The psychostimulant (±)-cis-4,4′-dimethylaminorex (4,4′-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters
Julian Maier, Felix P. Mayer, Dino Luethi, Marion Holy, Kathrin Jäntsch, Harald Reither, Lena Hirtler, Marius C. Hoener, Matthias E. Liechti, Christian Pifl, Simon D. Brandt, Harald H. Sitte
Neuropharmacology June 23, 2018 DOI: 10.1016/j.neuropharm.2018.06.018 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Interventions | 4 4′-DMAR |
| Topics | Serotonin |
| Keywords | Monoamine neurotransmitter Vesicular monoamine transporter Monoaminergic Pharmacology Dopamine transporter Serotonin transporter Tryptamine Norepinephrine transporter Receptor Biochemistry Endocrinology |
| Citations | 24 |
| Key points | 4,4′-DMAR is a potent non-selective monoamine releasing agent that inhibits human DAT, NET, and SERT and both rat and human VMAT2, with effects on SERT that may contribute to fatalities. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
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| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 8
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics Experimental Neurology June 4, 2021
- Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1-3 and Human Plasma Membrane Monoamine Transporter. International Journal of Molecular Sciences November 30, 2021
- DARK Classics in Chemical Neuroscience: Aminorex Analogues ACS Chemical Neuroscience September 30, 2018
- Bioisosteric analogs of MDMA: Improving the pharmacological profile? Journal of Neurochemistry September 1, 2024
and 3 more in the library
Cites 15
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