Base de dados : MEDLINE
Pesquisa : D03.132.478 [Categoria DeCS]
Referências encontradas : 320 [refinar]
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[PMID]:27986625
[Au] Autor:Nickell JR; Siripurapu KB; Horton DB; Zheng G; Crooks PA; Dwoskin LP
[Ad] Endereço:College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA.
[Ti] Título:GZ-793A inhibits the neurochemical effects of methamphetamine via a selective interaction with the vesicular monoamine transporter-2.
[So] Source:Eur J Pharmacol;795:143-149, 2017 Jan 15.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Lobeline and lobelane inhibit the behavioral and neurochemical effects of methamphetamine via an interaction with the vesicular monoamine transporter-2 (VMAT2). However, lobeline has high affinity for nicotinic receptors, and tolerance develops to the behavioral effects of lobelane. A water-soluble analog of lobelane, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), also interacts selectively with VMAT2 to inhibit the effects of methamphetamine, but does not produce behavioral tolerance. The current study further evaluated the mechanism underlying the GZ-793A-mediated inhibition of the neurochemical effects of methamphetamine. In contrast to lobeline, GZ-793A does not interact with the agonist recognition site on α4ß2 and α7 nicotinic receptors. GZ-793A (0.3-100µM) inhibited methamphetamine (5µM)-evoked fractional dopamine release from rat striatal slices, and did not evoke dopamine release in the absence of methamphetamine. Furthermore, GZ-793A (1-100µM) inhibited neither nicotine (30µM)-evoked nor electrical field-stimulation-evoked (100Hz/1min) fractional dopamine release. Unfortunately, GZ-793A inhibited [ H]dofetilide binding to human-ether-a-go-go related gene channels expressed on human embryonic kidney cells, and further, prolonged action potentials in rabbit cardiac Purkinje fibers, suggesting the potential for GZ-793A to induce ventricular arrhythmias. Thus, GZ-793A selectively inhibits the neurochemical effects of methamphetamine and lacks nicotinic receptor interactions; however, development as a pharmacotherapy for methamphetamine use disorders will not be pursued due to its potential cardiac liabilities.
[Mh] Termos MeSH primário: Lobelina/análogos & derivados
Metanfetamina/farmacologia
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Mh] Termos MeSH secundário: Animais
Comportamento Animal/efeitos dos fármacos
Dopamina/secreção
Canal de Potássio ERG1/metabolismo
Estimulação Elétrica
Células HEK293
Seres Humanos
Lobelina/metabolismo
Lobelina/farmacologia
Masculino
Coelhos
Ratos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ERG1 Potassium Channel); 0 (KCNH2 protein, human); 0 (N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine); 0 (Slc18a2 protein, rat); 0 (Vesicular Monoamine Transport Proteins); 44RAL3456C (Methamphetamine); D0P25S3P81 (Lobeline); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170508
[Lr] Data última revisão:
170508
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161218
[St] Status:MEDLINE


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[PMID]:27212067
[Au] Autor:Nickell JR; Culver JP; Janganati V; Zheng G; Dwoskin LP; Crooks PA
[Ad] Endereço:Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
[Ti] Título:1,4-Diphenalkylpiperidines: A new scaffold for the design of potent inhibitors of the vesicular monoamine transporter-2.
