrates.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/química
Domínio Catalítico
Microssomos Hepáticos/enzimologia
[Mh] Termos MeSH secundário: Compostos de Anilina/química
Compostos de Anilina/metabolismo
Animais
Hidrocarboneto de Aril Hidroxilases/metabolismo
Benzfetamina/química
Benzfetamina/metabolismo
Família 2 do Citocromo P450
Heme/química
Heme/metabolismo
Ligantes
Microssomos Hepáticos/química
Ligação Proteica
Conformação Proteica
Coelhos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Ligands); 0M3S43XK27 (Benzphetamine); 42VZT0U6YR (Heme); 7426719369 (N,N-dimethylaniline); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.14.1 (cytochrome P-450 CYP2B4 (rabbit))
[Em] Mês de entrada:1011
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100803
[St] Status:MEDLINE


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[PMID]:20557447
[Au] Autor:Virkel G; Carletti M; Cantiello M; Della Donna L; Gardini G; Girolami F; Nebbia C
[Ad] Endereço:Laboratorio de Farmacología, Departamento de Fisiopatología, Núcleo FISFARVET, Facultad de Ciencias Veterinarias, UNCPBA, Argentina-CONICET, 7000 Tandil, Argentina.
[Ti] Título:Characterization of xenobiotic metabolizing enzymes in bovine small intestinal mucosa.
[So] Source:J Vet Pharmacol Ther;33(3):295-303, 2010 Jun 01.
[Is] ISSN:1365-2885
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The intestinal mucosa plays a capital role in dictating the bioavailability of a large array of orally ingested drugs and toxicants. The activity and the expression of several xenobiotic metabolizing enzymes were measured in subcellular fractions from the duodenal mucosa of male veal calves and beef cattle displaying a functional rumen but differing in both age (about 8 months vs. 18 to 24 months) and dietary regimens (i.e., milk replacer plus hay and straw vs. corn and concentrated meal). Intestinal microsomes showed cytochrome P450 (CYP) 2B, 2C- and 3A-mediated activities and the presence of the corresponding immunorelated proteins, but no proof of CYP1A expression and/or functions could be provided. Intestinal microsomes were also active in performing reactions typically mediated by carboxylesterases (indophenylacetate hydrolysis), flavin-containing monooxygenases (methimazole S-oxidation), and uridindiphosphoglucuronyltransferases (1-naphthol glucuronidation), respectively. Cytosolic fractions displayed the glutathione S-transferase (GST)-dependent conjugation of 1-chloro-2,4-dinitrobenzene; besides, the GST-mediated conjugation of ethacrinic acid (GSTpi) or cumene hydroperoxide (GSTalpha) was matched by the presence of the corresponding immunorelated proteins. Conversely, despite the lack of measurable activity with 3,4-dichloronitrobenzene, a protein cross reacting with anti-rat GSTmu antibodies could be clearly detected. Although, as detected by densitometry, CYPs and GST isoenzymes tended to be more expressed in beef cattle than in veal calf preparations, there was a general poor correlation with the rate of the in vitro metabolism of the selected diagnostic probes.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/metabolismo
Mucosa Intestinal/enzimologia
Intestino Delgado/enzimologia
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Benzfetamina/metabolismo
Biotransformação
Western Blotting
Bovinos
Clorfeniramina/metabolismo
Dieta/veterinária
Duodeno/enzimologia
Eletroforese em Gel de Poliacrilamida
Etilmorfina/metabolismo
Glutationa Transferase/metabolismo
Masculino
Microssomos/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0M3S43XK27 (Benzphetamine); 3U6IO1965U (Chlorpheniramine); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 2.5.1.18 (Glutathione Transferase); RWO67D87EU (Ethylmorphine)
[Em] Mês de entrada:1010
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100619
[St] Status:MEDLINE
[do] DOI:10.1111/j.1365-2885.2009.01137.x


