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1.
Neuroimage ; 148: 123-129, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28089678

RESUMO

Physical activity has been shown to ameliorate dopaminergic degeneration in non-human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults.


Assuntos
Envelhecimento/metabolismo , Exercício Físico/fisiologia , Receptores de Dopamina D2/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto Jovem
2.
Bioorg Med Chem Lett ; 22(2): 1247-50, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22172702
3.
Psychopharmacology (Berl) ; 236(2): 581-590, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30350220

RESUMO

RATIONALE: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed. OBJECTIVES: Here, we sought to investigate sex differences in dopamine release after oral D-amphetamine administration. METHODS: We used [18F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBPND, an index of dopamine release) between placebo and D-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males. RESULTS: Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in D-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control. CONCLUSIONS: While our finding in young adults from one dataset of greater %ΔBPND in males is partially consistent with a previously published study on sex differences in D-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Estriado Ventral/efeitos dos fármacos , Adulto , Idoso , Benzamidas , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Caracteres Sexuais , Fatores Sexuais , Estriado Ventral/diagnóstico por imagem , Estriado Ventral/metabolismo , Adulto Jovem
4.
J Med Chem ; 56(20): 7788-803, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24093940

RESUMO

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Alanina/análogos & derivados , Alanina/síntese química , Alanina/farmacocinética , Alanina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzodiazepinonas/síntese química , Benzodiazepinonas/farmacocinética , Benzodiazepinonas/farmacologia , Western Blotting , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Compostos Heterocíclicos/farmacocinética , Humanos , Proteínas Inibidoras de Apoptose/química , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Nus , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Estrutura Terciária de Proteína , Ubiquitina-Proteína Ligases , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/química , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Bioorg Med Chem Lett ; 17(8): 2134-8, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17303421

RESUMO

A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents.


Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Tiazóis/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacologia
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