2005
DOI: 10.1124/mol.104.009266
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Molecular Determinants for the Interaction of the Valvulopathic Anorexigen Norfenfluramine with the 5-HT2BReceptor

Abstract: S-(ϩ)-Norfenfluramine (SNF)-an active metabolite of the nowbanned anorexigen fenfluramine-has been implicated in the drug's appetite-suppressing actions and its life-threatening cardiovascular side effects. SNF reduces appetite through serotonin 5-HT 2C receptor activation; it causes cardiopulmonary side effects through 5-HT 2B receptor activation. Thus, we attempted to identify molecular determinants of SNF binding to 5-HT 2B receptors distinct from those underlying SNF-5-HT 2C/2A receptor interactions. Mutag… Show more

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Cited by 63 publications
(56 citation statements)
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“…Although mutations in the Ci2 domain did not affect the The depicted model of the rat 5-HT1A receptor was based on the highresolution crystal structure of bovine rhodopsin in its inactive state and homology with previously published 5-HT receptor models (Shapiro et al, 2002;Setola et al, 2005; see Materials and Methods) and was obtained using Protein Explorer (PE, http://www.proteinexplorer. org) and molecular mechanics energy calculations.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Although mutations in the Ci2 domain did not affect the The depicted model of the rat 5-HT1A receptor was based on the highresolution crystal structure of bovine rhodopsin in its inactive state and homology with previously published 5-HT receptor models (Shapiro et al, 2002;Setola et al, 2005; see Materials and Methods) and was obtained using Protein Explorer (PE, http://www.proteinexplorer. org) and molecular mechanics energy calculations.…”
Section: Discussionmentioning
confidence: 99%
“…A preliminary model of the rat 5-HT1A receptor (inactive state) was prepared using bovine rhodopsin as a template using methods similar to those described previously (Shapiro et al, 2002;Setola et al, 2005). The full details of the model will be described in a subsequent publication.…”
mentioning
confidence: 99%
“…3 H]d-lysergic acid diethylamide (ϳ1 nM final; PerkinElmer Life and Analytical Sciences, Waltham, MA) to label 5-HT 2B receptors and varying concentrations of unlabeled ligand (spanning at least 5 orders of magnitude) to compete for radioligand binding (Setola et al, 2005) and 2) calcium flux assays (see Calcium Flux Assay) using varying concentrations of 5-HT and BW 723C86 to measure 5-HT 2B receptor activation. Cells were passaged fewer than 10 times beyond passage 0 to ensure stable 5-HT 2B receptor expression.…”
Section: Methodsmentioning
confidence: 99%
“…Cells stably expressing human 5-HT 2B receptors were generated using the FlpIn system (Invitrogen Corp., Carlsbad, CA). In brief, a cDNA for the human 5-HT 2B receptor was amplified by polymerase chain reaction from pUSF-5-HT 2B (Setola et al, 2005) using 5Ј and 3Ј BamHI linkers, and then subcloned into the BamHI site of pcDNA5.0/Frt to produce pFlpIn-5-HT 2B . Next, subconfluent (60%) FlpIn HEK293 cells in 10-cm dishes were cotransfected with 3 g of pFlpIn-5-HT 2B and 3 g of pOG5 (bearing the Frt recombinase; Invitrogen Corp.) using 30 l of FuGENE 6 transfection reagent (Roche Applied Science, Indianapolis, IN).…”
Section: Methodsmentioning
confidence: 99%
“…Benfluorex, like dexfenfluramine and fenfluramine, is metabolised into active metabolite norfenfluramine [1]. It is well accepted that norfenfluramine induces hypophagia through serotonin interaction [13]. Activation of 5HT serotonin receptors is also the mechanism proposed to be involved in cardiovascular side-effects, including valvular heart disease, as underlined by ROTHMAN et al [14].…”
Section: Discussionmentioning
confidence: 99%