[So] Source:Bioorg Med Chem Lett;26(13):2997-3000, 2016 07 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of 1,4-diphenalkylpiperidine analogs were synthesized and evaluated for their affinity and inhibitory potency at the [(3)H]dihydrotetrabenazine (DTBZ) binding site and [(3)H]dopamine (DA) uptake site on the vesicular monoamine transporter-2 (VMAT2). Results revealed that translocation of the phenethyl side chains of lobelane from C2 and C6 to C1 and C4 around the central piperidine ring slightly reduces affinity and inhibitory potency at VMAT2 with respect to lobelane. However, methoxy and fluoro-substitution of either phenyl ring of these 1,4-diphenethyl analogs afforded VMAT2 inhibition comparable or higher (5-fold) affinity at the DTBZ binding and DA uptake sites relative to lobelane, whereas replacement of the 4-phenethyl moiety in these analogs with a 4-phenmethyl moiety markedly reduced affinity for the DTBZ binding and DA uptake sites by 3- and 5-fold, respectively. Among the twenty five 1,4-diphenethylpiperidine analogs evaluated, compounds containing a 4-(2-methoxyphenethyl) moiety exhibited the most potent inhibition of DTBZ binding and vesicular DA uptake. From this subgroup, analogs 8h, 8j and 8m exhibited Ki values of 9.3nM, 13nM and 13nM, respectively, for inhibition of [(3)H]DA uptake by VMAT2, and represent some of the most potent inhibitors of VMAT2 function reported thus far.
[Mh] Termos MeSH primário: Piperidinas/farmacologia
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Encéfalo/metabolismo
Desenho de Drogas
Lobelina/análogos & derivados
Lobelina/farmacologia
Piperidinas/síntese química
Piperidinas/química
Ensaio Radioligante
Ratos
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 (1,4-bis(2-methoxyphenethyl)piperidine); 0 (1-(4-fluorophenethyl)-4-(2-methoxyphenethyl)piperidine); 0 (4-(2-methoxyphenethyl)-1-(3-methoxyphenethyl)piperidine); 0 (Piperidines); 0 (Slc18a2 protein, rat); 0 (Vesicular Monoamine Transport Proteins); 0 (lobelane); D0P25S3P81 (Lobeline)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160524
[St] Status:MEDLINE
[do] DOI:10.1016/j.bmcl.2016.05.025


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[PMID]:26702732
[Au] Autor:Li KC; Ho YL; Chen CY; Hsieh WT; Chang YS; Huang GJ
[Ad] Endereço:Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung 404, Taiwan.
[Ti] Título:Lobeline improves acute lung injury via nuclear factor-κB-signaling pathway and oxidative stress.
[So] Source:Respir Physiol Neurobiol;225:19-30, 2016 May.
[Is] ISSN:1878-1519
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Acute lung injury (ALI) is a severe, life-threatening medical condition whose pathogenesis is linked to neutrophil infiltration of the lung. Activation and recruitment of neutrophils to the lung is mostly attributed to the production of chemokines NO, IL-6, for instance. This study aims to investigate lobeline ability in reducing NO production, and nitric oxide synthase (iNOs) expression. Lobeline was tested by inhibiting phosphorylation of mitogen-activated protein kinases (MAPKs), NF-κB and IκBα in LPS-stimulated RAW 264.7 cells. When RAW 264.7 macrophages were given lobeline with LPS, a significant concentration-dependent inhibition of NO production was detected. In vivo tests, mice were either treated with normal saline, 10mg/kg dexmethasone or 5, 10, 20mg/kg lobeline intraperitoneally, and after an hour, the administration of 5mg/kg of LPS was given intratracheally. External performance, cytokines, MAPK pathways and antioxidative enzymes (AOEs) were also carried out to evaluate the effects of these drugs. This is the first investigation in which lobeline was found to effectively inhibit acute lung edema, which may provide a potential target for treating ALI. Lobeline may utilize MAPKs pathways as well as AOEs activity to attenuate LPS-induced nonspecific pulmonary inflammation.
