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1.
Bioorg Med Chem Lett ; 21(1): 34-7, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21146986

RESUMO

The discovery of a novel series of 5-HT(2C) agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT(2A) and 5-HT(2B) receptors were identified. One of the analogues (7 g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.


Assuntos
Azepinas/química , Compostos Heterocíclicos com 3 Anéis/química , Indenos/química , Doenças Metabólicas/tratamento farmacológico , Receptor 5-HT2C de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/química , Animais , Compostos Aza/química , Azepinas/farmacocinética , Azepinas/uso terapêutico , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Indenos/farmacocinética , Indenos/uso terapêutico , Masculino , Pirimidinas/química , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/química , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Relação Estrutura-Atividade
2.
J Lipid Res ; 50(1): 22-31, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18769020

RESUMO

Nuclear hormone receptors liver X receptor (LXRalpha and LXRbeta) ligands are attractive approaches for the treatment of dyslipidemia and atherosclerosis. To further elucidate the function of LXRalpha in liver lipid metabolism in a disease-relevant animal model, the KKAy mouse, we used adenoviral vectors to selectively knock down LXRalpha gene expression. Out of five different short hairpin RNAs (shRNAs) that were tested in vitro, one construct was selected for detailed analysis of LXRalpha knockdown in vivo. Reduction of LXRalpha transcript levels to 48 +/- 13% compared with control virus transduction resulted in a significant downregulation of the LXRalpha-regulated lipogenic genes sterol-regulatory element binding protein-1c (SREBP1c) and stearoyl CoA desaturase 1 in vivo. Interestingly, ABCA1 and phoshoenolpyruvate carboxykinase 1 expression was not affected, whereas lipoprotein lipase (LPL) expression was found to be increased. In addition, 8 days after virus transduction, both plasma and liver triglycerides (TGs) were reduced by about 50%. Changes in TG levels were not due to reduced food intake in virus-treated animals, because pair-fed mice showed unchanged TG levels. Taken together, liver-specific knockdown of LXRalpha in vivo by shRNA reduced expression of lipogenic master genes, like SREBP1c, and improved the lipid profile of hypertriglyceridemic KKAy mice.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Lipídeos/química , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Adenoviridae/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Experimental , Hipertrigliceridemia/metabolismo , Lipase Lipoproteica/metabolismo , Receptores X do Fígado , Camundongos , Modelos Biológicos , Receptores Nucleares Órfãos , RNA/metabolismo , RNA Mensageiro/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
3.
Circulation ; 110(23): 3553-9, 2004 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-15505097

RESUMO

BACKGROUND: Increasing sarcoplasmic/endoplasmic reticulum (SR) Ca2+-ATPase (SERCA) uptake activity is a promising therapeutic approach for heart failure. We investigated the effects of different levels of SERCA1a expression on contractility and Ca2+ cycling. We tested whether increased SERCA1a expression levels enhance myocyte contractility in a gene-dose-dependent manner. METHODS AND RESULTS: Rabbit isolated cardiomyocytes were transfected at different multiplicities of infection (MOIs) with adenoviruses encoding SERCA1a (or beta-galactosidase as control). Myocyte relaxation half-time was decreased by 10% (P=0.052) at SERCA1a MOI 10 and by 28% at MOI 50 (P<0.05). Myocyte fractional shortening was increased by 12% at MOI 10 (P<0.05) but surprisingly decreased at MOI 50 (-22%, P<0.05) versus control. SR Ca2+ uptake (in permeabilized myocytes) demonstrated a gene-dose-dependent decrease in K(m) by 29% and 46% and an increase in Vmax by 37% and 72% at MOI 10 and MOI 50, respectively (all P<0.05 versus control). Ca2+ transient amplitude was increased in Ad-SERCA1a-infected myocytes at MOI 10 (by 121%, P<0.05), but at MOI 50, the Ca2+ transient amplitude was not significantly changed. Caffeine-induced Ca2+ transients indicated significantly increased SR Ca2+ content in Ad-SERCA1a-infected cells, by 72% at MOI 10 and by 87% at MOI 50. Mathematical simulations demonstrate that the functional increase in SR Ca2+-ATPase uptake activity at MOI 50 (and increased cytosolic Ca2+ buffering) is sufficient to curtail the Ca2+ transient amplitude and explain the reduced contraction. CONCLUSIONS: Moderate SERCA1a gene transfer and expression improve contractility and Ca(2+) cycling. However, higher SERCA1a expression levels can impair myocyte shortening because of higher SERCA activity and Ca2+ buffering.


Assuntos
ATPases Transportadoras de Cálcio/biossíntese , Cálcio/metabolismo , Contração Miocárdica , Miócitos Cardíacos/fisiologia , Retículo Sarcoplasmático/metabolismo , Adenoviridae/genética , Animais , Sinalização do Cálcio , ATPases Transportadoras de Cálcio/genética , Tamanho Celular , Células Cultivadas , Técnicas de Transferência de Genes , Ventrículos do Coração/citologia , Relaxamento Muscular , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Coelhos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático
4.
Cardiovasc Res ; 55(2): 300-8, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12123769

RESUMO

OBJECTIVE: Increased levels of inhibitory G proteins have been observed in heart failure, but their physiological relevance in mediating the reduced beta-adrenergic response is largely unknown. METHODS: To evaluate the functional consequences of Galpha(i2) overexpression, we studied myocardial contraction in intact isometric contracting cardiac rabbit trabeculae and isolated myocytes after adenovirus-mediated gene transfer of Galpha(i2). RESULTS: Neither Galpha(i2) nor lacZ (control) overexpression altered baseline contractile force. After 72 h of continuous contractions, developed force (F(dev)) increased after addition of 1 microM isoproterenol by 28.5+/-9.7 mN/mm(2) in the control group, which was unchanged from the initial response at t=0 h (23.7+/-3.8 mN/mm(2)). In sharp contrast, in preparations transfected with AdGalpha(i2), the response to isoproterenol was significantly attenuated (5.9+/-2.0 vs. 27.6+/-4.2 mN/mm(2), t=72 vs. 0 h, respectively, P<0.01). In a primary culture of transfected isolated myocytes from a nearly identical baseline, isoproterenol increased cell shortening by 3.1+/-0.6% in the lacZ transfected myocytes, but only by 1.3+/-0.5% in Galpha(i2) transfected myocytes (t=72 h, P<0.01). In Galpha(i2) transfected myocytes, pertussis toxin restored beta-adrenergic responsiveness, indicating specificity of attenuation by the transgene. CONCLUSIONS: Overexpression of Galpha(i2) attenuates the positive inotropic effects of beta-adrenergic stimulation in myocardium. In addition, the method we developed allows investigation of a causal link between altered protein expression and subsequent alterations in contractile function in a physiological relevant in vitro manner.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Cardiotônicos/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Contração Miocárdica/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Adenoviridae , Animais , Técnicas de Cultura de Células , Tamanho Celular/efeitos dos fármacos , Subunidade alfa Gi2 de Proteína de Ligação ao GTP , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Vetores Genéticos , Isoproterenol/farmacologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/citologia , Miocárdio/metabolismo , Toxina Pertussis , Proteínas Proto-Oncogênicas/genética , Coelhos , Transfecção , Transgenes , Regulação para Cima , Fatores de Virulência de Bordetella/farmacologia
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