Metabolism study for CUMYL‐4CN‐BINACA in human hepatocytes and authentic urine specimens: Free cyanide is formed during the main metabolic pathway

Åstrand, Anna; Vikingsson, Svante; Lindstedt, Daniel; Thelander, Gunilla; Henrik, Green; Kronstrand, Robert; Wohlfarth, Ariane

doi:10.1002/dta.2373

Cited by 16 publications

(7 citation statements)

References 10 publications

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“…In some cases, the metabolite exhibits toxicity not observed with the parent (Couceiro et al, 2016). Further, toxicity may not even involve cannabinoid receptor mechanisms, as metabolism of CUMYL-4CN-BINACA has been reported to liberate cyanide (Åstrand et al, 2018;Kevin et al, 2018). Thus synthetic cannabinoids could produce toxicity by a multitude of ways.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Gamage

Farquhar

McKinnie

et al. 2018

J Pharmacol Exp Ther

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Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. Although the structural bases of these compounds are scaffolds with known affinity and efficacy at the human cannabinoid type-1 receptor (hCB 1 ), upon ingestion or inhalation they can be metabolized to multiple chemical entities of unknown pharmacological activity. A large proportion of these metabolites are hydroxylated on the pentyl chain, a key substituent that determines receptor affinity and selectivity. Thus, the pharmacology of SC metabolites may be an important component in understanding the in vivo effects of SCs. We examined nine SCs (AB-PINACA, 5F-AB-PINACA, ADB/MDMB-PINACA, 5F-ADB, 5F-CUMYL-PINACA, AMB-PINACA, 5F-AMB, APINACA, and 5F-APINACA) and their hydroxypentyl (either 4-OH or 5-OH) metabolites in [ 3 H]CP55,940 receptor binding and the [ 35 S] GTPgS functional assay to determine the extent to which these metabolites retain activity at cannabinoid receptors. All of the SCs tested exhibited high affinity (,10 nM) and efficacy for hCB 1 and hCB 2 . The majority of the hydroxypentyl metabolites retained full efficacy at hCB 1 and hCB 2 , albeit with reduced affinity and potency, and exhibited greater binding selectivity for hCB 2 . These data suggest that phase I metabolites may be contributing to the in vivo pharmacology and toxicology of abused SCs. Considering this and previous reports demonstrating that metabolites retain efficacy at the hCB 1 receptor, the full pharmacokinetic profiles of the parent compounds and their metabolites need to be considered in terms of the pharmacological effects and time course associated with these drugs.

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Section: Discussionmentioning

confidence: 99%

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Gamage

Farquhar

McKinnie

et al. 2018

J Pharmacol Exp Ther

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“…A nitrile group occurs in more than 30 approved pharmaceuticals; commonly as an aromatic nitrile, but less commonly as an aliphatic nitrile since the latter may release cyanide in vivo (Tanii and Hashimoto, 1984). Indeed, CUMYL-4CN-BINACA undergoes apparent metabolic nitrile hydrolysis, which may contribute to toxicity including renal failure (Åstrand et al, 2018; El Zahran et al, 2019). AM-2232 ( 3 ) is an analogue of the historically prevalent SCRA AM-2201 ( 4 ) described in a patent granted to Makriyannis and Deng (2001), and featuring a terminal nitrile group, that was previously detected in the German NPS market (Langer et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

et al. 2019

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Synthetic cannabinoid receptor agonists (SCRAs) are the largest class of new psychoactive substances (NPS). New examples are detected constantly, and some are associated with a series of adverse effects, including seizures. CUMYL-4CN-BINACA (1-(4-cyanobutyl)- N -(2-phenylpropan-2-yl)indazole-3-carboxamide) is structurally related to potent, cumylamine-derived SCRAs such as 5F-CUMYL-PINACA, but is unusual due to a terminal aliphatic nitrile group not frequently encountered in SCRAs or pharmaceuticals. We report here that CUMYL-4CN-BINACA is a potent CB 1 receptor agonist ( K i = 2.6 nM; EC 50 = 0.58 nM) that produces pro-convulsant effects in mice at a lower dose than reported for any SCRA to date (0.3 mg/kg, i.p). Hypothermic and pro-convulsant effects in mice could be reduced or blocked, respectively, by pretreatment with CB 1 receptor antagonist SR141716, pointing to at least partial involvement of CB 1 receptors in vivo . Pretreatment with CB2 receptor antagonist AM-630 had no effect on pro-convulsant activity. The pro-convulsant properties and potency of CUMYL-4CN-BINACA may underpin the toxicity associated with this compound in humans.

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“…Recently, a standard flow (>100 µL min −1 ) ion thermal focusing electrospray ionization (AJS‐ESI) source has been developed which improves desolvation and spatial focusing of ions when coupled with ion funnel technology, thereby increasing ion transfer into the mass spectrometer . This ion source has been used to perform a series of metabolomic and lipidomic studies . However, implementation for proteomics has been limited and includes only studies of Escherichia Coli and Arabidopsis thaliana .…”

Section: Introductionmentioning

confidence: 99%

Quantitative, Label‐Free Proteomics in the Symptomatic Niemann–Pick, Type C1 Mouse Model Using Standard Flow Liquid Chromatography and Thermal Focusing Electrospray Ionization

et al. 2019

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Niemann–Pick disease, type C1 (NPC1) is a fatal, autosomal recessive, neurodegenerative disorder caused by mutations in the NPC1 gene. As a result, there is accumulation of unesterified cholesterol and sphingolipids in the late endosomal/lysosomal system. This abnormal accumulation results in a cascade of pathophysiological events including progressive, cerebellar neurodegeneration, among others. While significant progress has been made to better understand NPC1, the downstream effects of cholesterol storage and the major mechanisms that drive neurodegeneration remain unclear. In the current study, a) the use of a commercial, highly efficient standard flow‐ESI platform for protein biomarker identification is implemented and b) protein biomarkers are identified and evaluated at a terminal time point in the NPC1 null mouse model. In this study, alterations are observed in proteins related to fatty acid homeostasis, calcium binding and regulation, lysosomal regulation, and inositol biosynthesis and metabolism, as well as signaling by Rho family GTPases. New observations from this study include altered expression of Pcp2 and Limp2 in Npc1 mutant mice relative to control, with Pcp2 exhibiting multiple isoforms and specific to the cerebella. This study provides valuable insight into pathways altered in the late‐stage pathophysiology of NPC1.

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Metabolism study for CUMYL‐4CN‐BINACA in human hepatocytes and authentic urine specimens: Free cyanide is formed during the main metabolic pathway

Cited by 16 publications

References 10 publications

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

Quantitative, Label‐Free Proteomics in the Symptomatic Niemann–Pick, Type C1 Mouse Model Using Standard Flow Liquid Chromatography and Thermal Focusing Electrospray Ionization

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