Synthesis and in vitro cytotoxicity profile of the R-enantiomer of 3,4-dihydroxymethamphetamine (R-(-)-HHMA): comparison with related catecholamines

Chemical Research in Toxicology
Anne FelimMartine Largeron

Abstract

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a chiral drug that is essentially metabolized in humans through O-demethylenation into 3,4-dihydroxymethamphetamine (HHMA). There has recently been a resurgence of interest in the possibility that MDMA metabolites, especially 5-(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (designated as 5-NAC-HHMA), might play a role in MDMA neurotoxicity. However, the chirality of MDMA was not considered in previously reported in vivo studies because HHMA, the precursor of the 5-NAC-HHMA metabolite, was used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the first total synthesis of R-(-)-HHMA is reported. Using L-DOPA as the chiral source, the preparation of R-(-)-HHMA is achieved through seven steps, in 30% overall yield and 99.5% enantiomeric excess. The cytotoxicity of R-(-)-HHMA and related catecholamines has been further determined by flow cytometric analysis of propidium iodide uptake in human dopaminergic neuroblastoma SH-SY5Y cells and by an Escherichia coli plate assay, specific for the detection of oxidative toxicity. The good correlation between the toxicities observed in both systems suggests that SH-SY5Y cell...Continue Reading

References

Aug 1, 1979·Journal of Medicinal Chemistry·J G CannonR J Naylor
Jun 1, 1989·Pharmacology, Biochemistry, and Behavior·M HiramatsuA K Cho
Apr 1, 1974·Journal of Medicinal Chemistry·R J BorgmanR E Stitzel
Feb 1, 1996·Journal of Clinical Pathology·C M MilroyA R Forrest
Oct 26, 1999·Forensic Science International : Synergy·V FineschiE Turillazzi
Oct 5, 2001·Journal of Medicinal Chemistry·G J WellsR Bihovsky
Apr 2, 2003·Pharmacology & Therapeutics·J C Cole, H R Sumnall
May 10, 2003·Brain Research. Brain Research Reviews·Johnalyn Lyles, Jean Lud Cadet
Jul 18, 2003·Journal of Neuroscience Research·Cristina Gómez-SantosSantiago Ambrosio
Jul 19, 2003·Pharmacological Reviews·A Richard GreenM Isabel Colado
Jan 7, 2005·The Journal of Pharmacology and Experimental Therapeutics·Douglas C JonesTerrence J Monks
Jan 22, 2005·Current Opinion in Pharmacology·Jenny Morton
Jun 21, 2005·Lancet·George A Ricaurte, Una D McCann
Sep 22, 2006·Organic Letters·Shengzhuang TangMinghui Chai
Oct 2, 2007·The Journal of Pharmacology and Experimental Therapeutics·Gladys V ErivesTerrence J Monks
Nov 24, 2007·Pharmacology, Biochemistry, and Behavior·Gary A Gudelsky, Bryan K Yamamoto
Feb 13, 2008·Experimental and Clinical Psychopharmacology·William E Fantegrossi
Aug 30, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Markus R MeyerHans H Maurer
Oct 10, 2008·Brain : a Journal of Neurology·Maartje M L de WinWim van den Brink
Mar 12, 2009·The Journal of Pharmacology and Experimental Therapeutics·William E FantegrossiRafael de la Torre
Apr 8, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ximena PerfettiRafael de la Torre
Apr 18, 2009·Molecular Neurobiology·João Paulo CapelaFélix Carvalho
Jul 25, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Melanie MuellerGeorge A Ricaurte

Related Concepts

alpha-methylepinine, (S)-isomer
Catecholamines
Epinine
Flow Cytometry
Levopa
Molecular Stereochemistry
Toxicity Tests
N-Methyl-3,4-methylenedioxyamphetamine Hydrochloride
Cell Line, Tumor
Acetylcysteine

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis