Synthetic cannabimimetic agents metabolized by carboxylesterases

Thomsen, Ragnar; Nielsen, Line Marie; Holm, Niels Bjerre; Rasmussen, Henrik Berg; Línnet, Kristían

doi:10.1002/dta.1731

Cited by 80 publications

(126 citation statements)

References 47 publications

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“…Terminal carboxamide hydrolysis, a reaction predominantly catalyzed by carboxylesterase 1 (29), yielded the most intense AB-PINACA metabolite at 1 and 3 h, AB-PINACA carboxylic acid (A23), with an absolute MS peak area 10 times higher than the second most intense metabolite A8 (Fig. 1a).…”

Section: Metabolites Generated By Carboxamide Hydrolysismentioning

confidence: 99%

“…Takayama et al incubated AB-PINACA with HLM and identified three hydroxylated metabolites (28), while Thomsen et al identified 10 metabolites in HLM, with AB-PINACA carboxylic acid as the major metabolite. The latter also identified carboxylesterase 1 (CES1) as the key enzyme for amide hydrolysis (29). No 5F-AB-PINACA metabolism data are available.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Metabolites Generated By Carboxamide Hydrolysismentioning

confidence: 99%

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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“…Major metabolites were identified which included monohydroxylated, dihydroxylated, trihydroxylated, and mono-and dihydroxylated glucuronide conjugates, and dihydroxylated with ketone formation at the N-pentyl side chain. 26 Thomsen et al 27 studied the metabolism of two indazole carboxamide derivatives, AB-PINACA and AB-FUBINACA, by incubation with human liver microsomes (HLM), and human pulmonary microsomes (HPM). The major metabolites were the carboxylic acid derivatives of both synthetic cannabinoids.…”

Section: Pharmacology and Toxicologymentioning

confidence: 99%

How Present Synthetic Cannabinoids Can Help Predict Symptoms in the Future

Mozayani¹

2016

MOJT

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Abbreviations: SCs, synthetic cannabinoids; Δ-9-THC, delta-9-tetrahydracannabinol; UHPLC, ultra high performance liquid chromatography; DAD, photodiode array; MS, mass spectrometry; GC, gas chromatography; DART, direct analysis in real time; TOF, time of flight spectrometry; NMR, nuclear magnetic resonance; ATR, attenuated total resonance; FTIR, fourier transform infrared spectrometry; TIC, total ion chromatogram; LC-MS/MS, liquid chromatography tandem mass spectrometry; CNS, central nervous system; LOD, limit of detection; LOQ, limit of quantitation; ULOL, upper limit of linearity; DUID, driving under the influence of drug; HLM, human liver microsomes; HPM, human pulmonary microsomes; CES 1, carboxylesterase 1 IntroductionSynthetic cannabinoids (SCs) are synthetic compounds sprayed on herbal products and have spread worldwide since 2004. Many of these compounds, more specifically l-valinamides and l-tert-leucinamides, are often characterized as part of the third, fourth and fifth generation of synthetic cannabinoids. There are many street names for herbal like compounds which are sprayed with these compounds, referred to as "Spice" such as Spice Diamond, Spice Gold, Spice Arctic Energy, Magic, Voodoo and Yucatan Fire. Such drugs are easily obtainable via the Internet, in smoke shops, and street markets. To evade law enforcement, these herbal incense products are often labeled "not for human consumption". Despite this, many countries have entered many synthetic cannabinoids to schedule 1. 1,2Initial reports of synthetic cannabinoids (SCs) in Unites States were in November 2008. In December 2008, German forensic laboratories initially identified JWH-018 and cannabicyclohexanol (CP-47,497 C8 homologue). The synthetic cannabinoids are frequently applied on plant material and inhaled. In January 2010, the popularity of these cannabinoids and their associated products appeared to have increased in the United States.3 Numerous SCs have been identified as adulterants, which have been seized by law enforcement. JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologues were the first SCs identified as being abused. New generations of synthetic cannabinoids quickly emerged to evade law enforcement. After various laws were passed in the United States, different generations of SCs emerged varying only by slight modifications in structure. Some recent SCs include AB-CHMINACA and AB-PINACA. These substances are commonly marketed under the guise of being a ''legal high'' with a disclaimer of ''not for human consumption''. Law enforcement, public health officials, and clinicians are encountering cases in which there has been abuse of these substances, 4 requiring up to date information of the drug legislation, chemistry of the compounds and their detection, as well as the toxicology to be able to help identify these compounds when they present clinically.After the passage of the Synthetic Drug Abuse Prevent Act of 2012 in the United States, a third and fourth generation of SCs including UR-144, XLR11, and AKB-48 emerged...

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“…Moreover, Takayama et al [2014] incubated several substrates including AB‐FUBINACA with human liver microsomes, which yielded one mono‐hydroxylated metabolite. Thomsen et al [2015] did the similar experiment incubated several substrates including AB‐FUBINACA with human liver microsomes. The discovered that using AB‐FUBINACA substrate yield three product ions at m/z 109, 253, and 324; these are mono‐ and di‐ hydroxylation derivatives.…”

Section: Discussionmentioning

confidence: 99%

“…Although there are no specific references to the name AB‐FUBINACA, the patent describes 523 analogues with C 20 H 21 FN 4 O 2 references to AB‐FUBINACA as “Example 2”. In vitro data shows that this compound is a very potent ligand for the cannabinoid (CB1) receptor, with a binding constant of 0.9 nM and an EC 50 of 23.2 nM for receptor activation as measured by GTPγS hydrolysis [Thomsen et al, 2015]. By 2012, AB‐FUBINACA was found in blended herbal products in Japan, Europe, and the United States.…”

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confidence: 99%

Detection and Characterization of the Effect of AB‐FUBINACA and Its Metabolites in a Rat Model

Chen

Dip

Ahmed

et al. 2015

J of Cellular Biochemistry

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Synthetic cannabinoids were originally developed by academic and pharmaceutical laboratories with the hope of providing therapeutic relief from the pain of inflammatory and degenerative diseases. However, recreational drug enthusiasts have flushed the market with new strains of these potent drugs that evade detection yet endanger public health and safety. Although many of these drug derivatives were published in the medical literature, others were merely patented without further characterization. AB‐FUBINACA is an example of one of the new indazole‐carboxamide synthetic cannabinoids introduced in the past year. Even though AB‐FUBINACA has become increasingly prominent in forensic drug and toxicology specimens analyses, little is known about the pharmacology of this substance. To study its metabolic fate, we utilized Wistar rats to study the oxidative products of AB‐FUBINACA in urine and its effect on gene expressions in liver and heart. Rats were injected with 5 mg/kg of AB‐FUBINACA each day for 5 days. Urine samples were collected every day at the same time. On day 5 after treatment, we collected the organs such as liver and heart. The urine samples were analyzed by mass spectrometry, which revealed several putative metabolites and positioning of the hydroxyl addition on the molecule. We used quantitative PCR gene expression array to analyze the hepatotoxicity and cardiotoxicity on these rats and confirmed by real‐time quantitative RT‐PCR. We identified three genes significantly associated with dysfunction of oxidation and inflammation. Our study reports in vivo metabolites of AB‐FUBINACA in urine and its effect on the gene expressions in liver and heart. J. Cell. Biochem. 117: 1033–1043, 2016. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals. Inc.

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Synthetic cannabimimetic agents metabolized by carboxylesterases

Cited by 80 publications

References 47 publications

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

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

How Present Synthetic Cannabinoids Can Help Predict Symptoms in the Future

Detection and Characterization of the Effect of AB‐FUBINACA and Its Metabolites in a Rat Model

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