Fluorinated phenmetrazine “legal highs” act as substrates for high-affinity monoamine transporters of the SLC6 family
Felix P. Mayer, Nadine V. Burchardt, Ann M Decker, John S. Partilla, Yang Li, Gavin McLaughlin, Pierce V. Kavanagh, Walter Sandtner, Bruce E. Blough, Simon D. Brandt, Michael H. Baumann, Harald H. Sitte
Neuropharmacology October 12, 2017 DOI: 10.1016/j.neuropharm.2017.10.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | HEK293 cells and rat brain synaptosomes |
| Intervention | 3-fluorophenmetrazine |
| Topics | Serotonin |
| Keywords | Monoamine neurotransmitter Pharmacology Amphetamine Catecholamine Monoaminergic Dopamine transporter Receptor Biochemistry Endocrinology |
| Citations | 30 |
| Key points | 2-, 3-, and 4-fluorophenmetrazine inhibit dopamine and norepinephrine transporters with potencies comparable to cocaine and induce monoamine release, identifying them as monoamine releasers with potential for abuse. |
Abstract
A variety of new psychoactive substances (NPS) are appearing in recreational drug markets worldwide. NPS are compounds that target various receptors and transporters in the central nervous system to achieve their psychoactive effects. Chemical modifications of existing drugs can generate NPS that are not controlled by current legislation, thereby providing legal alternatives to controlled substances such as cocaine or amphetamine. Recently, 3-fluorophenmetrazine (3-FPM), a derivative of the anorectic compound phenmetrazine, appeared on the recreational drug market and adverse clinical effects have been reported. Phenmetrazine is known to elevate extracellular monoamine concentrations by an amphetamine-like mechanism. Here we tested 3-FPM and its positional isomers, 2-FPM and 4-FPM, for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We found that 2-, 3- and 4-FPM inhibit uptake mediated by DAT and NET in HEK293 cells with potencies comparable to cocaine (IC50 values < 2.5 μM), but display less potent effects at SERT (IC50 values >80 μM). Experiments directed at identifying transporter-mediated reverse transport revealed that FPM isomers induce efflux via DAT, NET and SERT in HEK293 cells, and this effect is augmented by the Na+/H+ ionophore monensin. Each FPM evoked concentration-dependent release of monoamines from rat brain synaptosomes. Hence, this study reports for the first time the mode of action for 2-, 3- and 4-FPM and identifies these NPS as monoamine releasers with marked potency at catecholamine transporters implicated in abuse and addiction. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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 9
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones Frontiers in Pharmacology April 24, 2019
- Stimulant and hallucinogenic novel psychoactive substances; an update Expert Review of Clinical Pharmacology November 2, 2023
- The psychostimulant (±)-cis-4,4′-dimethylaminorex (4,4′-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters Neuropharmacology June 23, 2018
- DARK Classics in Chemical Neuroscience: Aminorex Analogues ACS Chemical Neuroscience September 30, 2018
and 4 more in the library
Cites 8
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- Baths Salts, Spice, and Related Designer Drugs: The Science Behind the Headlines Journal of Neuroscience November 12, 2014
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- The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue. Neuropharmacology February 2016
and 3 more in the library