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[PMID]:19720728
[Au] Autor:Zhang H; Lin HL; Walker VJ; Hamdane D; Hollenberg PF
[Ad] Endereço:Department of Pharmacology, The University of Michigan, Ann Arbor, MI 48109-5632, USA.
[Ti] Título:tert-Butylphenylacetylene is a potent mechanism-based inactivator of cytochrome P450 2B4: inhibition of cytochrome P450 catalysis by steric hindrance.
[So] Source:Mol Pharmacol;76(5):1011-8, 2009 Nov.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have demonstrated that 4-(tert-butyl)-phenylacetylene (tBPA) is a potent mechanism-based inactivator for cytochrome P450 2B4 (P450 2B4) in the reconstituted system. It inactivates P450 2B4 in a NADPH- and time-dependent manner with a K(I) of 0.44 microM and k(inact) of 0.12 min(-1). The partition ratio was approximately zero, indicating that inactivation occurs without the reactive intermediate leaving the active site. Liquid chromatography-mass spectrometry analyses revealed that tBPA forms a protein adduct with a 1:1 stoichiometry. Peptide mapping of the tBPA-modified protein provides evidence that tBPA is covalently bound to Thr302. This is consistent with results of molecular modeling that show the terminal carbon of the acetylenic group is only 3.65 A away from Thr302. To characterize the effect of covalent modification of Thr302, tBPA-modified P450 2B4 was purified to homogeneity from the reconstituted system. The Soret band of tBPA-modified protein is red-shifted by 5 to 422 nm compared with unmodified protein. Benzphetamine binding to the modified P450 2B4 causes no spin shift, indicating that substrate binding and/or the heme environment has been altered by covalently bound tBPA. Cytochrome P450 reductase reduces the unmodified and tBPA-modified P450s at approximately the same rate. However, addition of benzphetamine stimulates the rate of reduction of unmodified P450 2B4 by approximately 20-fold but only marginally stimulates reduction of the tBPA-modified protein. This large discrepancy in the stimulation of the first electron transfer by benzphetamine strongly suggests that the impairment of P450 catalysis is due to inhibition of benzphetamine binding to the tBPA-modified P450 2B4.
[Mh] Termos MeSH primário: Acetileno/análogos & derivados
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores
Hidrocarboneto de Aril Hidroxilases/metabolismo
[Mh] Termos MeSH secundário: Acetileno/farmacologia
Benzfetamina/farmacologia
Catálise/efeitos dos fármacos
Domínio Catalítico/efeitos dos fármacos
Família 2 do Citocromo P450
Ligação Proteica/efeitos dos fármacos
Ligação Proteica/fisiologia
Estereoisomerismo
Especificidade por Substrato/efeitos dos fármacos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0M3S43XK27 (Benzphetamine); 239WSR2IBO (phenylacetylene); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.14.1 (cytochrome P-450 CYP2B4 (rabbit)); OC7TV75O83 (Acetylene)
[Em] Mês de entrada:0911
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090902
[St] Status:MEDLINE
[do] DOI:10.1124/mol.109.059808


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[PMID]:19596602
[Au] Autor:Li W; Tang Y; Hoshino T; Neya S
[Ad] Endereço:Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
[Ti] Título:Molecular modeling of human cytochrome P450 2W1 and its interactions with substrates.
[So] Source:J Mol Graph Model;28(2):170-6, 2009 Sep.
[Is] ISSN:1873-4243
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The human cytochrome P450 2W1 (CYP2W1) was categorized into the so-called "orphan" CYPs because of its unknown enzymatic function. However, recent studies showed that the recombinant CYP2W1 exhibited broad catalytic activity towards several chemicals. Furthermore, this enzyme was selectively expressed in some forms of cancers, whereas a very low expression was found in human normal issues. These render CYP2W1 as a potential drug target for cancer therapy. At present, however, little information is available on the active site topology and the substrate binding modes of CYP2W1. In this study, the three-dimensional model of CYP2W1 was constructed using the homology modeling method. Two known substrates, benzphetamine and indole, were then docked into the active site, and refined by molecular dynamics simulations. The interaction energy between the substrates and the enzyme was calculated and analyzed by using the MM-GBSA method. The results indicated that the constructed CYP2W1 model can account for the regioselectivity of this enzyme towards the known substrates and van der Waals interactions were the driving force for the substrate binding. Several key residues were identified to be responsible for the binding of indole and benzphetamine with CYP2W1. These findings provide useful information for the detailed characterization of the biological roles of CYP2W1 and structure-based drug design of this enzyme.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/metabolismo
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Benzfetamina/química
Benzfetamina/metabolismo
Família 2 do Citocromo P450
Seres Humanos
Dados de Sequência Molecular
Ligação Proteica
Estrutura Secundária de Proteína
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0M3S43XK27 (Benzphetamine); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (CYP2W1 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 2)
[Em] Mês de entrada:0912
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090715
[St] Status:MEDLINE
[do] DOI:10.1016/j.jmgm.2009.06.002


