Chemical synthesis, characterisation and in vitro and in vivo metabolism of the synthetic opioid MT-45 and it's newly identified fluorinated analogue 2F-MT-45 with metabolite confirmation in urine samples from known drug users

Craig McKenzie (Lead / Corresponding author), Oliver B. Sutcliffe (Lead / Corresponding author), Kevin Read, Stanley Scullion, Rafiu Epemolu, Daniel Fletcher, Anders Helander, Olof Beck, Alexia Rylski, Lysbeth Antonides, Jennifer Riley, Shannah Smith, Niamh Nic Daeid

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Abstract

Purpose: The detection of a novel psychoactive substance, 2F-MT-45, a fluorinated analogue of the synthetic opioid MT-45, was reported in a single seized tablet. MT-45, 2F-, 3F- and 4F-MT-45 were synthesised and reference analytical data were reported. The in vitro and in vivo metabolisms of MT-45 and 2F-MT-45 were investigated. Method: The reference standards and seized sample were characterised using nuclear magnetic resonance spectroscopy, ultra-performance liquid chromatography–quadrupole time of flight mass spectrometry, gas chromatography–mass spectrometry, attenuated total reflectance-Fourier transform infrared spectroscopy and Raman spectroscopy. Presumptive tests were performed and physicochemical properties of the compounds determined. Metabolite identification studies using human liver microsomes, human hepatocytes, mouse hepatocytes and in vivo testing using mice were performed and identified MT-45 metabolites were confirmed in authentic human urine samples. Results: Metabolic pathways identified for MT-45 and 2F-MT-45 were N-dealkylation, hydroxylation and subsequent glucuronidation. The major MT-45 metabolites identified in human in vitro studies and in authenticated human urine were phase I metabolites and should be incorporated as analytical targets to existing toxicological screening methods. Phase II glucuronidated metabolites were present in much lower proportions. Conclusions: 2F-MT-45 has been detected in a seized tablet for the first time. The metabolite identification data provide useful urinary metabolite targets for forensic and clinical testing for MT-45 and allows screening of urine for 2F-MT-45 and its major metabolites to determine its prevalence in case work.

Original languageEnglish
Pages (from-to)359-374
Number of pages16
JournalForensic Toxicology
Volume36
Issue number2
Early online date5 Apr 2018
DOIs
Publication statusPublished - Jul 2018

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Metabolites
Drug Users
Metabolism
Opioid Analgesics
Urine
Pharmaceutical Preparations
(+,-)-1-cyclohexyl-4-(1,2-diphenylethyl)piperazine
In Vitro Techniques
Tablets
Hepatocytes
Screening
Dealkylation
Hydroxylation
Raman Spectrum Analysis
Testing
Liver Microsomes
Fourier Transform Infrared Spectroscopy
Metabolic Networks and Pathways
Liver
Toxicology

Keywords

  • Novel psychoactive substances
  • MT-45
  • 2F-MT-45
  • Metabolite profiles
  • Forensic Toxicology
  • Clinical Toxicology
  • Synthetic Opioids
  • analytical chemistry

Cite this

@article{c25c4c583c9f41d88b7f299223aeb234,
title = "Chemical synthesis, characterisation and in vitro and in vivo metabolism of the synthetic opioid MT-45 and it's newly identified fluorinated analogue 2F-MT-45 with metabolite confirmation in urine samples from known drug users",
abstract = "Purpose: The detection of a novel psychoactive substance, 2F-MT-45, a fluorinated analogue of the synthetic opioid MT-45, was reported in a single seized tablet. MT-45, 2F-, 3F- and 4F-MT-45 were synthesised and reference analytical data were reported. The in vitro and in vivo metabolisms of MT-45 and 2F-MT-45 were investigated. Method: The reference standards and seized sample were characterised using nuclear magnetic resonance spectroscopy, ultra-performance liquid chromatography–quadrupole time of flight mass spectrometry, gas chromatography–mass spectrometry, attenuated total reflectance-Fourier transform infrared spectroscopy and Raman spectroscopy. Presumptive tests were performed and physicochemical properties of the compounds determined. Metabolite identification studies using human liver microsomes, human hepatocytes, mouse hepatocytes and in vivo testing using mice were performed and identified MT-45 metabolites were confirmed in authentic human urine samples. Results: Metabolic pathways identified for MT-45 and 2F-MT-45 were N-dealkylation, hydroxylation and subsequent glucuronidation. The major MT-45 metabolites identified in human in vitro studies and in authenticated human urine were phase I metabolites and should be incorporated as analytical targets to existing toxicological screening methods. Phase II glucuronidated metabolites were present in much lower proportions. Conclusions: 2F-MT-45 has been detected in a seized tablet for the first time. The metabolite identification data provide useful urinary metabolite targets for forensic and clinical testing for MT-45 and allows screening of urine for 2F-MT-45 and its major metabolites to determine its prevalence in case work.",
keywords = "Novel psychoactive substances, MT-45, 2F-MT-45, Metabolite profiles, Forensic Toxicology, Clinical Toxicology, Synthetic Opioids, analytical chemistry",
author = "Craig McKenzie and Sutcliffe, {Oliver B.} and Kevin Read and Stanley Scullion and Rafiu Epemolu and Daniel Fletcher and Anders Helander and Olof Beck and Alexia Rylski and Lysbeth Antonides and Jennifer Riley and Shannah Smith and {Nic Daeid}, Niamh",
note = "S.A. Smith is funded by the Engineering and Physical Sciences Research Council (EPSRC) Doctoral Training Programme. The authors acknowledge the work of L. Ellis of the Drug Discovery Unit, University of Dundee for Physico-Chemical analysis and Y. Shishikura, F. Simeons, L. Ferguson, E. Pinto and L. Stojanovski also of the Drug Discovery Unit, University of Dundee; and S. Ward for presumptive testing. S. Ward was funded by a Royal Society of Chemistry Analytical Chemistry Trust Fund Internship Grant.",
year = "2018",
month = "7",
doi = "10.1007/s11419-018-0413-1",
language = "English",
volume = "36",
pages = "359--374",
journal = "Forensic Toxicology",
issn = "1860-8965",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - Chemical synthesis, characterisation and in vitro and in vivo metabolism of the synthetic opioid MT-45 and it's newly identified fluorinated analogue 2F-MT-45 with metabolite confirmation in urine samples from known drug users