[Mh] Termos MeSH primário: Lesão Pulmonar Aguda/tratamento farmacológico
Lobelina/farmacologia
NF-kappa B/metabolismo
Estresse Oxidativo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Lesão Pulmonar Aguda/metabolismo
Animais
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/fisiologia
Ciclo-Oxigenase 2/metabolismo
Relação Dose-Resposta a Droga
Lipopolissacarídeos
Macrófagos/efeitos dos fármacos
Macrófagos/fisiologia
Masculino
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos ICR
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Inibidor de NF-kappaB alfa/metabolismo
Óxido Nítrico/metabolismo
Estresse Oxidativo/fisiologia
Distribuição Aleatória
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Lipopolysaccharides); 0 (NF-kappa B); 139874-52-5 (NF-KappaB Inhibitor alpha); 31C4KY9ESH (Nitric Oxide); D0P25S3P81 (Lobeline); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (Ptgs2 protein, rat); EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151226
[St] Status:MEDLINE


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[PMID]:26693882
[Au] Autor:Buoli M; Serati M; Cahn W
[Ad] Endereço:a Department of Psychiatry, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico , University of Milan , Milan , Italy.
[Ti] Título:Alternative pharmacological strategies for adult ADHD treatment: a systematic review.
[So] Source:Expert Rev Neurother;16(2):131-44, 2016.
[Is] ISSN:1744-8360
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard pharmacotherapy (methylphenidate and atomoxetine) improves ADHD symptoms in the short-term, but poor data were published about long-term treatment. In addition a number of patients present partial or no response to methylphenidate and atomoxetine. Research into the main database sources has been conducted to obtain an overview of alternative pharmacological approaches in adult ADHD patients. Among alternative compounds, amphetamines (mixed amphetamine salts and lisdexamfetamine) have the most robust evidence of efficacy, but they may be associated with serious side effects (e.g. psychotic symptoms or hypertension). Antidepressants, particularly those acting as noradrenaline or dopamine enhancers, have evidence of efficacy, but they should be avoided in patients with comorbid bipolar disorder. Finally metadoxine and lithium may be particularly suitable in case of comorbid alcohol misuse or bipolar disorder.
[Mh] Termos MeSH primário: Antidepressivos/uso terapêutico
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico
Estimulantes do Sistema Nervoso Central/uso terapêutico
Dopaminérgicos/uso terapêutico
Agonistas Nicotínicos/uso terapêutico
[Mh] Termos MeSH secundário: Agonistas alfa-Adrenérgicos/uso terapêutico
Adulto
Anfetaminas/uso terapêutico
Compostos Benzidrílicos/uso terapêutico
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico
Bupropiona/uso terapêutico
Desipramina/uso terapêutico
Droxidopa/uso terapêutico
Combinação de Medicamentos
Cloridrato de Duloxetina/uso terapêutico
Guanfacina/uso terapêutico
Histamínicos/uso terapêutico
Seres Humanos
Dimesilato de Lisdexanfetamina/uso terapêutico
Compostos de Lítio/uso terapêutico
Lobelina/uso terapêutico
Mecamilamina/uso terapêutico
Memantina/uso terapêutico
Morfolinas/uso terapêutico
Antagonistas Nicotínicos/uso terapêutico
Nomifensina/uso terapêutico
Paroxetina/uso terapêutico
Piridinas/uso terapêutico
Piridoxina/uso terapêutico
Ácido Pirrolidonocarboxílico/uso terapêutico
Quinazolinonas/uso terapêutico
Cloridrato de Venlafaxina/uso terapêutico
Promotores da Vigília/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (3-(5-chloro-2-furoyl)-3,7-diazabicyclo(3.3.0)octane); 0 (Adderall); 0 (Adrenergic alpha-Agonists); 0 (Amphetamines); 0 (Antidepressive Agents); 0 (Benzhydryl Compounds); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Central Nervous System Stimulants); 0 (Dopamine Agents); 0 (Drug Combinations); 0 (Histamine Agents); 0 (Lithium Compounds); 0 (MK-0249); 0 (Morpholines); 0 (Nicotinic Agonists); 0 (Nicotinic Antagonists); 0 (Pyridines); 0 (Quinazolinones); 0 (Wakefulness-Promoting Agents); 01ZG3TPX31 (Bupropion); 1LGS5JRP31 (Nomifensine); 30OMY4G3MK (Guanfacine); 3E05NBH9V5 (ispronicline); 41VRH5220H (Paroxetine); 6EE945D3OK (Mecamylamine); 7D7RX5A8MO (Venlafaxine Hydrochloride); 9044SC542W (Duloxetine Hydrochloride); 947S0YZ36I (reboxetine); D0P25S3P81 (Lobeline); EJQ7M98H5J (metadoxine); J7A92W69L7 (Droxidopa); KV2JZ1BI6Z (Pyridoxine); R3UK8X3U3D (modafinil); SJT761GEGS (Lisdexamfetamine Dimesylate); SZB83O1W42 (Pyrrolidonecarboxylic Acid); TG537D343B (Desipramine); W8O17SJF3T (Memantine)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170103
[Lr] Data última revisão:
170103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151224
[St] Status:MEDLINE
[do] DOI:10.1586/14737175.2016.1135735


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[PMID]:26455278
[Au] Autor:Roni MA; Rahman S
[Ad] Endereço:Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
[Ti] Título:Effects of lobeline and reboxetine, fluoxetine, or bupropion combination on depression-like behaviors in mice.
