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Mark D. Andrews, Paul V. Fish, Julian Blagg, Tiffini K. Brabham, Paul E. Brennan, Alison Bridgeland, Alan D. Brown, Peter J. Bungay, Kelly M. Conlon, Nicholas J. Edmunds, Kerry af Forselles, Colleen P. Gibbons, Martin P. Green, Giles Hanton, Mark Holbrook, Alan S. Jessiman, Karin McIntosh, Gordon McMurray, Carly L. Nichols, James A. Root, R. Ian Storer, Michael R. Sutton, Robin V. Ward, Dominique Westbrook, Gavin A. Whitlock. (2011) Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: Design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence. Bioorganic & Medicinal Chemistry Letters 21, 2715-2720 CrossRef
... A set of 9000 bioactive MP was randomly selected from the ChEMBL 27 database [18] using subsets of ligands against three well-known biological targets HERG [19], 5HT2B [20], and CYP2D6 [21], see Section 3 for the details. To classify molecular pairs as either similar or dissimilar in 2D and in 3D, we used an approach based on a similarity threshold with a small buffer region, similar to the one described by Ehrman et al. [22]. ...
... Since the new dataset needed also pairs of compounds sharing a certain degree of 2D similarity but admittedly different 3D pattern of interaction, we investigated ligands of cytochromes. Finally, we queried the ChEMBL 27 database [18,26,27] for molecules that targeted three well-known biological targets: HERG [28], 5HT2B [20], and CYP2D6 [21]. We included only compounds for which an inhibition constant was measured, using the pChEMBL values [27]. ...
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Molecular similarity is an impressively broad topic with many implications in several areas of chemistry. Its roots lie in the paradigm that ‘similar molecules have similar properties’. For this reason, methods for determining molecular similarity find wide application in pharmaceutical companies, e.g., in the context of structure-activity relationships. The similarity evaluation is also used in the field of chemical legislation, specifically in the procedure to judge if a new molecule can obtain the status of orphan drug with the consequent financial benefits. For this procedure, the European Medicines Agency uses experts’ judgments. It is clear that the perception of the similarity depends on the observer, so the development of models to reproduce the human perception is useful. In this paper, we built models using both 2D fingerprints and 3D descriptors, i.e., molecular shape and pharmacophore descriptors. The proposed models were also evaluated by constructing a dataset of pairs of molecules which was submitted to a group of experts for the similarity judgment. The proposed machine-learning models can be useful to reduce or assist human efforts in future evaluations. For this reason, the new molecules dataset and an online tool for molecular similarity estimation have been made freely available.
... There has been concern that psychedelics may cause cardiac valvular dysfunction via agonism at 5-HT 2B receptors, which are densely distributed in cardiac valves and regulate growth in these tissues. Other drugs with 5-HT 2B agonism have been associated with valvular heart disease including fenfluramine and MDMA, though it seems that chronic use is required to produce clinically significant changes in valvular function (Roth, 2007). No cases of valvular heart disease have been attributed directly to use of classic psychedelics to date. ...
... However, these substances were low efficacy partial agonists (EC 50 18-45%). Endocardial fibrosis has been associated with 5-HT 2B activation and is therefore a potential adverse effect to consider for chronic use of substances interacting with this receptor (Rothman et al., 2000;Droogmans et al., 2007;Roth 2007;Doly et al., 2008;Elangbam et al., 2008;Bhattacharyya et al., 2009;Huang et al., 2009;Elangbam 2010;Dawson and Moffatt 2012). As psychedelics are typically not used chronically, endocardial fibrosis is an unlikely adverse effect for users of such substances despite a potential interaction with the 5-HT 2B receptor subtype . ...
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3,4,5-Trimethoxyphenethylamine (mescaline) is a psychedelic alkaloid found in peyote cactus. Related 4-alkoxy-3,5-dimethoxy-substituted phenethylamines (scalines) and amphetamines (3C-scalines) are reported to induce similarly potent psychedelic effects and are therefore potential novel therapeutics for psychedelic-assisted therapy. Herein, several pharmacologically uninvestigated scalines and 3C-scalines were examined at key monoamine targets in vitro . Binding affinity at human serotonergic 5-HT 1A , 5-HT 2A , and 5-HT 2C , adrenergic α 1A and α 2A , and dopaminergic D 2 receptors, rat and mouse trace amine-associated receptor 1 (TAAR1), and human monoamine transporters were assessed using target specific transfected cells. Furthermore, activation of human 5-HT 2A and 5-HT 2B receptors, and TAAR1 was examined. Generally, scalines and 3C-scalines bound with weak to moderately high affinity to the 5-HT 2A receptor ( K i = 150–12,000 nM). 3C-scalines showed a marginal preference for the 5-HT 2A vs the 5-HT 2C and 5-HT 1A receptors whereas no preference was observed for the scalines. Extending the 4-alkoxy substituent increased 5-HT 2A and 5-HT 2C receptors binding affinities, and enhanced activation potency and efficacy at the 5-HT 2A but not at the 5-HT 2B receptor. Introduction of fluorinated 4-alkoxy substituents generally increased 5-HT 2A and 5-HT 2C receptors binding affinities and increased the activation potency and efficacy at the 5-HT 2A and 5-HT 2B receptors. Overall, no potent affinity was observed at non-serotonergic targets. As observed for other psychedelics, scalines and 3C-scalines interacted with the 5-HT 2A and 5-HT 2C receptors and bound with higher affinities (up to 63-fold and 34-fold increase, respectively) when compared to mescaline.
