Characteristics of the designer drug and synthetic cannabinoid receptor agonist AM‐2201 regarding its chemistry and metabolism

Hutter, Melanie; Moosmann, Bjoern; Kneisel, Stefan; Auwärter, Volker

doi:10.1002/jms.3229

Cited by 96 publications

(130 citation statements)

References 56 publications

(78 reference statements)

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“…Of note, 4Ј-OH-THJ-018 (THJ-018 specific) and 5Ј-OH-THJ-018 (shared) possessed similar physicochemical properties, making complete chromatographic separation challenging. However, chromatographic resolution of these 2 THJ-018 hydroxypentyl isomers might be important for distinguishing THJ-018 and THJ-2201 intake, similar to observations for JWH-018 and AM-2201 (14,16,37 ). THJ-2201 produced abundant 5Ј-OH-THJ-018 and no 4Ј-OH-THJ-018, whereas THJ-018 THJ-018 and THJ-2201 Metabolic Profile in Hepatocytes produced comparable amounts of 4Ј-OH-THJ-018 and 5Ј-OH-THJ-018.…”

Section: Specific Markers For Documenting Thj-018 and Thj-2201 Intakesupporting

confidence: 63%

“…Likewise, no indazole-hydroxylated metabolites were observed for AKB-48 and AB-PINACA (19,34 ). Both AM-2201 and THJ-2201 underwent oxidative defluorination with subsequent carboxylation and glucuronidation (11,16 ). Surprisingly, an uncommon pathway was observed for THJ-2201, i.e., glucuronidation after N-oxidation (F16).…”

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 99%

“…Major hydroxylated JWH-018 and AM-2201 metabolites such as 4Ј-OH-JWH-018, 5Ј-OH-JWH-018, and 4Ј-OH-AM-2201 remained full agonists at nanomolar concentrations (11,16 ). Because of structural similarity, high binding affinity and activity can be expected for hydroxypentyl THJ-018 and THJ-2201 metabolites, which may prolong or even enhance the adverse effects of THJ-018 and THJ-2201.…”

Section: Specific Markers For Documenting Thj-018 and Thj-2201 Intakementioning

confidence: 99%

“…JWH-018 undergoes monohydroxylation on the naphthalene, indole, and pentyl chain, as well as carboxylation (14,15 ). In contrast, AM-2201 primarily undergoes oxidative defluorination and subsequent carboxylation (12,16 ).…”

mentioning

confidence: 99%

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High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

Diao

Wohlfarth

Pang³

et al. 2016

Clinical Chemistry

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BACKGROUND Despite increasing prevalence of novel psychoactive substances, no human metabolism data are currently available, complicating laboratory documentation of intake in urine samples and assessment of the drugs' pharmacodynamic, pharmacokinetic, and toxicological properties. In 2014, THJ-018 and THJ-2201, synthetic cannabinoid indazole analogs of JWH-018 and AM-2201, were identified, with the National Forensic Laboratory Information System containing 220 THJ-2201 reports. Because of numerous adverse events, the Drug Enforcement Administration listed THJ-2201 as Schedule I in January 2015. METHODS We used high-resolution mass spectrometry (HR-MS) (TripleTOF 5600+) to identify optimal metabolite markers after incubating 10 μmol/L THJ-018 and THJ-2201 in human hepatocytes for 3 h. Data were acquired via full scan and information-dependent acquisition triggered product ion scans with mass defect filter. In silico metabolite predictions were performed with MetaSite and compared with metabolites identified in human hepatocytes. RESULTS Thirteen THJ-018 metabolites were detected, with the major metabolic pathways being hydroxylation on the N-pentyl chain and further oxidation or glucuronidation. For THJ-2201, 27 metabolites were observed, predominantly oxidative defluorination plus subsequent carboxylation or glucuronidation, and glucuronidation of hydroxylated metabolites. Dihydrodiol formation on the naphthalene moiety was observed for both compounds. MetaSite prediction matched well with THJ-018 hepatocyte metabolites but underestimated THJ-2201 oxidative defluorination. CONCLUSIONS With HR-MS for data acquisition and processing, we characterized THJ-018 and THJ-2201 metabolism in human hepatocytes and suggest appropriate markers for laboratories to identify THJ-018 and THJ-2201 intake and link observed adverse events to these new synthetic cannabinoids.

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Section: Specific Markers For Documenting Thj-018 and Thj-2201 Intakesupporting

confidence: 63%

Section: Thj-018 and Thj-2201 Metabolism Compared With Jwh-018 And Ammentioning

confidence: 99%

Section: Specific Markers For Documenting Thj-018 and Thj-2201 Intakementioning

confidence: 99%

mentioning

confidence: 99%

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High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

Diao

Wohlfarth

Pang³

et al. 2016

Clinical Chemistry

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“…Further, it is necessary to identify the most prevalent metabolites for synthesis of reference standards for analytical method development. Since the first appearance of synthetic cannabinoids, many metabolism studies with human liver microsomes (HLM), human hepatocytes, and/or authentic specimens elucidated their metabolic pathways (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

Wohlfarth

Castaneto

Zhu

et al. 2015

AAPS J

144

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Abstract. Whereas non-fluoropentylindole/indazole synthetic cannabinoids appear to be metabolized preferably at the pentyl chain though without clear preference for one specific position, their 5-fluoro analogs' major metabolites usually are 5-hydroxypentyl and pentanoic acid metabolites. We determined metabolic stability and metabolites of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) and 5-fluoro-AB-PINACA (5F-AB-PINACA), two new synthetic cannabinoids, and investigated if results were similar. In silico prediction was performed with MetaSite (Molecular Discovery). For metabolic stability, 1 μmol/L of each compound was incubated with human liver microsomes for up to 1 h, and for metabolite profiling, 10 μmol/L was incubated with pooled human hepatocytes for up to 3 h. Also, authentic urine specimens from AB-PINACA cases were hydrolyzed and extracted. All samples were analyzed by liquid chromatography high-resolution mass spectrometry on a TripleTOF 5600+ (AB SCIEX) with gradient elution (0.1% formic acid in water and acetonitrile). High-resolution full-scan mass spectrometry (MS) and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot (AB SCIEX) using different data processing algorithms. Both drugs had intermediate clearance. We identified 23 AB-PINACA metabolites, generated by carboxamide hydrolysis, hydroxylation, ketone formation, carboxylation, epoxide formation with subsequent hydrolysis, or reaction combinations. We identified 18 5F-AB-PINACA metabolites, generated by the same biotransformations and oxidative defluorination producing 5-hydroxypentyl and pentanoic acid metabolites shared with AB-PINACA. Authentic urine specimens documented presence of these metabolites. AB-PINACA and 5F-AB-PINACA produced suggested metabolite patterns. AB-PINACA was predominantly hydrolyzed to AB-PINACA carboxylic acid, carbonyl-AB-PINACA, and hydroxypentyl AB-PINACA, likely in 4-position. The most intense 5F-AB-PINACA metabolites were AB-PINACA pentanoic acid and 5-hydroxypentyl-AB-PINACA.

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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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Characteristics of the designer drug and synthetic cannabinoid receptor agonist AM‐2201 regarding its chemistry and metabolism

Cited by 96 publications

References 56 publications

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes

Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA

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

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