[So] Source:Pharmacol Biochem Behav;139(Pt A):1-6, 2015 Dec.
[Is] ISSN:1873-5177
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Evidence suggests that lobeline, a nicotinic acetylcholine receptor ligand, has antidepressant-like properties in mice. The present study investigated the possible additive or synergistic effects of lobeline in combination with commonly used antidepressants, such as reboxetine, fluoxetine, or bupropion, using the tail suspension test (TST) and the forced swim test (FST) in C57BL/6J mice. Reboxetine (5 or 10 mg/kg, i.p.), fluoxetine (5 or 10 mg/kg, i.p.), or bupropion (2 or 4 mg/kg, i.p.) were administered 30 min before TST or FST. A fixed dose of lobeline (1 mg/kg, i.p.) was injected 15 min prior to tests. Co-administration of lobeline and reboxetine, fluoxetine, or bupropion significantly reduced immobility time in the TST and FST in comparison to the antidepressants used alone. The results suggest that lobeline enhanced the effects of reboxetine, fluoxetine, or bupropion in mice. Therefore, lobeline or similar nicotinic receptor ligand may have therapeutic potential as an adjunct for the treatment of major depression.
[Mh] Termos MeSH primário: Antidepressivos/farmacologia
Comportamento Animal/efeitos dos fármacos
Bupropiona/farmacologia
Depressão/tratamento farmacológico
Fluoxetina/farmacologia
Lobelina/farmacologia
Morfolinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antidepressivos/uso terapêutico
Bupropiona/uso terapêutico
Depressão/fisiopatologia
Depressão/psicologia
Sinergismo Farmacológico
Quimioterapia Combinada
Fluoxetina/uso terapêutico
Resposta de Imobilidade Tônica/efeitos dos fármacos
Lobelina/uso terapêutico
Masculino
Camundongos
Morfolinas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Morpholines); 01K63SUP8D (Fluoxetine); 01ZG3TPX31 (Bupropion); 947S0YZ36I (reboxetine); D0P25S3P81 (Lobeline)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151126
[Lr] Data última revisão:
151126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151013
[St] Status:MEDLINE


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[PMID]:26259655
[Au] Autor:Kursinszki L; Szoke É
[Ad] Endereço:Department of Pharmacognosy, Semmelweis University, Ülloi út 26, H-1085, Budapest, Hungary.
[Ti] Título:HPLC-ESI-MS/MS of brain neurotransmitter modulator lobeline and related piperidine alkaloids in Lobelia inflata L.
[So] Source:J Mass Spectrom;50(5):727-33, 2015 May.
