The growing problem of mephedrone use in Warsaw, Poland, 2010–18

Ordak, Michał; Nasierowski, Tadeusz; Muszyńska, Elżbieta

doi:10.1016/s2215-0366(18)30305-5

Cited by 13 publications

(16 citation statements)

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“…If some NPS disappear right after being found and banned, others become established within the drug market contributing to the addiction plague (United Nations Office, 2016). Despite being banned in most of the western countries around 2010 (Green et al, 2014), MEPH became an established substance of abuse in some regions (Hockenhull et al, 2016;Ordak et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Effects of Hydroxylated Mephedrone Metabolites on Monoamine Transporter Activity in vitro

Niello¹,

Cintulová

Raithmayr

et al. 2021

Front. Pharmacol.

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Mephedrone is a largely abused psychostimulant. It elicits the release of monoamines via the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). Stereoselective metabolic reactions are involved in the inactivation and the elimination of its chemical structure. However, during these processes, several structures are generated and some of them have been reported to be still pharmacologically active. In this study 1) we have newly synthetized several putative mephedrone metabolites, 2) compared their activity at monoamine transporters, 3) generated quantitative structure activity relationships, and 4) exploited the chemical structure of the putative metabolites to screen a urine sample from a drug user and dissect mephedrone metabolism. We have found that most of the tested metabolites are weak inhibitors of monoamine transporters and that all of them are more potent at DAT and NET in comparison to SERT. The only exception is represented by the COOH-metabolite which shows no pharmacological activity at all three monoamine transporters. The enantioselectivity of mephedrone and its metabolites is present mainly at SERT, with only minor effects at DAT and NET being introduced when the β-keto group is reduced to an OH-group. Importantly, while at DAT the putative metabolites did not show changes in inhibitory potencies, but rather changes in their substrate/blocker profile, at SERT they showed mainly changes in inhibitory potencies. Molecular modeling suggests that the hydrophobic nature of a specific SERT subpocket may be involved in such loss of affinity. Finally, the assessment of the putative metabolites in one urine sample of mephedrone user displayed two previously uncharacterized metabolites, 4-COOH-nor-mephedrone (4-COOH-MC) and dihydro-4- nor-mephedrone (dihydro-4-MC). These results confirm and expand previous studies highlighting the importance of the stereochemistry in the pharmacodynamics of phase-1 metabolites of mephedrone, established their structure-activity relationships at DAT, NET and SERT and pave the way for a systematic dissection of mephedrone metabolic routes. Given the number of structures found having residual and modified pharmacological profiles, these findings may help in understanding the complex subjective effects of administered mephedrone. Moreover, the dissection of mephedrone metabolic routes may help in developing new therapies for treating psychostimulants acute intoxications.

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Section: Introductionmentioning

confidence: 99%

Effects of Hydroxylated Mephedrone Metabolites on Monoamine Transporter Activity in vitro

Niello¹,

Cintulová

Raithmayr

et al. 2021

Front. Pharmacol.

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show abstract

“…Mephedrone was banned in most western countries in 2010 to 2011 (Green et al, 2014). However, converging lines of evidence indicate persistent abuse of this compound (Archer et al, 2013;Archer et al, 2014;Castiglioni et al, 2015;Salomone et al, 2016;Styszko et al, 2016), indicating that mephedrone became a widely accepted drug for recreational consumption in some regions (Hockenhull et al, 2016;Ordak et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…This indicates the strong addictive potential of mephedrone. This is also confirmed by entries on special internet forums, such as hyperreal.info, where people taking mephedrone indicate its strong addictive potential [1, 3].…”

mentioning

confidence: 68%

“…Between 2010 and 2018, 601 patients on a mephedrone binge were hospitalized in the Nowowiejski Hospital in Warsaw. In each successive year, an increasing number of patients were hospitalized for this reason [1].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Response to commentary by Grifell and Hart, commentary on: The problem of mephedrone in Europe: Causes and suggested solutions

Ordak

Nasierowski

2019

Eur. psychiatr.

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The growing problem of mephedrone use in Warsaw, Poland, 2010–18

Cited by 13 publications

References 1 publication

Effects of Hydroxylated Mephedrone Metabolites on Monoamine Transporter Activity in vitro

Effects of Hydroxylated Mephedrone Metabolites on Monoamine Transporter Activity in vitro

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

Response to commentary by Grifell and Hart, commentary on: The problem of mephedrone in Europe: Causes and suggested solutions

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