AU - McKenzie, Craig

AU - Sutcliffe, Oliver B.

AU - Read, Kevin

AU - Scullion, Stanley

AU - Epemolu, Rafiu

AU - Fletcher, Daniel

AU - Helander, Anders

AU - Beck, Olof

AU - Rylski, Alexia

AU - Antonides, Lysbeth

AU - Riley, Jennifer

AU - Smith, Shannah

AU - Nic Daeid, Niamh

N1 - S.A. Smith is funded by the Engineering and Physical Sciences Research Council (EPSRC) Doctoral Training Programme. The authors acknowledge the work of L. Ellis of the Drug Discovery Unit, University of Dundee for Physico-Chemical analysis and Y. Shishikura, F. Simeons, L. Ferguson, E. Pinto and L. Stojanovski also of the Drug Discovery Unit, University of Dundee; and S. Ward for presumptive testing. S. Ward was funded by a Royal Society of Chemistry Analytical Chemistry Trust Fund Internship Grant.

PY - 2018/7

Y1 - 2018/7

N2 - Purpose: The detection of a novel psychoactive substance, 2F-MT-45, a fluorinated analogue of the synthetic opioid MT-45, was reported in a single seized tablet. MT-45, 2F-, 3F- and 4F-MT-45 were synthesised and reference analytical data were reported. The in vitro and in vivo metabolisms of MT-45 and 2F-MT-45 were investigated. Method: The reference standards and seized sample were characterised using nuclear magnetic resonance spectroscopy, ultra-performance liquid chromatography–quadrupole time of flight mass spectrometry, gas chromatography–mass spectrometry, attenuated total reflectance-Fourier transform infrared spectroscopy and Raman spectroscopy. Presumptive tests were performed and physicochemical properties of the compounds determined. Metabolite identification studies using human liver microsomes, human hepatocytes, mouse hepatocytes and in vivo testing using mice were performed and identified MT-45 metabolites were confirmed in authentic human urine samples. Results: Metabolic pathways identified for MT-45 and 2F-MT-45 were N-dealkylation, hydroxylation and subsequent glucuronidation. The major MT-45 metabolites identified in human in vitro studies and in authenticated human urine were phase I metabolites and should be incorporated as analytical targets to existing toxicological screening methods. Phase II glucuronidated metabolites were present in much lower proportions. Conclusions: 2F-MT-45 has been detected in a seized tablet for the first time. The metabolite identification data provide useful urinary metabolite targets for forensic and clinical testing for MT-45 and allows screening of urine for 2F-MT-45 and its major metabolites to determine its prevalence in case work.

AB - Purpose: The detection of a novel psychoactive substance, 2F-MT-45, a fluorinated analogue of the synthetic opioid MT-45, was reported in a single seized tablet. MT-45, 2F-, 3F- and 4F-MT-45 were synthesised and reference analytical data were reported. The in vitro and in vivo metabolisms of MT-45 and 2F-MT-45 were investigated. Method: The reference standards and seized sample were characterised using nuclear magnetic resonance spectroscopy, ultra-performance liquid chromatography–quadrupole time of flight mass spectrometry, gas chromatography–mass spectrometry, attenuated total reflectance-Fourier transform infrared spectroscopy and Raman spectroscopy. Presumptive tests were performed and physicochemical properties of the compounds determined. Metabolite identification studies using human liver microsomes, human hepatocytes, mouse hepatocytes and in vivo testing using mice were performed and identified MT-45 metabolites were confirmed in authentic human urine samples. Results: Metabolic pathways identified for MT-45 and 2F-MT-45 were N-dealkylation, hydroxylation and subsequent glucuronidation. The major MT-45 metabolites identified in human in vitro studies and in authenticated human urine were phase I metabolites and should be incorporated as analytical targets to existing toxicological screening methods. Phase II glucuronidated metabolites were present in much lower proportions. Conclusions: 2F-MT-45 has been detected in a seized tablet for the first time. The metabolite identification data provide useful urinary metabolite targets for forensic and clinical testing for MT-45 and allows screening of urine for 2F-MT-45 and its major metabolites to determine its prevalence in case work.

KW - Novel psychoactive substances

KW - MT-45

KW - 2F-MT-45

KW - Metabolite profiles

KW - Forensic Toxicology

KW - Clinical Toxicology

KW - Synthetic Opioids

KW - analytical chemistry

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U2 - 10.1007/s11419-018-0413-1

DO - 10.1007/s11419-018-0413-1

M3 - Article

C2 - 29963206

VL - 36

SP - 359

EP - 374

JO - Forensic Toxicology

JF - Forensic Toxicology

SN - 1860-8965

IS - 2

ER -