Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni').
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.
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
Simon D
SD
Brandt
Michael H
MH
Baumann
John S
JS
Partilla
Pierce V
PV
Kavanagh
John D
JD
Power
Brian
B
Talbot
Brendan
B
Twamley
Olivia
O
Mahony
John
J
O'Brien
Simon P
SP
Elliott
Roland P
RP
Archer
Julian
J
Patrick
Kuldip
K
Singh
Nicola M
NM
Dempster
Simon H
SH
Cosbey
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants; D015198:Designer Drugs / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D013287:Illicit Drugs / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007536:Isomerism; D008297:Male; D008958:Models, Molecular; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D000697:Central Nervous System Stimulants; D015198:Designer Drugs; D013287:Illicit Drugs; D010080:Oxazoles; D050493:Vesicular Monoamine Transport Proteins; C000598109:para-methyl-4-methylaminorex; C000081:4-methylaminorex
4-methylaminorex; Internet; aminorex; monoamine transporters; new psychoactive substances; para-methyl-4-methylaminorex; psychostimulants; synaptosomes