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Neuropharmacology. 2017 Oct 6. pii: S0028-3908(17)30473-2. doi: 10.1016/j.neuropharm.2017.10.006

Fluorinated phenmetrazine "legal highs" act as substrates for high-affinity monoamine transporters of the SLC6 family.

Mayer FP¹, Burchardt NV², Decker AM³, Partilla JS⁴, Li Y⁵, McLaughlin G⁶, Kavanagh PV⁷, Sandtner W⁸, Blough BE⁹, Brandt SD¹⁰, Baumann MH¹¹, Sitte HH¹²

Author information

¹Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13A, 1090, Vienna, Austria. Electronic address: felix.mayer@meduniwien.ac.at.
²Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13A, 1090, Vienna, Austria. Electronic address: nadine-burchardt@gmail.com.
³Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA. Electronic address: adecker@rti.org.
⁴Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA. Electronic address: jpartill@intra.nida.nih.gov.
⁵Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13A, 1090, Vienna, Austria.
⁶Department of Life and Physical Sciences, School of Science, Athlone Institute of Technology, Dublin Road, Westmeath, Ireland; Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland. Electronic address: gavinmclaughlin@research.ait.ie.
⁷Department of Life and Physical Sciences, School of Science, Athlone Institute of Technology, Dublin Road, Westmeath, Ireland. Electronic address: PKVANAGH@tcd.ie.
⁸Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13A, 1090, Vienna, Austria.
⁹Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA. Electronic address: beb@rti.org.
¹⁰School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK. Electronic address: s.brandt@ljmu.ac.uk.
¹¹Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA. Electronic address: mbaumann@irp.nida.nih.gov.
¹²Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13A, 1090, Vienna, Austria; Center for Addiction Research and Science - AddRess, Medical University Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria. Electronic address: harald.sitte@meduniwien.ac.at.

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.

KEYWORDS: Amphetamine, Legal high, Monoamine transporter, New psychoactive substances, Phenmetrazine

Publikations ID: 28988906
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