  9 / 310 MEDLINE  
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[PMID]:19243954
[Au] Autor:Vilches-Herrera M; Miranda-Sepúlveda J; Rebolledo-Fuentes M; Fierro A; Lühr S; Iturriaga-Vasquez P; Cassels BK; Reyes-Parada M
[Ad] Endereço:Department of Chemistry, Faculty of Sciences, University of Chile, Casilla 653, Santiago, Chile.
[Ti] Título:Naphthylisopropylamine and N-benzylamphetamine derivatives as monoamine oxidase inhibitors.
[So] Source:Bioorg Med Chem;17(6):2452-60, 2009 Mar 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of naphthylisopropylamine and N-benzyl-4-methylthioamphetamine derivatives were evaluated as monoamine oxidase inhibitors. Their potencies were compared with those of a series of amphetamine derivatives, to test if the increase of electron richness of the aromatic ring and overall size of the molecule might improve their potency as enzyme inhibitors. Molecular dockings were performed to gain insight regarding the binding mode of these inhibitors and rationalize their different potencies. In the case of naphthylisopropylamine derivatives, the increased electron-donating capacity and size of the aromatic moiety resulting from replacement of the phenyl ring of amphetamine derivatives by a naphthalene system resulted in more potent compounds. In the other case, extension of the arylisopropylamine molecule by N-benzylation of the amino group led to a decrease in potency as monoamine oxidase inhibitors.
[Mh] Termos MeSH primário: Benzfetamina/análogos & derivados
Inibidores da Monoaminoxidase/farmacologia
Naftalenos/farmacologia
Propilaminas/farmacologia
[Mh] Termos MeSH secundário: Animais
Benzfetamina/química
Benzfetamina/farmacologia
Espectroscopia de Ressonância Magnética
Modelos Moleculares
Inibidores da Monoaminoxidase/química
Naftalenos/química
Propilaminas/química
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Monoamine Oxidase Inhibitors); 0 (Naphthalenes); 0 (Propylamines); 0M3S43XK27 (Benzphetamine); 57378-23-1 (benzylamphetamine)
[Em] Mês de entrada:0906
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090227
[St] Status:MEDLINE
[do] DOI:10.1016/j.bmc.2009.01.074


  10 / 310 MEDLINE  
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[PMID]:19209859
[Au] Autor:Sheng X; Zhang H; Im SC; Horner JH; Waskell L; Hollenberg PF; Newcomb M
[Ad] Endereço:Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
[Ti] Título:Kinetics of oxidation of benzphetamine by compounds I of cytochrome P450 2B4 and its mutants.
[So] Source:J Am Chem Soc;131(8):2971-6, 2009 Mar 04.
[Is] ISSN:1520-5126
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochromes P450 are ubiquitous heme-containing enzymes that catalyze a wide range of reactions in nature including many oxidation reactions. The active oxidant species in P450 enzymes are widely thought to be iron(IV)-oxo porphyrin radical cations, termed Compound I species, but these intermediates have not been observed under turnover conditions. We prepared Compounds I of the mammalian hepatic P450 enzyme CYP2B4 and three mutants (E301Q, T302A, and F429H) by laser flash photolysis of the Compound II species that, in turn, were prepared by reaction of the resting enzymes with peroxynitrite. The PN treatment resulted in a small amount of nitration of the P450 as determined by mass spectrometry but no change in reactivity of the P450 in a test reaction. CYP2B4 Compound I oxidized benzphetamine to norbenzphetamine in high yield in bulk studies. In direct kinetic studies of benzphetamine oxidations, Compounds I displayed saturation kinetics with similar binding equilibrium constants (K(bind)) for each. The first-order oxidation rate constants (k(ox)) were comparable for Compounds I of CYP2B4, the E301Q mutant, and the T302A mutant, whereas the k(ox) for Compound I of the F429H mutant was reduced by a factor of 2. CYP119 Compound I, studied for comparison purposes, reacted with benzphetamine with a binding constant that was nearly an order of magnitude smaller than that of CYP2B4 but a rate constant that was similar. Substrate binding constants for P450 Compound I are important for controlling overall rates of oxidation reactions, and the intrinsic reactivities of Compounds I from various P450 enzymes are comparable.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/química
Benzfetamina/química
[Mh] Termos MeSH secundário: Proteínas Arqueais/química
Proteínas Arqueais/metabolismo
Hidrocarboneto de Aril Hidroxilases/metabolismo
Benzfetamina/metabolismo
Cromatografia Líquida de Alta Pressão
Sistema Enzimático do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/metabolismo
Família 2 do Citocromo P450
Cinética
Modelos Moleculares
Oxirredução
Processos Fotoquímicos
Fotólise
Espectrometria de Massas por Ionização por Electrospray
Espectrofotometria Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Archaeal Proteins); 0M3S43XK27 (Benzphetamine); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.- (CYP119 protein, Sulfolobus solfataricus); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.14.1 (cytochrome P-450 CYP2B4 (rabbit))
[Em] Mês de entrada:1007
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090213
[St] Status:MEDLINE
[do] DOI:10.1021/ja808982g



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