The psychostimulant (±)-cis-4, 4′-dimethylaminorex (4, 4′-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters. (August 2018)

• Record Type: Journal Article
• Authors: Maier, Julian; Mayer, Felix P.; Luethi, Dino; Holy, Marion; Jäntsch, Kathrin; Reither, Harald; Hirtler, Lena; Hoener, Marius C.; Liechti, Matthias E.; Pifl, Christian; Brandt, Simon D.; Sitte, Harald H.
• Is Part Of: Neuropharmacology. Volume 138(2018)
• Page Start: 282
• Page End: 291
• Publication Date: 2018-08
• Subjects: 4, 4′-DMAR -- Monoamine transporters -- SLC6 -- VMAT2 -- New psychoactive substances -- Serotonin syndrome; 4, 4′-DMAR (±)-cis-4, 4′-dimethylaminorex -- 4-MAR 4-methylaminorex -- 5-HT serotonin -- DAT dopamine transporter -- GAT1 gamma-aminobutyric acid (GABA) transporter subtype 1 -- MDMA 3, 4-methyledioxymethylamphetamine -- MPP+ 1-methyl-4-phenylpyridinium -- NET norepinephrine transporter -- SERT 5-HT transporter -- TAAR1 Trace amine-associated receptor 1 -- VMAT2 vesicular monoamine transporter 2; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.06.018
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: (±)- 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 (IC50 values < 2 μM). 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. Highlights: 4, 4′-Dimethylaminorex targets plasmalemmal and vesicular monoamine transporters. 4, 4′-DMAR is a non-selective monoamine transporter releasing agent. 4, 4′-DMAR's profile of action is similar to MDMA but it is a more potent releaser. 4, 4′-DMAR related deaths can be related to serotonin and norepinephrine toxicity. 4, 4′-DMAR inhibits VMAT2, suggestive of its long-term neurotoxic effects.