[Is] ISSN:1096-9888
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:There is a renewed interest in lobelia alkaloids because of their activity on the central nervous system. Lobeline, the most active of them, a nicotinic receptor ligand and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for metamphetamine abuse. In the present work, high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry in positive ion mode was used for investigating the alkaloid profile in Lobelia inflata L. Chromatographic separations were achieved on a Gemini C6-phenyl reversed-phase column providing good peak shape and improved selectivity. Being mostly 2,6-disubstituted piperidines, lobelia alkaloids presented abundant [M + H](+) ions with typical fragmentation. Identification was possible from a few specific ions, especially those resulting from excision of one of the substituents. Based on fragmentation pattern of lobeline as reference compound, 52 alkaloids were identified in the aqueous methanolic extract of L. inflata in contrast to the previously known some 20. Structural variability of these alkaloids identified arises basically from their substituents which can be phenyl-2-ketoethyl- or phenyl-2-hydroxyethyl units as well as their methyl-, ethyl- or propyl- homologues attached in different combinations. Several propyl homologue lobelia alkaloids and five hydroxypiperidine derivatives were found in the plant at the first time. In addition to 8-O-esters of 2-monosubstituted piperidine alkaloids previously reported by us in L. inflata, a 3-hydroxy-3-phenylpropanoic acid ester of hydroxyallosedamine ring-substituted was also identified as a new natural product. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry can be successfully applied to Lobeliacae plant samples in the routine screening for new and known bioactive constituents, quality control of the crude drug, lobelia herba, alkaloid production studies, breeding and chemotaxonomy.
[Mh] Termos MeSH primário: Alcaloides/análise
Cromatografia Líquida de Alta Pressão/métodos
Lobelia/química
Lobelina/análise
Neurotransmissores/análise
Espectrometria de Massas por Ionização por Electrospray/métodos
[Mh] Termos MeSH secundário: Piperidinas/análise
Extratos Vegetais/química
Espectrometria de Massas em Tandem/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Alkaloids); 0 (Neurotransmitter Agents); 0 (Piperidines); 0 (Plant Extracts); D0P25S3P81 (Lobeline)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150811
[Lr] Data última revisão:
150811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150812
[St] Status:MEDLINE
[do] DOI:10.1002/jms.3581


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[PMID]:26107096
[Au] Autor:Willyard C
[Ti] Título:Pharmacotherapy: Quest for the quitting pill.
[So] Source:Nature;522(7557):S53-5, 2015 Jun 25.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Comportamento Aditivo/tratamento farmacológico
Comportamento Aditivo/psicologia
Descoberta de Drogas
Prazer/efeitos dos fármacos
Recompensa
Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
Transtornos Relacionados ao Uso de Substâncias/psicologia
[Mh] Termos MeSH secundário: Animais
Comportamento Aditivo/imunologia
Buprenorfina/uso terapêutico
Combinação Buprenorfina e Naloxona
Ensaios Clínicos como Assunto
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico
Transtornos Relacionados ao Uso de Cocaína/imunologia
Transtornos Relacionados ao Uso de Cocaína/psicologia
Aconselhamento
Dopamina/metabolismo
Descoberta de Drogas/economia
Indústria Farmacêutica/economia
Seres Humanos
Ibogaína/análogos & derivados
Ibogaína/farmacologia
Ibogaína/uso terapêutico
Lobelina/uso terapêutico
Terapia de Alvo Molecular
Naloxona/uso terapêutico
Naltrexona/uso terapêutico
Oligopeptídeos/farmacologia
Oligopeptídeos/uso terapêutico
Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico
Transtornos Relacionados ao Uso de Opioides/imunologia
Transtornos Relacionados ao Uso de Opioides/psicologia
Prazer/fisiologia
Ratos
Receptores Nicotínicos/metabolismo
Transtornos Relacionados ao Uso de Substâncias/imunologia
Tabagismo/tratamento farmacológico
Tabagismo/imunologia
Vacinas/administração & dosagem
Vacinas/imunologia
Vacinas/uso terapêutico
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AT-1001); 0 (Buprenorphine, Naloxone Drug Combination); 0 (Oligopeptides); 0 (Receptors, Nicotinic); 0 (SLC18A2 protein, human); 0 (Vaccines); 0 (Vesicular Monoamine Transport Proteins); 0 (nicotinic receptor alpha3beta4); 36B82AMQ7N (Naloxone); 3S814I130U (Ibogaine); 40D3SCR4GZ (Buprenorphine); 5S6W795CQM (Naltrexone); D0P25S3P81 (Lobeline); KX8NQX91Z8 (18-methoxycoronaridine); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150625
[St] Status:MEDLINE
[do] DOI:10.1038/522S53a


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[PMID]:25991431
[Au] Autor:Ding D; Nickell JR; Dwoskin LP; Crooks PA
[Ad] Endereço:Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
[Ti] Título:Quinolyl analogues of norlobelane: novel potent inhibitors of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake at the vesicular monoamine transporter-2.
