Development, validation, and use of quantitative structure-activity relationship models of 5-hydroxytryptamine (2B) receptor ligands to identify novel receptor binders and putative valvulopathic compounds among common drugs.
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Effect of dietary manipulation on substrate flux and energy balance in obese women taking the appetite suppressant dexfenfluramine.
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BACKGROUND: Studies in lean men show poor regulation of energy (EB) and fat balance (FB) during manipulation of dietary ratios of fat to carbohydrate. High-fat (HF), high-energy diets cause hyperphagia and a positive EB and FB. OBJECTIVE: The protocol was designed to measure substrate flux and EB in obese women taking dexfenfluramine (DF) or placebo (PL) during an HF (50% of energy) or low-fat (25% of energy; LF) diet. We hypothesized that alterations in dietary fat would not be regulated and would lead to a positive EB and FB. DESIGN: The study was double-blind, randomized, and placebo-controlled, with 4 treatments (LF/DF, HF/DF, LF/PL, and HF/PL) and a crossover. Five days of continuous, whole-body calorimetry measurements were made in 6 subjects after 8 d of home DF/PL treatment. Macronutrient balance and EB were measured within the chamber as the cumulative difference between ad libitum intake and oxidation. RESULTS: The HF diet increased energy (HF, 10.50 MJ/d; LF, 8.13 MJ/d; P < 0.0001) and fat intakes (HF, 5.34 MJ/d; LF, 2.06 MJ/d; P < 0.0001), leading to a positive EB (delta = 2.37 MJ/d) and FB (delta = 2.31 MJ/d). DF reduced energy (DF, 8.96 MJ/d; PL, 9.66 MJ/d; P < 0.01) and macronutrient intakes, but did not increase energy expenditure (delta = -0.31 MJ/d; P < 0.01), or 24-h fat oxidation (delta = 0.03 MJ/d; P = 0.46). CONCLUSIONS: EB and FB are poorly regulated with HF, energy-dense diets in obese women, which leads to fat deposition and weight gain. (+info)
Inhibition of delayed rectifier K+ channels by dexfenfluramine (Redux).
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In light of recent reports linking K+ channel modulation with food intake and macronutrient preference, we investigated the effect of anorectic agent dexfenfluramine (d-FF), a 5-HT reuptake inhibitor and releasing agent, on the delayed rectifier K+ (DRK) channels in rat lingual taste cells using the patch-clamp technique in whole-cell configuration. In a concentration-dependent manner, d-FF caused a reduction of the DRK currents in taste cells with an IC50 of 30.5 microM. Other anorectics that promote 5-HT activity such as fenfluramine, sibutramine and m-chlorophenylpiperazine (a specific 5-HT2C receptor agonist) produced inhibition of DRK currents of a similar pattern with a respective IC50 of 69.0, 8.6 and 95.4 microM. The actions of all compounds had rapid onset and were readily reversible. The inhibitory effects were not secondary to their stimulation of 5-HT, because direct application of 5-HT up to 1 mM did not alter DRK current. In addition, d-FF-induced current reduction was not prevented by either the 5-HT synthesis inhibitor p-chlorophenylalanine or 5-HT receptor antagonist metergoline. d-FF was also tested in cardiac ventricular myocytes that are reportedly abundant in DRK channels and was found to depress the DRK currents concentration-dependently with an IC50 of 250.9 microM. These results indicate an important pharmacological role for d-FF as an inhibitor of the DRK channels. The common inhibitory effect on DRK channels in oral taste cells and cardiac cells by this class of compounds might contribute to the anorectic and some of the detrimental cardiovascular effect associated with long-term exposure. (+info)