PMID- 31038382 OWN - NLM STAT- MEDLINE DCOM- 20200728 LR - 20221207 IS - 1461-7285 (Electronic) IS - 0269-8811 (Print) IS - 0269-8811 (Linking) VI - 33 IP - 7 DP - 2019 Jul TI - Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems. PG - 831-841 LID - 10.1177/0269881119844185 [doi] AB - 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. FAU - Luethi, Dino AU - Luethi D AD - 1 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. FAU - Kolaczynska, Karolina E AU - Kolaczynska KE AD - 1 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. FAU - Walter, Melanie AU - Walter M AD - 1 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. FAU - Suzuki, Masaki AU - Suzuki M AD - 2 Drug Design and Synthesis Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA. AD - 3 On leave from the Medicinal Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. FAU - Rice, Kenner C AU - Rice KC AD - 2 Drug Design and Synthesis Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA. FAU - Blough, Bruce E AU - Blough BE AD - 4 Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA. FAU - Hoener, Marius C AU - Hoener MC AUID- ORCID: 0000-0001-6510-6250 AD - 5 Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. FAU - Baumann, Michael H AU - Baumann MH AD - 6 Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA. FAU - Liechti, Matthias E AU - Liechti ME AUID- ORCID: 0000-0002-1765-9659 AD - 1 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland. LA - eng GR - ZIA DA000523/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20190430 PL - United States TA - J Psychopharmacol JT - Journal of psychopharmacology (Oxford, England) JID - 8907828 RN - 0 (Benzodioxoles) RN - 0 (Central Nervous System Stimulants) RN - 0 (Membrane Transport Proteins) RN - 0 (Pyrrolidines) RN - 333DO1RDJY (Serotonin) RN - 44RAL3456C (Methamphetamine) RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) RN - L4I4B1R01F (methylone) RN - VTD58H1Z2X (Dopamine) RN - X4W3ENH1CV (Norepinephrine) RN - 0 (Synthetic Cathinone) SB - IM MH - Benzodioxoles/*pharmacology MH - Central Nervous System Stimulants/*pharmacology MH - Dopamine/metabolism MH - HEK293 Cells MH - Humans MH - Membrane Transport Proteins/metabolism MH - Methamphetamine/*analogs & derivatives/pharmacology MH - N-Methyl-3,4-methylenedioxyamphetamine/*metabolism MH - Norepinephrine/metabolism MH - Pyrrolidines/*pharmacology MH - Serotonin/metabolism MH - Synthetic Cathinone PMC - PMC8269116 MID - NIHMS1717802 OTO - NOTNLM OT - MDMA OT - MDPV OT - metabolite OT - methylone OT - transporter COIS- Declaration of conflicting interests M.C.H. is an employee of F. Hoffmann-La Roche. The other authors do not have any conflicts of interest to declare for this work. EDAT- 2019/05/01 06:00 MHDA- 2020/07/29 06:00 PMCR- 2021/07/09 CRDT- 2019/05/01 06:00 PHST- 2019/05/01 06:00 [pubmed] PHST- 2020/07/29 06:00 [medline] PHST- 2019/05/01 06:00 [entrez] PHST- 2021/07/09 00:00 [pmc-release] AID - 10.1177/0269881119844185 [doi] PST - ppublish SO - J Psychopharmacol. 2019 Jul;33(7):831-841. doi: 10.1177/0269881119844185. Epub 2019 Apr 30.