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The N -butyl indazole derivative, N -(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-butyl-1H-indazole-3-carboxamide (ADB-BUTINACA or ADB-BINACA), currently a drug of abuse in Russia, is reported to have a cannabinoid receptor potency and efficacy almost three times higher than JWH-018. ADB-BUTINACA was detected in blood from patients with suspected drug intoxications, as well as in blood, kidney and liver samples collected during postmortem investigations. Using liquid chromatography–time-of-flight–mass spectrometry, a number of ADB-BUTINACA metabolites were tentatively identified in urine samples. These include products of mono- and dihydroxylation, hydroxylation of the N-butyl side chain and dehydrogenation, formation of a dihydrodiol, hydrolysis of the terminal amide group, N-dealkylation of the indazole and a combination of these reactions. The dihydrodiol was found to be the predominant metabolite, with its chromatographic peak area exceeding those of other metabolites by almost an order of magnitude. For the routine analysis of blood, liver and kidney samples, the dihydrodiol and monohydroxylated metabolites along with the parent compound are recommended as target analytes. The same metabolites in free and glucuronidated forms are also recommended for analytical confirmation in urine samples. [ABSTRACT FROM AUTHOR]

Synthetic cannabinoids (SCs), mimicking the psychoactive effects of cannabis, consist of a vast array of structurally diverse compounds. A novel compound belonging to the SC family, (1‐(cyclohexylmethyl)‐1H‐indol‐3‐yl)‐(2,2,3,3‐tetramethylcyclopropyl)methanone (named TMCP‐CHM in this article) contains a cyclopropane ring that isomerizes during the smoking process, resulting in a ring‐opened thermal degradant with a terminal double bond in its structure. Metabolites of TMCP‐CHM were tentatively identified in vitro (after incubation of the parent substance with S9 pooled human liver fraction) and in vivo (rat experimental model) studies by accurate‐mass liquid chromatography–tandem mass spectrometry (LC–MS/MS). For the identification of the degradant metabolites, and to study biotransformation of parent substance in the human, urine and hair samples from patients, who had ingested the compound and were subsequently admitted to hospital with drug intoxications, were analyzed. Products of mono‐, di‐, trihydroxylation, carboxylation, and carboxylation combined with hydroxylation of TMCP‐CHM and its degradant were detected in human urine. Metabolism of the degradant included addition of water to the terminal double bond followed by dehydration and formation of a cyclic metabolite. Degradant metabolites prevailed in comparison with metabolites of the parent substance in each metabolite group examined, except carboxylation. N‐Dealkylated metabolites found in human urine originated only from the degradant. Most of the hydroxy metabolites were detected in human urine in both the free form and as glucuronides. The detection of monohydroxylated (M1.1‐M1.3, M/A1.10) and carboxylated/hydroxylated (M4.2, M/A4.3) metabolites of TMCP‐CHM and the hydrated form of the monohydroxylated metabolite of the degradant was found to be convenient for routine analysis. [ABSTRACT FROM AUTHOR]

A number of metabolites of a new synthetic cannabimimetic, which is a derivative of 2-(1-(cyclohexylmethyl)-1 H-indole-3-carboxamido)-3,3-dimethylbutanoic acid, were identified in human urine. The parent compound, a methyl ester of this acid, was identified in seizures in persons from the same city where analysis of drug-intoxication urine samples revealed the presence of the compound's metabolites. This compound named 'MDMB-CHMICA' was reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) in 2014. Hydrolysis of the ester was found to be the main metabolic pathway followed by mono-, di- and tri-hydroxylation, ketone formation, ketone formation with monohydroxylation, dealkylation, and dealkylation combined with hydroxylation. Additionally, the products by internal dehydration of hydroxylated forms with lactone formation were detected. Mono-hydroxylated metabolites were detected from their glucuronidated forms. Identification of metabolites was made on the basis of gas chromatography-mass spectrometry and liquid chromatography with time-of-flight mass spectrometry and ion trap mass spectrometry. To our knowledge, this is the first report on the metabolites of MBDB-CHMICA in human urine. [ABSTRACT FROM AUTHOR]

