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Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N ‐methoxy positional isomer, N ‐methoxymephedrone
Author(s) -
McLaughlin Gavin,
Morris Noreen,
Kavanagh Pierce V.,
Power John D.,
Dowling Geraldine,
Twamley Brendan,
O'Brien John,
Talbot Brian,
Walther Donna,
Partilla John S.,
Baumann Michael H.,
Brandt Simon D.
Publication year - 2017
Publication title -
drug testing and analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 54
eISSN - 1942-7611
pISSN - 1942-7603
DOI - 10.1002/dta.2053
Subject(s) - mephedrone , chemistry , monoamine neurotransmitter , norepinephrine transporter , dopamine transporter , transporter , serotonin transporter , reuptake , stereochemistry , serotonin , pharmacology , biochemistry , drug , biology , receptor , gene
3‐Methoxy‐2‐(methylamino)‐1‐(4‐methylphenyl)propan‐1‐one (mexedrone) appeared in 2015 and was advertised by UK Internet retailers as a non‐controlled mephedrone derivative (2‐(methylamino)‐1‐(4‐methylphenyl)propan‐1‐one), which was of particular interest to countries who operate generic drugs legislation. This study describes the synthesis and analytical characterization of mexedrone and the differentiation from its isomer, N ‐methoxymephedrone, which was predicted to be a suitable candidate before the identity of mexedrone was revealed. A full analytical characterization is described using various chromatographic, spectroscopic and mass spectrometric platforms and X‐ray crystal structure analysis. The analytical data obtained for a vendor sample were consistent with the synthesized mexedrone reference standard and analytical differentiation between the mexedrone and N ‐methoxymephedrone positional isomers was achieved. Furthermore, α‐chloromethylmephedrone was identified as a by‐product during mexedrone synthesis. All three substances were also studied for their uptake and releasing properties at dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) using in vitro monoamine transporter assays in rat brain synaptosomes and compared to mephedrone. Mexedrone was a weak non‐selective uptake blocker with IC 50 values in the low μM range. It was also devoid of releasing activity at DAT and NET but displayed weak releasing activity at SERT (EC 50 = 2.5 μM). The isomer N ‐methoxymephedrone was found to be a weak uptake blocker at DAT, NET and SERT, as well as a fully efficacious substrate‐type releasing agent across all three transporters with EC 50 values in the low micromolar range. The synthesis by‐product α‐chloromethylmephedrone was inactive in all assays. Copyright © 2016 John Wiley & Sons, Ltd.