RESUMEN
We report the novel combination of a selective beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor (sibutramine) with potential for the treatment of obesity. The synthesis and characterization of 6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide (LY377604), a human ß3-adrenergic receptor agonist and ß1- and ß2-adrenergic receptor antagonist with no sympathomimetic activity at the ß1- and ß2-adrenergic receptors, is reported. Some in vivo data in both rats and humans is presented.
RESUMEN
The synthesis and biological evaluation of a series of oxindole beta(3) adrenergic receptor agonists is described. A modulation of rat atrial tachycardia was observed with substitution at the 3-position of the oxindole moiety.
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Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntesis química , Agonistas Adrenérgicos beta/farmacología , Indoles/síntesis química , Indoles/farmacología , Taquicardia/tratamiento farmacológico , Agonistas Adrenérgicos beta/química , Animales , Células CHO , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Indoles/química , Estructura Molecular , Oxindoles , Ratas , Ratas Long-Evans , Receptores Adrenérgicos beta 3/biosíntesis , Receptores Adrenérgicos beta 3/genéticaRESUMEN
The synthesis and biological evaluation of a series of benzimidazolone beta(3) adrenergic receptor agonists are described. A trend toward the reduction of rat atrial tachycardia upon increasing steric bulk at the 3-position of the benzimidazolone moiety was observed.
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Antagonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacología , Bencimidazoles/farmacología , Agonistas Adrenérgicos beta/química , Bencimidazoles/química , HumanosRESUMEN
OBJECTIVE: To evaluate applicability, precision, and accuracy of a new quantitative magnetic resonance (QMR) analysis for whole body composition of conscious live mice. RESEARCH METHODS AND PROCEDURES: Repeated measures of body composition were made by QMR, DXA, and classic chemical analysis of carcass using live and dead mice with different body compositions. Caloric lean and dense diets were used to produce changes in body composition. In addition, different strains of mice representing widely diverse populations were analyzed. RESULTS: Precision was found to be better for QMR than for DXA. The coefficient of variation for fat ranged from 0.34% to 0.71% compared with 3.06% to 12.60% for DXA. Changes in body composition in response to dietary manipulation were easily detected using QMR. An increase in fat mass of 0.6 gram after 1 week (p < 0.01) was demonstrated in the absence of hyperphagia or a change in mean body weight. DISCUSSION: QMR and DXA detected similar fat content, but the improved precision afforded by QMR compared with DXA and chemical analysis allowed detection of a significant difference in body fat after 7 days of consuming a diet rich in fat even though average body weight did not significantly change. QMR provides a very precise, accurate, fast, and easy-to-use method for determining fat and lean tissue of mice without the need for anesthesia. Its ability to detect differences with great precision should be of value when characterizing phenotype and studying regulation of body composition brought about by pharmacological and dietary interventions in energy homeostasis.
Asunto(s)
Composición Corporal , Espectroscopía de Resonancia Magnética/métodos , Absorciometría de Fotón , Tejido Adiposo , Animales , Grasas de la Dieta/administración & dosificación , Ingestión de Energía , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/fisiopatología , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: to evaluate the applicability, precision, and accuracy of the new EchoMRI quantitative magnetic resonance (QMR) method for in-vitro bovine bone analysis and in-vivo whole-body-composition analysis of conscious live mice. RESEARCH METHODS AND PROCEDURES: bovine tibia bone samples were measured by QMR and dual-energy X-ray adsorptiometry (DEXA). Repeated measures of whole-body composition were made using live and dead mice with different levels of fat by QMR and DEXA and by classic chemical analysis of the mouse carcass. RESULTS: bone-mineral density (BMD) and bone-mineral content (BMC) measured in bovine tibia by QMR and DEXA were highly correlated. Precision of fat and lean measurement in mice was found to be better for QMR than for DEXA. The coefficient of variation ( CV) for fat was 0.34-0.71% for QMR compared with 3.06-12.60% for DEXA. DISCUSSION: QMR offers more specific parameters of bone structure than does DEXA. QMR and DEXA did not differ in the total amount of fat detected in live mice but QMR had improved precision. QMR was superior to DEXA in measuring fat in very small mice. CONCLUSIONS: in bone tissue there is a strong correlation between hydrogen NMR signal and bone-mineral density as measured by X-ray. QMR provides a very precise, accurate, fast, and easy to use method for determining fat and lean mass of mice without the need for anesthesia. Its ability to detect differences and monitor changes in body composition in mice with great precision should be of great value in characterizing phenotypes and studying drugs affecting obesity.
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Composición Corporal , Huesos/química , Imagen por Resonancia Magnética/métodos , Tejido Adiposo/química , Animales , Pollos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Músculos/química , Obesidad/metabolismo , Osteoporosis/metabolismoRESUMEN
Agonists to opioid receptors induce a positive energy balance, whereas antagonists at these receptors reduce food intake and body weight in rodent models of obesity. An analog of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, LY255582, is a potent non-morphinan antagonist for mu-, kappa-, and delta-receptors (K(i) of 0.4, 2.0, and 5.2 nM, respectively). In the present study, we examined the effects of oral LY255582 treatment on caloric intake, calorie expenditure, and body composition in dietary-induced obese rats. Acute oral treatment of LY255582 produced a dose-dependent decrease in energy intake and respiratory quotient (RQ), which correlated with the occupancy of central opioid receptors. Animals receiving chronic oral treatment with LY255582 for 14 days maintained a negative energy balance that was sustained by increased lipid use. Analysis of body composition revealed a reduction in fat mass accretion, with no change in lean body mass, in animals treated with LY255582. Therefore, chronic treatment with LY255582 reduces adipose tissue mass by reducing energy intake and stimulating lipid use.
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Tejido Adiposo/metabolismo , Conducta Alimentaria , Metabolismo de los Lípidos , Antagonistas de Narcóticos , Obesidad/metabolismo , Tejido Adiposo/efectos de los fármacos , Animales , Composición Corporal/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Ciclohexanos/administración & dosificación , Ciclohexanos/farmacología , Relación Dosis-Respuesta a Droga , Ingestión de Energía/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Masculino , Piperidinas/administración & dosificación , Piperidinas/farmacología , Ratas , Ratas Long-Evans , Receptores Opioides/metabolismoRESUMEN
Ames dwarf mice have primary deficiency of prolactin (PRL), growth hormone (GH), and thyroid-stimulating hormone (TSH), and live considerably longer than normal animals from the same line. In view of the documented effects of GH, PRL, and thyroid hormones on lean and fat body mass and skeletal growth, and the suspected relationship of body size and composition to life expectancy, it was of interest to examine age-related changes in body composition of Ames dwarf mice. Lean mass, fat mass, bone area, and bone mineral content (BMC) were determined in dwarf and normal mice at the ages of 2, 4.5 6, and 18 mo using dual X-ray absorptiometry. In addition to the expected significant declines in lean mass, bone area, and BMC, dwarf mice exhibited attenuation of the age-related increase in bone mineral density and delayed or attenuated increase in percentage of body fat. Percentage of body fat was lower in adult dwarfs than in the corresponding normal controls. Patterns of age-related changes in body composition in Ames dwarf mice are consistent with the recent report of age-related changes in body composition in PRL receptor knockout mice. We suspect that reduction in relative adiposity may contribute to the previously reported increase in insulin sensitivity of Ames dwarf mice and thus may be a factor in delayed aging and increased longevity of these animals.