Characterization of a novel and potentially lethal designer drug <i>(±)‐cis‐para</i>‐methyl‐4‐methylaminorex (4,4'‐DMAR, or ‘Serotoni’)

Brandt, Simon D.; Baumann, Michael H.; Partilla, John S.; Kavanagh, Pierce V.; Power, John D.; Talbot, Brian; Twamley, Brendan; Mahony, Olivia; O’Brien, John D.; Elliott, Simon; Archer, Roland; Patrick, J. Calie; Singh, Kuldip; Dempster, Nicola M.; Cosbey, Simon H.

doi:10.1002/dta.1668

Cited by 32 publications

(85 citation statements)

References 30 publications

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“…This effect resembled those previously observed with amphetamine and its analogs, such as phenethylamines/3,4-methylenedioxymethamphetamine--like drugs (Wellman et al, 2009;Pálení cek et al, 2011;López-Arnau et al, 2012;Aarde et al, 2013;Miliano et al, 2016), and is very likely attributable to the fact that cis-4,49-DMAR induces the release of biologic monoamines, particularly dopamine (Charntikov et al, 2011;Brandt et al, 2014;McLaughlin et al, 2015). The rapid appearance and rapid decline of this behavioral effect is consistent with the PK profile of the compound in the brain, although a delay of about 1 hour could be noted (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 83%

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Lucchetti

Marzo

Passoni

et al. 2017

J Pharmacol Exp Ther

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para-Methyl-4-methylaminorex (4,49-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,49-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,49-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (t max 5 30-60 minutes) and large (brain-to-plasma ratio 5 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,49-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the paramethyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,49-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

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Section: Discussionsupporting

confidence: 83%

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Lucchetti

Marzo

Passoni

et al. 2017

J Pharmacol Exp Ther

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“…A study carried out recently involving the characterization of 4,4′-DMAR obtained from online vendors and case samples revealed the presence of cis -4,4′-DMAR. [2,5] …”

Section: Introductionmentioning

confidence: 99%

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

McLaughlin

Morris

Kavanagh

et al. 2014

Drug Testing and Analysis

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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.

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“…Similar to the aminorex analogs previously detected on the NPS market, [20,21] the fluorinated analogs of phenmetrazine contain two chiral centres which yield the potential for four stereoisomers and two racemic mixtures (i.e., cisand trans-racemates) ( Figure 1C). The results observed for the preparation of the FPM isomers were consistent with the reported synthesis of phenmetrazine where the formation of the more trans-isomer was reported.…”

Section: Of the Fluoropropiophenone Starting Materials (A) Yielding αmentioning

confidence: 71%

“…Similar to that of other anorectic agents such as aminorex, [20,21] the chemical structure of phenmetrazine may be open to structural manipulation through Figure 1A) were synthesized and pharmacological evaluations revealed that both isomers were substrate-type monoamine releasers with higher selectivity toward catecholamines. [3] In the synaptosomal preparations used, 3-FPM showed higher potency than 4-FPM in the ability to induce dopamine and norepinephrine release and further investigations related to the 2-FPM isomer are needed for further comparisons.…”

Section: Introductionmentioning

confidence: 99%

Test purchase, synthesis and characterization of 3‐fluorophenmetrazine (3‐FPM) and differentiation from its ortho‐ and para‐substituted isomers

McLaughlin

Morris

Kavanagh

et al. 2016

Drug Testing and Analysis

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The knowledge captured in patent and scientific research literature stimulates new ideas and fosters new drug development efforts. Manufacturers and entrepreneurs dedicated to the sale of ‘research chemicals’ and/or new psychoactive substances (NPS) also make use of access to information to identify, prepare, and launch a range of new substances. One of the most recent compounds to appear on the NPS market is the phenmetrazine analog 3‐fluorophenmetrazine (3‐FPM) which represents one of many phenylmorpholines designed to explore treatment options in areas such as obesity and drug dependence. The anorectic drug analogs phenmetrazine and phendimetrazine, used as prescription medicines before they were withdrawn, feature amphetamine‐like properties associated with monoamine release. Available data on 3‐FPM suggest that the effects might show mechanistic overlaps. This study describes the synthesis and extensive analytical characterization of 3‐FPM and its differentiation from synthesized ortho‐ and para‐ substituted isomers, 2‐FPM and 4‐FPM, respectively. This study was triggered by the purchase of five powdered samples advertised as 3‐FPM by five different Internet vendors based in the United Kingdom. The analytical data obtained for the vendor samples were consistent with the synthesized 3‐FPM standard and differentiation between all three isomers was possible. The presence of positional isomers and the absence of suitable reference material can cause difficulties in the day‐to‐day operation of forensic work and given the rate at which many of the newly emerging NPS appear on the market, a comprehensive approach is needed when attempting to decipher the identity of NPS arriving onto the drug market. Copyright © 2016 John Wiley & Sons, Ltd.

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

Cited by 32 publications

References 30 publications

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

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

Test purchase, synthesis and characterization of 3‐fluorophenmetrazine (3‐FPM) and differentiation from its ortho‐ and para‐substituted isomers

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