ArticleMolecular pharmacology2016
Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters.
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Article in Molecular pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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40citing papers in PubMed, 1 pooled it
2.5field-weighted citation impact, top 11% of its field
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.
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- MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial.Nature medicine · 2023Trial
- TRACT assay-based in vitro characterization of substituted cathinones: inhibition and release at the serotonin transporter.Archives of toxicology · 2026Article
- Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights.ACS chemical neuroscience · 2025Article
- Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine.The Journal of pharmacology and experimental therapeutics · 2024Article
- Structure-Activity Relationship of Synthetic Cathinones: An Updated Review.ACS pharmacology & translational science · 2024Review
- Bioisosteric analogs of MDMA: Improving the pharmacological profile?Journal of neurochemistry · 2024Article
- Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties.Molecular psychiatry · 2024Article
- Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors.Nature communications · 2024Article
- Development and validation of an automated microfluidic perfusion platform for parallelized screening of compounds in vitro.Basic & clinical pharmacology & toxicology · 2023Article
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- Determining Ligand and Ion-Induced Conformational Changes in Serotonin Transporter with Its Fluorescent Substrates.International journal of molecular sciences · 2022Article
- Structural basis of GABA reuptake inhibition.Nature · 2022Article
- Allosteric Binding of MDMA to the Human Serotonin Transporter (hSERT) via Ensemble Binding Space Analysis with ΔG Calculations, Induced Fit Docking and Monte Carlo Simulations.Molecules (Basel, Switzerland) · 2022Article
- (2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Article
- A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy.Frontiers in psychiatry · 2022Review
- Article
- Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats.Frontiers in behavioral neuroscience · 2021Article
- Genetic deletion ofJournal of psychopharmacology (Oxford, England) · 2020Article
- The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats.Psychopharmacology · 2020Article
Corrections and comments
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Authors and funding
14 authors at 1 institution in 2 countries.
Walter SandtnerInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Thomas StocknerInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Peter S HasenhuetlInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
John S PartillaInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Amir SeddikInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Yuan-Wei ZhangInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Jianjing CaoInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Marion HolyInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Thomas SteinkellnerInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Gary RudnickInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Michael H BaumannInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Gerhard F EckerInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Amy Hauck NewmanInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.).
Harald H SitteInstitute of Pharmacology, Center for Physiology and Pharmacology (W.S., T.Sto., P.S.H., M.H., T.Ste., H.H.S.) and Center for Addiction Research and Science (H.H.S.), Medical University of Vienna, Vienna, Austria; Designer Drug Research Unit (J.S.P., M.H.B.) and Medicinal Chemistry Section (J.J.C., A.H.N.), Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria (A.S., G.F.E.); and Department of Pharmacology, Yale University, New Haven, Connecticut (Y.-W.Z., G.R.) harald.sitte@meduniwien.ac.at.ORCID http://orcid.org/0000-0002-1339-7444
University of Vienna · AT
Funding
Preclinical medication development for stimulant use disorderZIADA000522 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI BAUMANN, MICHAEL · 2009 to 2025
$8.9MION AND BIOGENIC AMINE TRANSPORT MECHANISMSR01DA007259 · NIDA · YALE UNIVERSITY · PI RUDNICK, GARY W · 1992 to 2016
$4.7MMonoamine Transporter NanoprobesZIADA000610 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI NEWMAN, AMY HAUCK · 2016 to 2020
$2.5MSYNTHETIC STRATEGIES TOWARD THE ELUCIDATION OF CENTRAL MECHANISMS IN THE BEHAVIORZ01DA000389 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI NEWMAN, AMY HAUCK · 1996 to 2008
$1.3MNEUROCHEMISTRY OF AMPHETAMINE INDUCED AROUSALK02DA000389 · NIDA · UNIVERSITY OF WISCONSIN-MADISON · PI BERRIDGE, CRAIG W · 1999 to 2008
$1.1MAustrian Science Fund FWF F 3502Austrian Science Fund FWF F 3524Austrian Science Fund FWF W 1232Intramural NIH HHS Z01 DA000389NIDA NIH HHS DA000389NIDA NIH HHS K02 DA000389NIDA NIH HHS R01 DA007259
Abstract
Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective protein-ligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high-affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a low-affinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation.
Indexed as
AnimalsBinding SitesBiological TransportHEK293 CellsHeLa CellsHumansMaleN-Methyl-3,4-methylenedioxyamphetamineProtein Structure, TertiaryRatsRats, Sprague-DawleyVesicular Monoamine Transport ProteinsN-Methyl-3,4-methylenedioxyamphetamineVesicular Monoamine Transport Proteins
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