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Stereochemistry of phase-1 metabolites of mephedrone determines their effectiveness as releasers at the serotonin transporter.

التفاصيل البيبلوغرافية
العنوان: Stereochemistry of phase-1 metabolites of mephedrone determines their effectiveness as releasers at the serotonin transporter.
المؤلفون: Mayer FP; Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria., Cintulova D; Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria., Pittrich DA; Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria., Wimmer L; Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria., Luethi D; University Hospital Basel and University of Basel, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, Basel, Switzerland., Holy M; Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria., Jaentsch K; Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria., Tischberger S; Doping Control Laboratory, Seibersdorf Labor GmbH, Seibersdorf, Austria., Gmeiner G; Doping Control Laboratory, Seibersdorf Labor GmbH, Seibersdorf, Austria., Hoener MC; Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Liechti ME; University Hospital Basel and University of Basel, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, Basel, Switzerland., Mihovilovic MD; Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria., Sitte HH; Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria; Center for Addiction Research and Science - AddRess, Medical University Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria. Electronic address: harald.sitte@meduniwien.ac.at.
المصدر: Neuropharmacology [Neuropharmacology] 2019 Apr; Vol. 148, pp. 199-209. Date of Electronic Publication: 2019 Jan 02.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Pergamon Press Country of Publication: England NLM ID: 0236217 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7064 (Electronic) Linking ISSN: 00283908 NLM ISO Abbreviation: Neuropharmacology Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Pergamon Press
Original Publication: Oxford, New York, Pergamon.
مواضيع طبية MeSH: Methadone/*analogs & derivatives , Selective Serotonin Reuptake Inhibitors/*pharmacology, Adrenergic Uptake Inhibitors/pharmacology ; Animals ; Cells, Cultured ; Dopamine Uptake Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Humans ; Methadone/pharmacology ; Methadone/urine ; Mice ; Radioligand Assay ; Rats ; Receptors, Catecholamine/drug effects ; Receptors, Serotonin/drug effects ; Stereoisomerism
مستخلص: Mephedrone (4-methyl-N-methylcathinone) is a psychostimulant that promotes release of monoamines via the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). Metabolic breakdown of mephedrone results in bioactive metabolites that act as substrate-type releasers at monoamine transporters and stereospecific metabolism of mephedrone has been reported. This study compared the effects of the enantiomers of the phase-1 metabolites nor-mephedrone, 4-hydroxytolyl-mephedrone (4-OH-mephedrone) and dihydro-mephedrone on (i) DAT, NET and SERT mediated substrate fluxes, (ii) determined their binding affinities towards a battery of monoamine receptors and (iii) examined the relative abundance of the enantiomers in human urine. Each of the enantiomers tested inhibited uptake mediated by DAT, NET and SERT. No marked differences were detected at DAT and NET. However, at SERT, the S-enantiomers of nor-mephedrone and 4-OH-mephedrone were several times more potent than the corresponding R-enantiomers. Moreover, the R-enantiomers were markedly less effective as releasers at SERT. S-nor-mephedrone displayed moderate affinities towards human alpha 1A , human 5-HT 2A and rat and mouse trace amine-associated receptor 1. These results demonstrate that stereochemistry dictates the pharmacodynamics of the phase-1 metabolites of mephedrone at SERT, but not at DAT and NET, which manifests in marked differences in their relative potencies, i.e. DAT/SERT ratios. Chiral analysis of urine samples demonstrated that nor-mephedrone predominantly exists as the S-enantiomer. Given the asymmetric abundance of the enantiomers in biological samples, these findings may add to our understanding of the subjective effects of administered mephedrone, which indicate pronounced effects on the serotonergic system.
(Copyright © 2018. Published by Elsevier Ltd.)
معلومات مُعتمدة: W 1232 Austria FWF_ Austrian Science Fund FWF
فهرسة مساهمة: Keywords: Cathinones; Dopamine; Mephedrone; New psychoactive substance; Serotonin; Stereoisomers
المشرفين على المادة: 0 (Adrenergic Uptake Inhibitors)
0 (Dopamine Uptake Inhibitors)
0 (Receptors, Catecholamine)
0 (Receptors, Serotonin)
0 (Serotonin Uptake Inhibitors)
KR2L2A68XL (normethadone)
UC6VBE7V1Z (Methadone)
تواريخ الأحداث: Date Created: 20190106 Date Completed: 20191227 Latest Revision: 20221207
رمز التحديث: 20240628
DOI: 10.1016/j.neuropharm.2018.12.032
PMID: 30610839
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-7064
DOI:10.1016/j.neuropharm.2018.12.032