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

Jacopo Lucchetti, Claudio M Marzo, Alice Passoni, Angelo Di Clemente, Federico Moro, Renzo Bagnati, Marco Gobbi, Luigi Cervo

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Abstract

para-Methyl-4-methylaminorex (4,4'-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 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4'-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, (tmax = 30-60 minutes) and large (brain-to-plasma ratio = 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-4,4'-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 para-methyl 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-4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

Original languageEnglish
Pages (from-to)492-500
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume361
Issue number3
DOIs
Publication statusPublished - Jun 2017

Fingerprint

Brain
Locomotion
Therapeutics
Pharmacokinetics
Tandem Mass Spectrometry
Intraperitoneal Injections
Half-Life
para-methyl-4-methylaminorex
Permeability
Mass Spectrometry
High Pressure Liquid Chromatography
Injections
Pharmaceutical Preparations

Keywords

  • Animals
  • Brain
  • Drug Administration Schedule
  • Locomotion
  • Male
  • Oxazoles
  • Rats
  • Rats, Wistar
  • Street Drugs
  • Tissue Distribution
  • Journal Article

Cite this

@article{5eee431cb7d54507b505e3a89516883a,
title = "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",
abstract = "para-Methyl-4-methylaminorex (4,4'-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 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4'-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, (tmax = 30-60 minutes) and large (brain-to-plasma ratio = 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-4,4'-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 para-methyl 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-4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.",
keywords = "Animals, Brain, Drug Administration Schedule, Locomotion, Male, Oxazoles, Rats, Rats, Wistar, Street Drugs, Tissue Distribution, Journal Article",
author = "Jacopo Lucchetti and Marzo, {Claudio M} and Alice Passoni and {Di Clemente}, Angelo and Federico Moro and Renzo Bagnati and Marco Gobbi and Luigi Cervo",
note = "Copyright {\circledC} 2017 by The American Society for Pharmacology and Experimental Therapeutics.",
year = "2017",
month = "6",
doi = "10.1124/jpet.117.240788",
language = "English",
volume = "361",
pages = "492--500",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
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TY - JOUR

T1 - Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4'-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats

T2 - Correlation with Central Behavioral Effects

AU - Lucchetti, Jacopo

AU - Marzo, Claudio M

AU - Passoni, Alice

AU - Di Clemente, Angelo

AU - Moro, Federico

AU - Bagnati, Renzo

AU - Gobbi, Marco

AU - Cervo, Luigi

N1 - Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

PY - 2017/6

Y1 - 2017/6

N2 - para-Methyl-4-methylaminorex (4,4'-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 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4'-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, (tmax = 30-60 minutes) and large (brain-to-plasma ratio = 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-4,4'-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 para-methyl 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-4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

AB - para-Methyl-4-methylaminorex (4,4'-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 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4'-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, (tmax = 30-60 minutes) and large (brain-to-plasma ratio = 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-4,4'-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 para-methyl 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-4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

KW - Animals

KW - Brain

KW - Drug Administration Schedule

KW - Locomotion

KW - Male

KW - Oxazoles

KW - Rats

KW - Rats, Wistar

KW - Street Drugs

KW - Tissue Distribution

KW - Journal Article

U2 - 10.1124/jpet.117.240788

DO - 10.1124/jpet.117.240788

M3 - Article

C2 - 28404688

VL - 361

SP - 492

EP - 500

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -