151. Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems
- Author
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Michael H. Baumann, Karolina E. Kolaczynska, Dino Luethi, Melanie Walter, Marius C. Hoener, Matthias E. Liechti, Bruce E. Blough, Masaki Suzuki, and Kenner C. Rice
- Subjects
Serotonin ,Pyrrolidines ,Dopamine ,N-Methyl-3,4-methylenedioxyamphetamine ,medicine.medical_treatment ,Methylone ,Metabolite ,Pharmacology ,Ring (chemistry) ,Article ,Methamphetamine ,Norepinephrine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Monoaminergic ,medicine ,Humans ,Pharmacology (medical) ,Benzodioxoles ,Amphetamine ,Chemistry ,Membrane Transport Proteins ,MDMA ,Transporter ,Synthetic Cathinone ,030227 psychiatry ,Stimulant ,Psychiatry and Mental health ,HEK293 Cells ,Central Nervous System Stimulants ,030217 neurology & neurosurgery ,medicine.drug - 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-methylenedioxymethamphetmine (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.
- Published
- 2019