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3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro

Department of Medicinal Chemistry, Virginia Commonwealth University, Ричмонд, Virginia, United States
Molecular Pharmacology (Impact Factor: 4.12). 07/2003; 63(6):1223-9. DOI: 10.1124/mol.63.6.1223
Source: PubMed

ABSTRACT Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor in mediating the heart valve fibroplasia [valvular heart disease (VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux). Via large-scale, random screening of a portion of the receptorome, we have discovered that the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its N-demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) each preferentially bind to and activate human recombinant 5-HT2B receptors. We also demonstrate that MDMA and MDA, like fenfluramine and its N-deethylated metabolite norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT2B receptors, thus validating this assay system for its ability to predict medications that might induce VHD. Our discovery that MDMA and a major metabolite, MDA, induce prolonged mitogenic responses in vitro similar to those induced by fenfluramine and norfenfluramine in vivo (i.e., valvular interstitial cell fibroplasia) predict that long-term MDMA use could lead to the development of fenfluramine-like VHD. Because of the widespread abuse of MDMA, these findings have major public health implications. These findings also underscore the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans.

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    • "Activation of 5-HT 2B receptors in some cell types has also been shown to stimulate nitric oxide synthase (Manivet et al., 2000). In fibroblasts and smooth muscle cells, the biological result of activating 5-HT 2B receptors is mitosis (Fitzgerald et al., 2000; Nebigil et al., 2000a, 2000b; Setola et al., 2003) and secretion of inflammatory cytokines and extracellular matrix (ECM) components (Hafizi et al., 2000; Jaffre et al., 2009). As such, 5-HT 2B receptors appear to play a crucial role in allowing these cells to maintain the structural homeostasis of the tissues comprising them (e.g., myocardium, heart valves, and blood vessels). "
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    ABSTRACT: Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting.
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    • "One alternative explanation for the different effects of the stereoisomers on dopamine levels in the microdialysis studies could be a difference in potency rather than qualitative differences between the two compounds. Potency differences on this measure are a reasonable expectation because whereas S(ϩ)-MDMA is 30 times more potent than R(Ϫ)MDMA at releasing dopamine in vitro, R(Ϫ)- MDMA does release dopamine under these conditions when the dose is escalated (Setola et al., 2003). Therefore, the effects of R(Ϫ)-MDMA were tested at 3.0 mg/kg. "
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    • "It is also clear from the present studies that, when the structural and pharmacological similarity of the test compounds to MDMA was reduced, the previously observed qualitative differences between the interoceptive effects of the MDMA enantiomers were replaced by simple potency differences . Cocaine has no notable structural features in common with MDMA, and although both compounds alter synaptic monoamine levels, MDMA does so through transporter-mediated release (Setola et al., 2003) while cocaine passively blocks monoamine reuptake (Kuhar et al., 1999). "
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