title: 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.
authors.affiliation: Department of Life and Physical Sciences, School of Science, Athlone Institute of Technology, Dublin Road, Athlone, Co. Westmeath, Ireland.|Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors.forename: Gavin
authors.initials: G
authors.lastname: McLaughlin
authors.affiliation: Department of Life and Physical Sciences, School of Science, Athlone Institute of Technology, Dublin Road, Athlone, Co. Westmeath, Ireland.
authors.forename: Noreen
authors.initials: N
authors.lastname: Morris
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors.forename: Pierce V
authors.initials: PV
authors.lastname: Kavanagh
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.|Forensic Science Laboratory, Garda HQ, Dublin 8, Ireland.
authors.forename: John D
authors.initials: JD
authors.lastname: Power
authors.affiliation: TCD Small Molecule X-ray Facility, Trinity College, Dublin 2, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Twamley
authors.affiliation: School of Chemistry, Trinity College, Dublin 2, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Talbot
authors.affiliation: The State Laboratory, Backweston Laboratory Complex, Young's Cross, Celbridge, Co. Kildare, Ireland.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Dowling
authors.affiliation: School of Chemical and Pharmaceutical Sciences, Dublin Institute of Technology, Dublin 2, Ireland.
authors.forename: Olivia
authors.initials: O
authors.lastname: Mahony
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L33 AF, UK.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Brandt
authors.affiliation: Scientific Supplies Ltd, Hanover Street, London, W1S 1YH, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Patrick
authors.affiliation: States Analyst's Laboratory, Longue Rue, St Martin's, GY4 6LD, Guernsey.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Archer
authors.affiliation: Designer Drug Research Unit of the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Designer Drug Research Unit of the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
mesh_terms: D000635:Aminorex / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D000697:Central Nervous System Stimulants / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008297:Male; D011619:Psychotropic Drugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D011619:Psychotropic Drugs; D050493:Vesicular Monoamine Transport Proteins; D000635:Aminorex
keywords: 4,4′-DMAR; aminorex; forensic; new psychoactive substances; psychostimulants