[So] Source:Bioorg Med Chem Lett;25(13):2613-6, 2015 Jul 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We have previously shown that quinolyl moieties are attractive structural replacements for the phenyl groups in lobelane. These quinolyl analogues had improved water-solubility over lobelane and retained the potent vesicular monoamine transporter-2 (VMAT-2) inhibitory properties of the parent compound, with quinlobelane (4) exhibiting potent inhibition of uptake at VMAT-2 (Ki=51nM). However, the VMAT-2 inhibitory properties of quinolyl analogues of norlobelane, which is equipotent with lobeline as an inhibitor of [(3)H]dopamine (DA) uptake at VMAT-2, have not been reported. In the current communication, we describe the synthesis of some novel des-methyl quinolyl analogues of lobelane that exhibit greater affinity (Ki=178-647nM) for the dihydrotetrabenazine binding site located on VMAT-2 compared with lobelane (Ki=970nM), norlobelane (Ki=2310nM) and quinlobelane (Ki=2640nM). The most potent compounds, 14 and 15, also exhibited inhibition of [(3)H]DA uptake at VMAT-2 (Ki=42nM) which was comparable to both lobelane (Ki=45nM) and norlobelane (Ki=43nM). Results reveal that binding affinity at VMAT-2 serves as an accurate predictor of inhibition of the function of VMAT-2 for the majority of these analogues. These novel analogues are under consideration for further development as treatments for methamphetamine abuse.
[Mh] Termos MeSH primário: Dopamina/metabolismo
Lobelina/análogos & derivados
Tetrabenazina/análogos & derivados
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo
Animais
Sítios de Ligação
Seres Humanos
Técnicas In Vitro
Cinética
Lobelina/química
Lobelina/farmacologia
Metanfetamina/metabolismo
Ratos
Relação Estrutura-Atividade
Vesículas Sinápticas/efeitos dos fármacos
Vesículas Sinápticas/metabolismo
Tetrabenazina/metabolismo
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Slc18a2 protein, rat); 0 (Vesicular Monoamine Transport Proteins); 3466-75-9 (dihydrotetrabenazine); 44RAL3456C (Methamphetamine); D0P25S3P81 (Lobeline); VTD58H1Z2X (Dopamine); Z9O08YRN8O (Tetrabenazine)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150521
[St] Status:MEDLINE


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[PMID]:25794424
[Au] Autor:Arias HR; Feuerbach D; Ortells M
[Ad] Endereço:Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA, USA. Electronic address: hugo.arias@cnsu.edu.
[Ti] Título:Functional and structural interaction of (-)-lobeline with human α4ß2 and α4ß4 nicotinic acetylcholine receptor subtypes.
[So] Source:Int J Biochem Cell Biol;64:15-24, 2015 Jul.
