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Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N-methoxy positional isomer, N-methoxymephedrone

McLaughlin, G and Morris, N and Kavanagh, PV and Power, JD and Dowling, G and Twamley, B and O’Brien, J and Talbot, B and Walther, D and Partilla, JS and Baumann, MH and Brandt, SD (2017) Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N-methoxy positional isomer, N-methoxymephedrone. Drug Testing and Analysis, 9 (3). pp. 358-368. ISSN 1942-7611

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Abstract

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 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 IC50 values in the low µM range. It was also devoid of releasing activity at DAT and NET, but displayed weak releasing activity at SERT (EC50 = 2.5 µM). The isomer N-methoxymephedrone was found to be a weak uptake blocker at DAT, NET and SERT and a fully efficacious substrate-type releasing agent across all three transporters with EC50 values in the low micromolar range. The synthesis by-product α-chloromethylmephedrone was inactive in all assays.

Item Type: Article
Additional Information: This is the peer reviewed version of the following article: McLaughlin, G., Morris, N., Kavanagh, P. V., Power, J. D., Dowling, G., Twamley, B., O'Brien, J., Talbot, B., Walther, D., Partilla, J. S., Baumann, M. H., and Brandt, S. D. (2017) Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N-methoxy positional isomer, N-methoxymephedrone. Drug Test. Analysis, 9: 358–368. doi: 10.1002/dta.2053, which has been published in final form at http://dx.doi.org/10.1002/dta.2053. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
Uncontrolled Keywords: 0301 Analytical Chemistry, 1115 Pharmacology And Pharmaceutical Sciences
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Wiley
Date Deposited: 15 Aug 2016 12:17
Last Modified: 21 Sep 2017 00:50
DOI or Identification number: 10.1002/dta.2053
URI: http://researchonline.ljmu.ac.uk/id/eprint/4020

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