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 (4,49-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.

DARK Classics in Chemical Neuroscience: Aminorex Analogues

“…It was also hypothesized that the methyl group might inhibit the hydrolysis of the amino-oxazoline ring. Lucchetti and colleagues could produce similar results for (±)- cis -4,4'-DMAR215. They discovered four metabolites, caused by hydrolysis, hydroxylation, deamination (which has already been shown for 4-MAR) and oxidation of the compound.…”

“…They discovered four metabolites, caused by hydrolysis, hydroxylation, deamination (which has already been shown for 4-MAR) and oxidation of the compound. The main metabolite located in plasma and brain was the one not detected in 4-MAR, caused by oxidation of 4,4'-DMAR’s para -methyl group215. It has been demonstrated that aminorex is mostly eliminated renally over the course of 72 hours211.…”

“…These results allude to the possibility that increased locomotor activity in rats could be attributed to high extracellular dopamine levels and that it is dose-dependent. It has been unveiled for (±)- cis -4,4'-DMAR that the substance also increases locomotor activity215.…”

Metabolic profile of the synthetic drug 4,4′-dimethylaminorex in urine by LC–MS-based techniques: selection of the most suitable markers of its intake

“…In 2013, 4,4′-DMAR was associated with 31 deaths in Europe. For this reason, the Commission on Narcotic Drugs, in 2016, decided to internationally control this new synthetic drug by adding it into Schedule II of the Convention on Psychotropic Substances of 1971 [12,13]. 4,4′-DMAR was initially sold as a "research chemical" on the illicit Internet market in powder form, under different names (e.g., "4-methylU4Euh", "4-methyl-euphoria", "Serotoni") [14,15].…”

“…So far, little is known about the pharmacokinetics of 4,4′-DMAR and its analogs; Lucchetti et al [12] identified four metabolites (hydroxylated, carboxylated, deaminated, and 4-methylnorephedrine) of cis-4,4′-DMAR in rat plasma and brain tissues. No information was, instead, available on the urinary excretion profile of the 4,4′-DMAR isomers.…”