... Hence, drugs that stimulate the 5-HT 2B receptor could induce cardiac valvulopathies 80,162,163 . ...
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Despite the availability of over 30 antiseizure medications (ASMs), there is no "one size fits it all", so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5-hydroxytryptamine, 5-HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only few ASM, such as fenfluramine (FA), act via 5-HT. There are 14 different 5-HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5-HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each '5-HT subtype' separately and its relation to 'epilepsy or seizures'. Most research underlines the antiseizure activity of 5-HT1A,1D,2A,2C,3 agonism and 5-HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5-HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment.
... (5) The appetite suppressant benfluorex activates the serotonin 5-HT2B receptor pathway that may lead to cellular proliferation and cardiac valvular fibrosis. (1,9,10) In France, epidemiology studies found that the period of use of benfluorex from 1976 to 2009 is approximately responsible for 3100 hospitalizations and 1300 deaths due to valvular insufficiency.(11) A prospective multicenter case-control study demonstrated that the use of benfluorex was associated with a three-fold increase in the frequency of left heart valve regurgitation in diabetic patients. ...
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Background Drug-induced valvular heart disease (DI-VHD) is a well-defined condition associated with specific pathology features. However, clinical presentations may broadly vary and thereby make DI-VHD diagnosis more challenging. Case summary We report two patients with a history of benfluorex administration, who developed extensive mitral calcific lesions which evolved towards caseous necrosis. Discussion Prospective follow-up over several years of these two patients who initially had typical DI-VHD findings provided monitoring evidence of extensive calcifications and subsequent caseous necrosis. These reports suggest a link between calcific heart injury and benfluorex exposure. The diagnosis of DI-VHD may be overlooked at this late stage.
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Chapter
The serotonin (5-hydroxytryptamine, 5-HT) 2A receptor is most well known as the common target for classic psychedelic compounds. Interestingly, the 5-HT2A receptor is the most widely expressed mammalian serotonin receptor and is found in nearly every examined tissue type including neural, endocrine, endothelial, immune, and muscle, suggesting it could be a novel and pharmacological target for several types of disorders. Despite this, the bulk of research on the 5-HT2A receptor is focused on its role in the central nervous system (CNS). Recently, activation of 5-HT2A receptors has emerged as a new anti-inflammatory strategy. This review will describe recent findings regarding psychedelics as anti-inflammatory compounds, as well as parse out differences in functional selectivity and immune regulation that exist between a number of well-known hallucinogenic compounds.
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Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.
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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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Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (+/-)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (+/-)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (+/-)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor. Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors.
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Appetite suppressants fenfluramine, dexfenfluramine, and phentermine have been used alone or in combination as an alternative to diet and surgery in the management of obesity. This therapy was halted in 1997 after reports of valvular lesions affecting almost one third of patients treated with these drugs. Fortunately, most cases of appetite suppressant-related valve disease are mild or moderate and rarely required valve repair or replacement. Follow-up studies have suggested improvement in valvulopathy after discontinuation of the treatment. The mechanism of valve disease induced by these drugs is speculative and may be related to their serotonergic effects. Echocardiographic features are similar to carcinoid heart disease and valvulopathy associated with ergot use. Most cases require only follow-up and endocarditis prophylaxis; surgery is rarely needed.
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Ergot alkaloids, such as ergotamine, have been associated with numerous vascular complications and with valvular heart disease. The authors describe a man who developed fibrosis of three heart valves during a 5-year treatment with bromocriptine for Parkinson disease. There were no other plausible causes. To our knowledge, such a side effect has never been described with this drug.
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To the Editor: A 74-year-old man presented with progressive and severe dyspnea of two months' duration. The patient had Parkinson's disease that had initially been treated with levodopa, to which cabergoline had been added during the preceding four months. The physical examination was notable for increased jugular venous pressure, bilateral rales, and edema in both legs. On auscultation, a gallop rhythm and a 2/6 pansystolic murmur radiating to the axilla were noted. A chest radiograph showed mild cardiomegaly and signs of acute pulmonary edema. Electrocardiography demonstrated sinus rhythm at 80 beats per minute with left atrial enlargement. Transthoracic echocardiography revealed . . .
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The in vitro pharmacological profiling of drugs using a large panel of cloned receptors (e.g., G protein-coupled receptors, ligand-gated ion channels, Na(+)-dependent monoamine transporters), an approach that has come to be known as 'receptorome screening', has unveiled novel molecular mechanisms responsible for the actions and/or side effects of certain drugs. For instance, receptorome screening has been employed to uncover novel molecular targets involved in the actions of antipsychotic medications and the hallucinogenic mint extract salvinorin A. This review highlights the recent application of receptorome screening to discover why the anorexigen fenfluramine causes serious cardiopulmonary side effects. Receptorome screening has implicated N-deethylation of fenfluramine and serotonin 5-hydroxy-t-ryptamine 2B receptors in the adverse effects of the drug; subsequent studies corroborated this finding. The results discussed highlight the utility of determining the potential activity of drugs -- and, importantly, of their in vivo metabolites -- at as many molecular targets as possible in order to reliably predict side effect profiles. Receptorome screening represents one of the most effective methods for identifying potentially serious drug-related side effects at the preclinical stage, thereby avoiding significant economic and human health consequences.