Dino Luethi1, Karolina E Kolaczynska1, Melanie Walter1, Masaki Suzuki2,3, Kenner C Rice2, Bruce E Blough4, Marius C Hoener5, Michael H Baumann6, Matthias E Liechti1. 1. 1 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. 2. 2 Drug Design and Synthesis Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA. 3. 3 On leave from the Medicinal Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. 4. 4 Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA. 5. 5 Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 6. 6 Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
Abstract
BACKGROUND: Amphetamine analogs with a 3,4-methylenedioxy ring-substitution are among the most popular illicit drugs of abuse, exerting stimulant and entactogenic effects. Enzymatic N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to metabolites that may be pharmacologically active. Indeed, previous studies in rats show that specific metabolites of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) can interact with monoaminergic systems. AIM: Interactions of metabolites of MDMA, methylone and MDPV with human monoaminergic systems were assessed. METHODS: The ability of parent drugs and their metabolites to inhibit uptake of tritiated norepinephrine, dopamine and serotonin (5-HT) was assessed in human embryonic kidney 293 cells transfected with human monoamine transporters. Binding affinities and functional activity at monoamine transporters and various receptor subtypes were also determined. RESULTS: MDMA and methylone displayed greater potency to inhibit norepinephrine uptake as compared to their effects on dopamine and 5-HT uptake. N-demethylation of MDMA failed to alter uptake inhibition profiles, whereas N-demethylation of methylone decreased overall transporter inhibition potencies. O-demethylenation of MDMA, methylone and MDPV resulted in catechol metabolites that maintained norepinephrine and dopamine uptake inhibition potencies, but markedly reduced activity at 5-HT uptake. O-methylation of the catechol metabolites significantly decreased norepinephrine uptake inhibition, resulting in metabolites lacking significant stimulant properties. CONCLUSIONS: Several metabolites of MDMA, methylone and MDPV interact with human transporters and receptors at pharmacologically relevant concentrations. In particular, N-demethylated metabolites of MDMA and methylone circulate in unconjugated form and could contribute to the in vivo activity of the parent compounds in human users.
BACKGROUND:Amphetamine analogs with a 3,4-methylenedioxy ring-substitution are among the most popular illicit drugs of abuse, exerting stimulant and entactogenic effects. Enzymatic N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to metabolites that may be pharmacologically active. Indeed, previous studies in rats show that specific metabolites of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) can interact with monoaminergic systems. AIM: Interactions of metabolites of MDMA, methylone and MDPV with humanmonoaminergic systems were assessed. METHODS: The ability of parent drugs and their metabolites to inhibit uptake of tritiated norepinephrine, dopamine and serotonin (5-HT) was assessed in humanembryonic kidney293 cells transfected with humanmonoamine transporters. Binding affinities and functional activity at monoamine transporters and various receptor subtypes were also determined. RESULTS:MDMA and methylone displayed greater potency to inhibit norepinephrine uptake as compared to their effects on dopamine and 5-HT uptake. N-demethylation of MDMA failed to alter uptake inhibition profiles, whereas N-demethylation of methylone decreased overall transporter inhibition potencies. O-demethylenation of MDMA, methylone and MDPV resulted in catechol metabolites that maintained norepinephrine and dopamine uptake inhibition potencies, but markedly reduced activity at 5-HT uptake. O-methylation of the catechol metabolites significantly decreased norepinephrine uptake inhibition, resulting in metabolites lacking significant stimulant properties. CONCLUSIONS: Several metabolites of MDMA, methylone and MDPV interact with human transporters and receptors at pharmacologically relevant concentrations. In particular, N-demethylated metabolites of MDMA and methylone circulate in unconjugated form and could contribute to the in vivo activity of the parent compounds in human users.
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