Structure-metabolism relationships of valine and tert-leucine-derived synthetic cannabinoid receptor agonists: a systematic comparison of the in vitro phase I metabolism using pooled human liver microsomes and high-resolution mass spectrometry

Franz, Florian; Jechle, Hanna; Wilde, Maurice; Angerer, Verena; Huppertz, Laura M.; Longworth, Mitchell; Kassiou, Michael; Jung, Manfred; Auwärter, Volker

doi:10.1007/s11419-018-00462-x

Cited by 26 publications

(48 citation statements)

References 29 publications

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“…The metabolism of many synthetic cannabinoids has been determined via HLM incubations . The findings reported in the current study contributes to the body of knowledge available on indazole carboxamide synthetic cannabinoid metabolism via HLM incubations.…”

Section: Discussionsupporting

confidence: 58%

“…CHM‐hydroxylated MDMB‐CHMINACA metabolites are specific to this synthetic cannabinoid and allow for discrimination between metabolites of structurally related analogs. The primary biotransformations of MDMB‐CHMINACA reported in the current study are consistent with those recently presented by Franz et al The authors reported monohydroxylation of the CHM moiety and ester hydrolysis as the major metabolic pathways. In addition to these biotransformations, a number of others were identified and reported in the present study.…”

Section: Discussionmentioning

confidence: 99%

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In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB‐CHMINACA via human liver microsome incubation and high‐resolution mass spectrometry

Presley

Logan

Jansen‐Varnum

2019

Drug Testing and Analysis

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Synthetic cannabinoids have proliferated over the last decade and have become a major public health and analytical challenge, critically impacting the clinical and forensic communities. Indazole carboxamide class synthetic cannabinoids have been particularly rampant, and exhibit severe toxic effects upon consumption due to their high binding affinity and potency at the cannabinoid receptors (CB1 and CB2). MDMB‐CHMINACA, methyl 2‐[1‐(cyclohexylmethyl)‐1H‐indazole‐3‐carboxamido]‐3,3‐dimethylbutanoate, a compound of this chemical class, has been identified in forensic casework and is structurally related to several other synthetic cannabinoids. This study presents the first extensive report on the Phase I metabolic profile of MDMB‐CHMINACA, a potent synthetic cannabinoid. The in vitro metabolism of MDMB‐CHMINACA was determined via incubation with human liver microsomes and high‐resolution mass spectrometry. The accurate masses of precursor and fragments, mass error (ppm), and chemical formula were obtained for each metabolite. Twenty‐seven metabolites were identified, encompassing twelve metabolite types. The major biotransformations observed were hydroxylation and ester hydrolysis. Hydroxylations were located predominantly on the cyclohexylmethyl (CHM) moiety. Ester hydrolysis was followed by additional biotransformations, including dehydrogenation; mono‐ and dihydroxylation and ketone formation, each with dehydrogenation. Minor metabolites were identified and reported. The authors propose that CHM‐monohydroxylated metabolites specific to MDMB‐CHMINACA are the most suitable candidates for implementation into bioanalytical assays to demonstrate consumption of this synthetic cannabinoid. Due to the structural similarity of MDMB‐CHMINACA and currently trending synthetic cannabinoids whose metabolic profiles have not been reported, the results of this study can be used as a guide to predict their metabolic pathways.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB‐CHMINACA via human liver microsome incubation and high‐resolution mass spectrometry

Presley

Logan

Jansen‐Varnum

2019

Drug Testing and Analysis

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“…The metabolic profiles of several indole carboxamide synthetic cannabinoids possessing fluoropentyl side chains have been reported by Franz et al (). These include 5F‐AB‐PICA, 5F‐ADB‐PICA, 5F‐AMB‐PICA, and 5F‐MDMB‐PICA.…”

Section: Discussionmentioning

confidence: 79%

Phase I metabolism of synthetic cannabinoid receptor agonist PX‐1 (5F‐APP‐PICA) via incubation with human liver microsomes and UHPLC–HRMS

Presley

Logan

Jansen‐Varnum

2020

Biomedical Chromatography

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Studies of the metabolic and pharmacological profiles of indole carboxamide synthetic cannabinoids (a prevalent class of new psychoactive substances) are critical in ensuring that their use can be detected through bioanalytical testing. We have determined the in vitro Phase I metabolism of one such compound, PX‐1 (5F‐APP‐PICA), and appropriate markers to demonstrate human consumption. PX‐1 was incubated with human liver microsomes, followed by analysis of the extracts via high‐resolution mass spectrometry. A total of 10 metabolites were identified, with simultaneous defluorination and monohydroxylation of the pentyl side chain as the primary biotransformation product (M1). Additional metabolites formed were hydroxylation products of the indole and benzyl moieties, distal amide hydrolysis, N‐desfluoropentyl, and carboxypentyl metabolites. Three monohydroxylated metabolites specific to PX‐1 were identified and are reported for the first time in this study. The primary metabolite, M1, was further oxidized to M5, a carboxypentyl metabolite. M8 is PX‐1 specific, possessing an intact fluoropentyl side chain. These three metabolites are the most suitable for implementation into bioanalytical assays for demonstrating PX‐1 consumption. The findings of this study can be used by analytical scientists and medical professionals to determine PX‐1 ingestion and predict the metabolites of synthetic cannabinoids sharing structural elements.

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“…The metabolism of MMB‐FUBINACA , 5F‐MDMB‐PINACA , and 5F‐MDMB‐PICA , synthetic cannabinoids structurally similar to 4F‐MDMB‐BINACA, has been previously reported. These studies have identified several metabolites, but the prominent metabolite in each study was formed by ester hydrolysis.…”

mentioning

confidence: 80%

4F‐MDMB‐BINACA: A New Synthetic Cannabinoid Widely Implicated in Forensic Casework

Krotulski

Mohr

Kacinko³

et al. 2019

Journal of Forensic Sciences

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This is the first report regarding the characterization of the new synthetic cannabinoid 4F‐MDMB‐BINACA. 4F‐MDMB‐BINACA was first analytically confirmed in seized drug material using gas chromatography–mass spectrometry (GC‐MS), liquid chromatography–quadrupole time‐of‐flight mass spectrometry (LC‐QTOF), and nuclear magnetic resonance (NMR) spectroscopy. Subsequent to this characterization, 4F‐MDMB‐BINACA was detected in biological specimens collected as part of forensically relevant casework, including medicolegal death investigations and drug impaired driving investigations, from a variety of regions in the United States. Further analysis of biological specimens resulted in the identification of the metabolites 4F‐MDMB‐BINACA 3,3‐dimethylbutanoic acid and 4‐OH‐MDMB‐BINACA. 4F‐MDMB‐BINACA is appearing with increasing frequency as a contributory factor in deaths, creating morbidity and mortality risks for drug users. Laboratories must be aware of its presence and impact, incorporating 4F‐MDMB‐BINACA into workflows for detection and confirmation.

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Structure-metabolism relationships of valine and tert-leucine-derived synthetic cannabinoid receptor agonists: a systematic comparison of the in vitro phase I metabolism using pooled human liver microsomes and high-resolution mass spectrometry

Cited by 26 publications

References 29 publications

In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB‐CHMINACA via human liver microsome incubation and high‐resolution mass spectrometry

In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB‐CHMINACA via human liver microsome incubation and high‐resolution mass spectrometry

Phase I metabolism of synthetic cannabinoid receptor agonist PX‐1 (5F‐APP‐PICA) via incubation with human liver microsomes and UHPLC–HRMS

4F‐MDMB‐BINACA: A New Synthetic Cannabinoid Widely Implicated in Forensic Casework

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