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

Summary

A newly emerged psychoactive substance, 3,4-methylenedioxy-4-methylaminorex (MDMAR), was synthesized and characterized. Analysis of vendor-sourced MDMAR found it to be predominantly the cis-isomer (90%), which could artificially convert to the trans-isomer under certain liquid chromatography conditions. Both MDMAR isomers, along with cis- and trans-4,4'-DMAR, were more potent than MDMA in releasing dopamine and norepinephrine in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR, and trans-MDMAR fully released serotonin, trans-4,4'-DMAR acted as a serotonin uptake blocker. The high potency of these analogues at monoamine transporters may indicate potential for serious side-effects at high doses.

Study at a glance

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.