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: 4.13). 07/2003; 63(6):1223-9. DOI: 10.1124/mol.63.6.1223
Source: PubMed


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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Available from: Richard B Rothman, Jul 25, 2014
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    • "Activation of 5-HT 2B receptors by 5-APB, leading to contraction of rat stomach fundus in vitro, was also reported by Dawson et al (2013). Setola et al (2003) found that MDMA and MDA selectively interacted with h5-HT 2B receptors and induced fenfluramine-like proliferative actions on human cardiac valve tissue in vitro. The finding that MDMA, MDA, 5-and 6-ABP activate 5-HT 2B receptors suggests that there is a potential risk of cardiac toxicity associated with their long-term use, as has been reported for other 5-HT 2B receptor agonists, such as fenfluramine (Rothman et al, 2000; Dawson & Moffatt, 2012). "
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    • "In the 1980s it was determined that retroperitoneal fibrosis caused by the ergot methysergide is due to the metabolism of this compound into methylergonovine which converts it from a 5-HT 2B receptor antagonist to agonist [25]. Subsequently agonism of 5-HT 2B has been implicated in fibrosis caused by fenfluramine used in the treatment of obesity [26] and psychiatric disorders [27] and the hallucinogen MDMA [28], both of which trigger 5-HT 2B signaling. Dopamine agonists with structural similarity to 5-HT such as pergolide and cabergoline that are used in the treatment of Parkinson's disease have also been associated with development of fibrosis in heart valves involving 5-HT 2B agonism, thus limiting their clinical utility [29]. "
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