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Ghrelin, an acylated peptide secreted from the stomach, acts as a short-term signal of nutrient depletion. Ghrelin is an endogenous ligand for the GH secretagogue receptor 1a, a G protein-coupled receptor expressed in the hypothalamus and pituitary. We used a synthetic oligonucleotide, NOX-B11-2, capable of specific high-affinity binding to bioactive(More)
The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These(More)
The two most closely related isoenzymes of protein kinase C (PKC), PKC betaI and betaII, are distinct but highly homologous isoenzymes derived via alternative splicing of the same gene product. In this study, PKC betaII, but not PKC betaI, translocated to the actin cytoskeleton upon stimulation of cells with phorbol esters. In cells, antibodies to PKC(More)
Structure-activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-carboxamide analogs as human CB1 receptor inverse agonists resulted in the discovery of the two amide derivatives 24a and b (hCB1 IC50 = 6.1 and 4.0 nM) which also demonstrated efficacy in overnight feeding studies in the rat for reduction in both food intake(More)
Two fructose diphosphate aldolases (EC were detected in extracts of Escherichia coli (Crookes' strain) grown on pyruvate or lactate. The two enzymes can be resolved by chromatography on DEAE-cellulose at pH7.5, or by gel filtration on Sephadex G-200, and both have been obtained in a pure state. One is a typical bacterial aldolase (class II) in(More)
The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the(More)
1. ICI D7114 is a novel, beta-adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04 mg kg-1, p.o.) and BAT mitochondrial guanosine diphosphate (GDP)-binding (ED50, 0.15 mg kg-1,(More)
Platinum cytotoxics play an important role globally in the management of solid tumours. Cisplatin sets the standard for efficacy in both regions with careful administration to reduce nephrotoxicity. Carboplatin is associated with neurotoxicity, but has become the leading product in the US due largely to the easier to manage toxicity profile. Both agents(More)
The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (8) has been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 10. Potency was generally markedly reduced by placing substituents on the(More)
The post-natal development of interscapular brown adipose tissue (BAT) was studied in the guinea pig by monitoring changes in DNA, triglycerides and mitochondrial protein as well as the activity of cytochrome oxidase and atractyloside insensitive GDP-binding. The results demonstrate that neonatal brown fat develops into a tissue with the gross(More)