Studies on the pyrolysis of the synthetic cannabinoid agonist UR-144 ((1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone) have shown that its major pyrolysis product is a tetramethylcyclopropane ring-opened alkene. Considering that smoking is a common way of ingesting synthetic cannabimimetics, the presence of the metabolites of this pyrolysis product would be expected in biological fluids. Using GC-MS and LC–MS-MS methods, a series of phase I metabolites of UR-144 and its pyrolysis product were detected in the urine samples from patients admitted to hospital with suspected drug intoxication. The metabolites were tentatively identified as the products of mono-hydroxylation, di-hydroxylation, mono-hydroxylation with formation of the carbonyl group on the N-alkyl chain, carboxylation and N-dealkylation with mono-hydroxylation. In the case of the UR-144 pyrolysis product, metabolites with hydration of the aliphatic double bond were also identified. The parent compounds were detected as trace amounts in some urine samples, and the hydrated derivative of the UR-144 pyrolysis product was detected in the majority of samples. The detection of mono-hydroxylated metabolites of UR-144 (LC–MS-MS) and mono-hydroxylated/with hydration metabolites of the UR-144 pyrolysis product (GC-MS) was found to be the most useful method of establishing UR-144 ingestion. [ABSTRACT FROM AUTHOR]

AM-694 (1-[(5-fluoropentyl)-1 H-indol-3-yl]-(2-iodophenyl)methanone), a synthetic indole-based cannabimimetic, was first reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) by Irish authorities in 2010. Using gas chromatography-mass spectrometry (GC-MS), we have identified six AM-694 metabolites in post-ingestion samples. The metabolites were tentatively identified as products of (1) hydrolytic defluorination, (2) carboxylation, (3) monohydroxylation of N-alkyl chain, and (4) hydrolytic defluorination combined with monohydroxylation of N-alkyl chain. The parent compound was not detected. The excretion of major metabolites was observed up to 117 h following administration. One metabolite (a product of hydrolytic defluorination) was also identified in urine samples from two individuals admitted to hospital suffering from suspected drug overdoses. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

3-[(Adamantan-1-yl)carbonyl]-1-pentylindole (AB-001), a synthetic cannabimimetic, was identified in head shop products in Ireland in 2010. German authorities also reported it to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) in 2011. As indole-derived cannabimimetics, such as JWH-018, JWH-073, and JWH-250, undergo extensive metabolism, it was expected that AB-001 would behave similarly. To include it in our toxicological screening protocols, we have identified its urinary metabolites in humans following oral administration. The major metabolites were found to be adamantane mono-hydroxylated and adamantane mono-hydroxylated/ N-dealkylated products. No parent compound was found in urine, and metabolites were detectable for up to 160 h following administration. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

2-Benzylbenzimidazole derivatives comprise a small but forensically significant group of synthetic opioids. In humans, the metabolism of some members of this group is extensive, with little or none of the parent compound remaining. The recent detection of the 2-benzylbenzimidazole derivative, etazene (etodesnitazene), in products seized in Russia required the detection of its metabolites in biofluids for forensic toxicology purposes. Using gas chromatography--mass spectrometry (GC-MS) and high resolution accurate mass (HRAM) liquid chromatography-mass spectrometry (LC-MS), eight etazene metabolites were found in the urine and serum of rats. These were tentatively identified as products of N-deethylation, O-deethylation, hydroxylation or N-oxidation of benzimidazole moiety and combinations of these processes. The parent substance and its O-deethylated metabolite prevailed in rat serum, while in urine, the level of etazene was low compared to N,O-deethylated and N-deethylated with hydroxylation metabolites. Glucuronidated, sulfonated and glutathionated forms were not found. Taking into account reports on the study of the metabolism of other 2-benzylbenzimidazole derivatives in humans, it may be concluded that the mono-deethylated and mono-hydroxylated metabolites are suitable as target analytes in urine., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

3-(4-Methoxybenzoyl)-1-pentylindole (RCS-4), a synthetic indole-derived cannabimimetic, was first reported to the European Monitoring Centre for Drugs and Drug Addiction via the Early Warning System by Hungarian authorities in 2010 and later identified in head shop test purchases in Ireland. Using gas chromatography-mass spectrometry, we have identified a series of RCS-4 metabolites in urine samples from individuals admitted to hospitals with symptoms of drug intoxication. The metabolites were tentatively identified as products of (i) aromatic monohydroxylation; (ii) dihydroxylation; (iii) aromatic hydroxylation/oxidation of the N-pentyl chain to a ketone; (iv) O-demethylation; (v) O-demethylation/monohydroxylation of N-pentyl chain; (vi) O-demethylation/oxidation of the N-pentyl chain to a ketone; (vii) O-demethylation/aromatic hydroxylation/oxidation of the N-pentyl chain to a ketone; (viii) N-depentylation/aromatic monohydroxylation; and (ix) N and O-dealkylation. The parent compound was not detected. The O-demethylated metabolites were found to be the most useful metabolic markers for the identification of RCS-4 ingestion.