Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')

Abstract

During the second half of 2013, a total of 26 deaths involving para-methyl-4-methylaminorex (4,4'-DMAR) were reported to the European Monitoring Centre for Drugs and Drug Addiction. While aminorex and 4-methylaminorex (4-MAR) are known psychostimulants, nothing is known about the comparatively new para-methyl analog. Analytical characterization of two independent samples obtained from online vendors confirmed the presence of the (±)-cis isomer that also appeared to be associated with at least 18 of the 26 deaths. Extensive characterizations included crystal structure analysis, single, tandem, and high-resolution mass spectrometry, liquid and gas chromatography, and nuclear magnetic resonance spectroscopy. For the work described here, both the (±)-cis and (±)-trans racemates were also synthesized, confirming that the differentiation between these two forms was straight-forward. Monoamine transporter activity was studied using rat brain synaptosomes which included the comparison with d-amphetamine, aminorex and (±)-cis-4-MAR. (±)-cis-4,4'-DMAR was a potent, efficacious substrate-type releaser at transporters for dopamine, norepinephrine and serotonin with EC50 values of 8.6 ± 1.1 nM (DAT), 26.9 ± 5.9 nM (NET) and 18.5 ± 2.8 nM (SERT), respectively. The potency of (±)-cis-4,4'-DMAR at DAT and NET rivalled that of other psychomotor stimulant drugs like d-amphetamine and aminorex. However, (±)-cis-4,4'-DMAR had much more potent actions at SERT and activity at SERT varied more than 100-fold across the four drugs. The potent releasing activity of (±)-cis-4,4'-DMAR at all three monoamine transporters predicts a potential for serious side-effects such as psychotic symptoms, agitation, hyperthermia and cardiovascular stimulation, especially after high-dose exposure or following combination with other psychostimulants.

Keywords: 4-methylaminorex; Internet; aminorex; monoamine transporters; new psychoactive substances; para-methyl-4-methylaminorex; psychostimulants; synaptosomes.

Figure 1

A: Chemical structures of the three psychostimulants aminorex, 4-methylaminorex (4-MAR) and para-methyl-4-methylaminorex (4,4'-DMAR). B: structural representations of all four existing 4,4'-DMAR enantiomers; 4'-Ph represents the para-substituted phenyl ring. C: synthetic route to both (±)-cis- and (±)-trans-4,4'-DMAR. Both isomers were prepared from the same 4'-methylnorephedrine precursor (e) using cyanogen bromide or potassium cyanate to yield the (±)-cis- and (±)-trans product, respectively. 214×246mm (300 × 300 DPI)

Figure 2

Mass spectra of (±)-cis-4,4'-DMAR HCl obtained from an Internet vendor using gas chromatography for sample introduction. A: electron ionization (EI) quadrupole MS. B: EI ion trap MS which varied from quadrupole MS in terms of relative abundance values. C: CI ion trap MS and a suggested loss from of NH3 and HNCO from the protonated molecule. 246×411mm (300 × 300 DPI)

Figure 3

A: Proposed EI-MS fragmentation pattern for (±)-cis-4,4'-DMAR HCl. The following mass spectra were obtained from the donated (±)-cis-4,4'-DMAR HCl. Both isomers yielded identical mass spectra, see supplemental information for comparison. B: ESI-triple quadrupole MS/MS. C: High-resolution UHPLC-Q-TOF-MS/MS. 221×233mm (300 × 300 DPI)

Figure 4

Chromatographic analysis of donated and synthesized 4,4'-DMAR. A–C: GC-MS analysis confirmed that the donated 4,4'-DMAR HCl was consistent with the synthesized (±)-cis-4,4'-DMAR standard. Conversion of the hydrochloride salt to the free base (trace B) improved detectability. D and E: LC-ESI-quadrupole-MS/MS analysis in MRM mode to obtain separation. F and G: LC-single quadrupole-MS analysis of the donated (±)-cis-4,4'-DMAR HCl and improved separation of cis and trans racemates. 247×302mm (300 × 300 DPI)

Figure 5

1H NMR and DEPTQ comparison of (±)-cis-4,4'-DMAR HCl obtained from a donation (July 2013) and a test purchase from an alternative Internet vendor (March 2014). A spectral comparison revealed that both samples were spectroscopically identical. Note the difference in chemical shifts observed with the synthesized (±)-cis free base (e.g. H-4 and H-5, see Experimental section) as a reflection of salt formation and use of different deuterated solvents (CDCl3 base vs. CD3OD HCl salt). A: 1H NMR of donated product. B: 1H NMR of test purchase. This was then followed by 13C NMR analysis. C: DEPTQ of donated product. D: DEPTQ of test purchase. 289×410mm (300 × 300 DPI)

Figure 6

Crystal structure of (±)-cis-4,4'-DMAR HCl. 586×469mm (300 × 300 DPI)

Figure 7

Dose-response effects of d-amphetamine, aminorex, (±)-cis-4,MAR and (±)-cis-4,4'-DMAR to evoke release from monoamine transporters in rat brain synaptosomes. DAT: dopamine transporter; NET: norepinephrine transporter; SERT: serotonin transporter. (±)-cis-4,4'-DMAR elicited potent release of all three monoamines including serotonin. 151×146mm (300 × 300 DPI)