Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)

Abstract

The recent occurrence of deaths associated with the psychostimulant cis-4,4'-dimethylaminorex (4,4'-DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4-methylenedioxy-4-methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis- and trans-MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis-isomer (90%). Exposure of the cis-isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans-isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non-selective monoamine releasing agent (+)-3,4-methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis- and trans-4,4'-DMAR, were assessed under identical conditions. cis-MDMAR, trans-MDMAR, cis-4,4'-DMAR and trans-4,4'-DMAR were more potent than MDMA in their ability to function as efficacious substrate-type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR and trans-MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans-4,4'-DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring-substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side-effects after high dose exposure.

Keywords: 4,4′-DMAR; aminorex; forensic; new psychoactive substances; psychostimulants.

Figure 1

(A) Chemical structures of the three psychostimulants aminorex, 4-methylaminorex (4-MAR), para-methyl-4-methylaminorex (4,4′-DMAR) and the new psychoactive substance 3′,4′-methylenedioxy-4-methylaminorex (MDMAR). (B) Structural representation of all four MDMAR enantiomers. (C) Synthetic route to both (±)-cis- and (±)-trans- MDMAR. Both isomers were prepared from the same 3′,4′-methylenedioxynorephedrine prescursor (e) using cyanogen bromide or potassium cyanate to yield the (±)-cis and (±)-trans-MDMAR product, respectively. (D) Molecular structure of synthesized cis-MDMAR (50% displacement ellipsoids).

Figure 2

(A) GC-MS data obtained for the (±)-cis-MDMAR isomer. (B) GC-MS data obtained for the (±)-trans-MDMAR isomer. (C) A proposed EI-MS fragmentation pattern for (±)-cis- and (±)-trans-MDMAR.

Figure 3

(A) Suggested mechanism for the formation of the m/z 178 ion following loss of HCNO. (B) Graph representing the cis to trans conversion overtime. (C) Suggested mechanism to explain the cis to trans conversion where the cis isomer reacts with the H₂O in the LC mobile phase which resulted in a change of configuration.

Figure 4

¹H NMR data obtained for the cis to trans conversion of MDMAR monitored over 24 h.

Figure 5

Dose-response effects of cis-DMAR, trans-DMAR, cis-MDMAR and trans-MDMAR on transmitter release at DAT, NET, and SERT. Data are mean ± SD for N = 3–4 experiments performed in triplicate.