The Stereoisomers of 4-Methylaminorex

Klein, Robert F.; Sperling, Albert R.; Cooper, Donald A.; Kram, Theodore C.

doi:10.1520/jfs12723j

Cited by 19 publications

(23 citation statements)

References 7 publications

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“…The four optical isomers (trans-4R,5R, trans-4S,5S, cis-4R,5S, and cis-4S,5R) of 4-methylaminorex were prepared in the Laboratory of Organic Chemistry, University of Helsinki, Helsinki, Finland, by using synthesis methods described by Poos et al (1963) and Klein et al (1989). Identity of the isomers was confirmed by determining their melting points and rotation angles, as well as 1 H NMR and 13 C NMR spectra.…”

Section: Methodsmentioning

confidence: 99%

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Acute Neurochemical and Behavioral Effects of Stereoisomers of 4-Methylaminorex in Relation to Brain Drug Concentrations

Kankaanpää

Ellermaa²,

Meririnne³

et al. 2002

J Pharmacol Exp Ther

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4-Methylaminorex is a stimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. These isomers have previously been shown to differ markedly in various respects. In the present study we assessed the effects of the isomers of 4-methylaminorex (2.5, 5.0, and 10 mg/kg i.p.) on extracellular dopamine and 5-hydroxytryptamine (5-HT) levels in the nucleus accumbens, as well as behavior in the rats simultaneously. The relative concentrations of the isomers in the brain were also measured. The samples were collected by in vivo microdialysis and then analyzed for neurotransmitters with highperformance liquid chromatography/electrochemical detection and for cis-and trans-4-methylaminorex with gas chromatography/mass spectrometry. The behavioral effects of the isomers were assessed from videotapes recorded during the microdialysis experiments. All isomers elevated the extracellular levels of both dopamine and 5-HT, with the exception of trans-4R,5R. The rank order of potency for elevating dopamine was trans-4S,5S Ͼ cis-4S,5R Ϸ cis-4R,5S Ͼ trans-4R,5R, and for elevating 5-HT cis-4S,5R Ͼ trans-4S,5S Ϸ cis-4R,5S Ͼ trans-4R,5R. Analysis of the behavioral data, together with the neurochemical data, suggests that behavioral effects of the isomers of 4-methylaminorex are related to drug-induced dopamine release and, in the case of higher doses of the most efficacious isomers, to 5-HT as well. The brain concentrations of the isomers did not reflect their neurochemical efficacy, which implies that their differences are pharmacodynamic rather than pharmacokinetic.

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Section: Methodsmentioning

confidence: 99%

“…This compound was originally developed by the pharmaceutical industry, and more recently the mixture of cis-isomers has turned up in the clandestine market with street names "U4Euh" and "Ice" (Davis and Brewster, 1987;Klein et al, 1989). Since the advent of the Internet it has also been promoted worldwide on drug culture-related web sites.…”

mentioning

confidence: 99%

Acute Neurochemical and Behavioral Effects of Stereoisomers of 4-Methylaminorex in Relation to Brain Drug Concentrations

Kankaanpää

Ellermaa²,

Meririnne³

et al. 2002

J Pharmacol Exp Ther

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show abstract

“…The four optical stereoisomers (trans-4R,5R, trans-4S,5S, cis-4R,5S, and cis-4S,5R) of 4-methylaminorex were prepared at the Laboratory of Organic Chemistry (University of Helsinki, Helsinki, Finland) using the synthesis methods described previously (Poos et al, 1963;Klein et al, 1989). The identity of the isomers was confirmed by determining their melting points and rotation angles, and the 1 H NMR and 13 C NMR spectra.…”

Section: Methodsmentioning

confidence: 99%

“…mer being even more potent than the other isomers (Glennon and Misenheimer, 1989;Batsche et al, 1994;Ashby et al, 1995;Kankaanpä ä et al, 2002), and instructions for their synthesis are readily available (Poos et al, 1963;Klein et al, 1989), which together render them a potential alternative among drugs of abuse. Accordingly, experiences of alleged trans-4-methylaminorex intake can be found on the Internet.…”

mentioning

confidence: 99%

Pharmacokinetics and Tissue Distribution of the Stereoisomers of 4-Methylaminorex in the Rat

Meririnne

Ellermaa²,

Kankaanpää³

et al. 2004

J Pharmacol Exp Ther

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4-Methylaminorex, a potential psychostimulant drug of abuse, exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R, which were shown previously to possess stereospecific effects. This study characterized their pharmacokinetic and tissue distribution profiles, and metabolic turnover to norephedrine and norpseudoephedrine, in male Wistar rats. The rats received each isomer intravenously, intraperitoneally, or orally, followed by blood sample collection via cannula (pharmacokinetic study), or tissue sample collection at predetermined time points (tissue distribution study). The samples were analyzed for cis-and trans-isomers, and when appropriate for norephedrine and norpseudoephedrine, with gas chromatography/mass spectrometry. Trans-4S,5S-, cis-4R,5S-, and cis-4S,5R-isomers behaved comparably kinetically (volume of distribution 1.7-2.3 l/kg, distribution half-life 3.8 -7.0 min, elimination half-life 35-42 min, and bioavailability 32-57% intraperitoneally or 4 -16% orally), whereas trans-4R,5R-isomer differed from the others, with a longer elimination half-life (118 -169 min) and higher bioavailability (100% intraperitoneally or 83% orally). The highest isomer concentrations were observed in the kidney followed most frequently by the liver, brain, muscle, and last by fat and blood. The elimination half-lives of the stereoisomers from the tissues were generally similar to those in blood. No pharmacologically significant amounts of norephedrine or norpseudoephedrine were detected in blood or the brain. In conclusion, differences between the stereoisomers of 4-methylaminorex in the pharmacokinetics and tissue distribution are described. However, these differences are not compatible with, and thus may not account for, the distinct behavioral and neurochemical effects of the stereoisomers demonstrated previously. Furthermore, metabolic turnover to norephedrine and norpseudoephedrine does not seem to contribute significantly to 4-methylaminorex pharmacology.

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“…Il s'agit de l'aminorex, du 4-méthy-laminorex et de la méthcathinone (20,21). Des intoxications mortelles avec une très forte hypertension pulmonaire ont été décrites (22,23).…”

Section: Les Phényléthylaminesunclassified