PMID- 29908239 OWN - NLM STAT- MEDLINE DCOM- 20190213 LR - 20220727 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 138 DP - 2018 Aug TI - The psychostimulant (+/-)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters. PG - 282-291 LID - S0028-3908(18)30297-1 [pii] LID - 10.1016/j.neuropharm.2018.06.018 [doi] AB - (+/-)-cis-4,4'-Dimethylaminorex (4,4'-DMAR) is a new psychoactive substance (NPS) that has been associated with 31 fatalities and other adverse events in Europe between June 2013 and February 2014. We used in vitro uptake inhibition and transporter release assays to determine the effects of 4,4'-DMAR on human high-affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). In addition, we assessed its binding affinities to monoamine receptors and transporters. Furthermore, we investigated the interaction of 4,4'-DMAR with the vesicular monoamine transporter 2 (VMAT2) in rat phaeochromocytoma (PC12) cells and synaptic vesicles prepared from human striatum. 4,4'-DMAR inhibited uptake mediated by human DAT, NET or SERT, respectively in the low micromolar range (IC(50) values < 2 muM). Release assays identified 4,4'-DMAR as a substrate type releaser, capable of inducing transporter-mediated reverse transport via DAT, NET and SERT. Furthermore, 4,4'-DMAR inhibited both the rat and human isoforms of VMAT2 at a potency similar to 3,4-methylenedioxymethylamphetamine (MDMA). This study identified 4,4'-DMAR as a potent non-selective monoamine releasing agent. In contrast to the known effects of aminorex and 4-methylaminorex, 4,4'-DMAR exerts profound effects on human SERT. The latter finding is consistent with the idea that fatalities associated with its abuse may be linked to monoaminergic toxicity including serotonin syndrome. The activity at VMAT2 suggests that chronic abuse of 4,4'-DMAR may result in long-term neurotoxicity. CI - Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Maier, Julian AU - Maier J AD - Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Wahringerstrasse 13A, 1090, Vienna, Austria. FAU - Mayer, Felix P AU - Mayer FP AD - Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Wahringerstrasse 13A, 1090, Vienna, Austria. FAU - Luethi, Dino AU - Luethi D AD - University Hospital Basel and University of Basel, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, Hebelstrasse 20, 4031, Basel, Switzerland. FAU - Holy, Marion AU - Holy M AD - Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Wahringerstrasse 13A, 1090, Vienna, Austria. FAU - Jantsch, Kathrin AU - Jantsch K AD - Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Wahringerstrasse 13A, 1090, Vienna, Austria. FAU - Reither, Harald AU - Reither H AD - Medical University of Vienna, Center for Brain Research, Department of Molecular Neurosciences, Spitalgasse 4, 1090, Vienna, Austria. FAU - Hirtler, Lena AU - Hirtler L AD - Medical University of Vienna, Center for Anatomy and Cell Biology, Wahringerstrasse 13, 1090, Vienna, Austria. FAU - Hoener, Marius C AU - Hoener MC AD - F. Hoffmann - La Roche Ltd., pRED, Roche Innovation Center Basel, Neuroscience Research, Department of Neurosymptomatic Domains, Grenzacherstrasse 124, 4070, Basel, Switzerland. FAU - Liechti, Matthias E AU - Liechti ME AD - University Hospital Basel and University of Basel, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, Hebelstrasse 20, 4031, Basel, Switzerland. FAU - Pifl, Christian AU - Pifl C AD - Medical University of Vienna, Center for Brain Research, Department of Molecular Neurosciences, Spitalgasse 4, 1090, Vienna, Austria. FAU - Brandt, Simon D AU - Brandt SD AD - School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK. FAU - Sitte, Harald H AU - Sitte HH AD - Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Wahringerstrasse 13A, 1090, Vienna, Austria; Center for Addiction Research and Science, Medical University Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria. Electronic address: harald.sitte@meduniwien.ac.at. LA - eng GR - W 1232/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180623 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Central Nervous System Stimulants) RN - 0 (Oxazoles) RN - 0 (Plasma Membrane Neurotransmitter Transport Proteins) RN - 0 (SLC18A2 protein, human) RN - 0 (Slc18a2 protein, rat) RN - 0 (Vesicular Monoamine Transport Proteins) RN - 18Y239214S (para-methyl-4-methylaminorex) RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) SB - IM MH - Animals MH - Central Nervous System Stimulants/chemistry/*pharmacology MH - Corpus Striatum/drug effects/metabolism MH - HEK293 Cells MH - Humans MH - N-Methyl-3,4-methylenedioxyamphetamine/pharmacology MH - Oxazoles/chemistry/*pharmacology MH - PC12 Cells MH - Plasma Membrane Neurotransmitter Transport Proteins/*metabolism MH - Rats MH - Synaptic Vesicles/drug effects/metabolism MH - Vesicular Monoamine Transport Proteins/antagonists & inhibitors/*metabolism OTO - NOTNLM OT - 4,4'-DMAR OT - Monoamine transporters OT - New psychoactive substances OT - SLC6 OT - Serotonin syndrome OT - VMAT2 EDAT- 2018/06/17 06:00 MHDA- 2019/02/14 06:00 CRDT- 2018/06/17 06:00 PHST- 2018/03/26 00:00 [received] PHST- 2018/05/01 00:00 [revised] PHST- 2018/06/12 00:00 [accepted] PHST- 2018/06/17 06:00 [pubmed] PHST- 2019/02/14 06:00 [medline] PHST- 2018/06/17 06:00 [entrez] AID - S0028-3908(18)30297-1 [pii] AID - 10.1016/j.neuropharm.2018.06.018 [doi] PST - ppublish SO - Neuropharmacology. 2018 Aug;138:282-291. doi: 10.1016/j.neuropharm.2018.06.018. Epub 2018 Jun 23.