Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N‐methoxy positional isomer, N‐methoxymephedrone
Gavin McLaughlin, Noreen Morris, Pierce V. Kavanagh, John D. Power, Geraldine Dowling, Brendan Twamley, John O’Brien, Brian Talbot, Donna Walther, John S. Partilla, Michael H. Baumann, Simon D. Brandt
Drug Testing and Analysis August 15, 2016 DOI: 10.1002/dta.2053 via OpenAlex
Summary
Mexedrone, a derivative of mephedrone that appeared in 2015, was synthesized and analytically characterized. It was a weak non-selective uptake blocker at dopamine, norepinephrine, and serotonin transporters with IC50 values in the low micromolar range, and lacked releasing activity at dopamine and norepinephrine transporters but showed weak releasing activity at serotonin transporters (EC50 = 2.5 μM). Its isomer, N-methoxymephedrone, acted as a weak uptake blocker and a fully efficacious substrate-type releasing agent across all three transporters with EC50 values in the low micromolar range. A synthesis by-product, α-chloromethylmephedrone, was inactive in all assays.
Study at a glance
| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Rat brain synaptosomes |
| Intervention | Mexedrone |
| Topics | Serotonin |
| Keywords | Mephedrone Monoamine neurotransmitter Norepinephrine transporter Serotonin transporter Dopamine transporter |
| Citations | 23 |
| Key finding | Mexedrone was a weak non-selective uptake blocker at dopamine, norepinephrine, and serotonin transporters and showed weak releasing activity only at serotonin transporters. |
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 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.