[Is] ISSN:1878-5875
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:To determine the pharmacologic activity of (-)-lobeline between human (h)α4ß2 and hα4ß4 nicotinic acetylcholine receptors (AChRs), functional and structural experiments were performed. The Ca(2+) influx results established that (-)-lobeline neither actives nor enhances the function of the studied AChR subtypes, but competitively inhibits hα4ß4 AChRs with potency ∼10-fold higher than that for hα4ß2 AChRs. This difference is due to a higher binding affinity for the [(3)H]cytisine sites at hα4ß4 compared to hα4ß2 AChRs, which, in turn, can be explained by our molecular dynamics (MD) results: (1) higher stability of (-)-lobeline and its hydrogen bonds within the α4ß4 pocket compared to the α4ß2 pocket, (2) (-)-lobeline promotes Loop C to cap the binding site at the α4ß4 pocket, but forces Loop C to get apart from the α4ß2 pocket, precluding the gating process elicited by agonists, and (3) the orientation of (-)-lobeline within the α4ß4, but not the α4ß2, subpocket, promoted by the t- (or t+) rotameric state of α4-Tyr98, remains unchanged during the whole MD simulation. This study gives a detailed view of the molecular and dynamics events evoked by (-)-lobeline supporting the differential binding affinity and subsequent inhibitory potency between hα4ß2 and hα4ß4 AChRs, and supports the possibility that the latter subtype is also involved in its activity.
[Mh] Termos MeSH primário: Lobelina/farmacologia
Agonistas Nicotínicos/farmacologia
Receptores Nicotínicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Células CHO
Sinalização do Cálcio
Cricetinae
Cricetulus
Células HEK293
Seres Humanos
Ligações de Hidrogênio
Concentração Inibidora 50
Lobelina/química
Simulação de Dinâmica Molecular
Agonistas Nicotínicos/química
Ligação Proteica
Estrutura Secundária de Proteína
Receptores Nicotínicos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nicotinic Agonists); 0 (Receptors, Nicotinic); 0 (alpha(4)beta(4) nicotinic receptor); 0 (nicotinic receptor alpha4beta2); D0P25S3P81 (Lobeline)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150608
[Lr] Data última revisão:
150608
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150322
[St] Status:MEDLINE


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[PMID]:25451721
[Au] Autor:Roni MA; Rahman S
[Ad] Endereço:Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
[Ti] Título:The effects of lobeline on depression-like behavior and hippocampal cell proliferation following chronic stress in mice.
[So] Source:Neurosci Lett;584:7-11, 2015 Jan 01.
[Is] ISSN:1872-7972
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:We have reported that brain nicotinic acetylcholine receptor (nAChR) ligand lobeline has antidepressant-like effects in mice. The present study examined the effects of lobeline on chronic unpredictable stress (CUS)-induced depression-like behavior, deficits in brain-derived neurotrophic factor (BDNF) expression and cell proliferation in the hippocampus. Adult C57BL/6J mice were exposed to CUS for 6 weeks. Lobeline (1 or 4 mg/kg, s.c.) or saline was administered once daily during the last 14 days of CUS. CUS-exposed mice showed increased immobility time in the FST compared to control. Pretreatment with lobeline (1 mg/kg) significantly reduced immobility time in the CUS-exposed mice. Twenty-four hour following lobeline or saline treatment, BDNF expression or cell proliferation was measured in the hippocampus using Western blotting and bromodeoxyuridine immunohistochemistry, respectively. Lobeline (1 mg/kg) treatment prevented CUS-induced reduction in BDNF expression and cell proliferation in the hippocampus. Overall, our findings suggest that antidepressant-like effects of lobeline could involve nAChR mediated signaling, BDNF expression, and/or hippocampal cell proliferation.
[Mh] Termos MeSH primário: Antidepressivos/farmacologia
Depressão/psicologia
Hipocampo/efeitos dos fármacos
Lobelina/farmacologia
Estresse Psicológico/psicologia
[Mh] Termos MeSH secundário: Animais
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Proliferação Celular
Doença Crônica
Depressão/etiologia
Depressão/patologia
Hipocampo/metabolismo
Hipocampo/patologia
Masculino
Camundongos Endogâmicos C57BL
Estresse Psicológico/complicações
Estresse Psicológico/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Brain-Derived Neurotrophic Factor); D0P25S3P81 (Lobeline)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:141216
[Lr] Data última revisão:
141216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE



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