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

NEUROPHARMACOLOGY

卷:148

Article

Mayer, Felix P.^1,8  Cintulova, Daniela²  Pittrich, Dorothea A.¹  Wimmer, Laurin²  Luethi, Dino^3,4  Holy, Marion¹  Jaentsch, Kathrin¹  Tischberger, Sonja⁵  Gmeiner, Guenter⁵  Hoener, Marius C.⁶  Liechti, Matthias E.^3,4  Mihovilovic, Marko D.²  Sitte, Harald H.^1,7 

[1] Med Univ Vienna, Inst Pharmacol, Ctr Physiol & Pharmacol, Waehringerstr 13a, A-1090 Vienna, Austria

[2] Vienna Univ Technol, Inst Appl Synthet Chem, Vienna, Austria

[3] Univ Hosp Basel, Basel, Switzerland

[4] Univ Basel, Div Clin Pharmacol & Toxicol, Dept Biomed, Basel, Switzerland

[5] Seibersdorf Lab GmbH, Doping Control Lab, Seibersdorf, Austria

[6] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, pRED, Neurosci Res, Basel, Switzerland

[7] Med Univ Vienna, Ctr Addict Res & Sci AddRess, Waehringerstr 13A, A-1090 Vienna, Austria

[8] Charles E Schmidt Coll Med, Dept Biomed Sci, Boca Raton, FL USA

关键词: New psychoactive substance;    Dopamine;    Serotonin;    Cathinones;    Mephedrone;    Stereoisomers;   

DOI  :  10.1016/j.neuropharm.2018.12.032

来源: Elsevier

【 摘 要 】

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-HT2A 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 wine 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.

【 授权许可】

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