Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity

Pinson, Anna; Yarbrough, Azure; Bush, John; Cabanlong, Christian V.; Shoeib, Amal; Jackson, Bailey; Fukuda, Saki; Gogoi, Jyoti; Fantegrossi, William E.; McCain, Keith R.; Prather, Paul L.; Fujiwara, Ryoichi; Radominska‐Pandya, Anna

doi:10.1016/j.pbb.2020.172949

Cited by 17 publications

(18 citation statements)

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“…Second, oxidative defluorination of 5F-APINACA yielded the loss of fluorine and addition of a hydroxyl group at the terminus of the N-pentyl group. Unfortunately, our attempts to obtain fragments other than the N-fluoropentyl indazole acylium ion ( m / z 233.0) were unsuccessful in line with observations by others [ 8 , 10 , 19 , 20 ].…”

Section: Resultssupporting

confidence: 56%

“…We characterized specific metabolites from 5F-APINACA reactions based on reported characteristic MS features [ 8 , 10 , 19 , 20 ]. First, loss of the adamantyl group ( m / z 153.1) is a dominant fragment ion for unmetabolized 5F-APINACA as well as its metabolites.…”

Section: Resultsmentioning

confidence: 99%

“…A later generation of the drug involved introduction of fluorine at the pentyl terminus, creating N -(1-adamantyl)-1-(5-pentyl)-1 H -indazole-3-carboxamide (5F-APINACA, also known as 5F-AKB48). The fluorine increases drug lipophilicity to increase drug distribution across the blood–brain barrier, and thus improve access and high-affinity [ 3 , 4 , 5 ] binding to cannabinoid type 1 receptors (CB1Rs) in the central nervous system, as shown by in vitro cell culture [ 3 , 6 ] and in vivo rodent studies [ 7 , 8 ]. Those qualities may facilitate the toxic effects such as nausea, vomiting, tachycardia, and occasionally death resulting from exposure [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…5F-APINACA undergoes extensive metabolism including oxidative defluorination of the N -pentyl group and hydroxylation of the adamantyl moiety. In vitro studies with human liver microsomes provide insights into the occurrence of those reactions and enzymes likely responsible for them [ 8 , 10 , 11 ]. Presence of the resulting metabolites in urine surveys from abusers provides clinical evidence for those specific metabolic pathways [ 10 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In following, prior research on 5F-APINACA metabolism identified possible metabolic pathways but not the relative significance of those steps. Kinetic studies provide a tractable approach to scale the efficiencies of reactions impacting drug structure and hence, potency and response; however, published microsomal studies for 5F-APINACA were not carried out under steady-state conditions [ 8 , 10 , 11 ], so the relative efficiencies of reaction steps and pathways, and thus their relevance remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Significance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics

et al. 2020

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In 2020, nearly one-third of new drugs on the global market were synthetic cannabinoids including the drug of abuse N-(1-adamantyl)-1-(5-pentyl)-1H-indazole-3-carboxamide (5F-APINACA, 5F-AKB48). Knowledge of 5F-APINACA metabolism provides a critical mechanistic basis to interpret and predict abuser outcomes. Prior qualitative studies identified which metabolic processes occur but not the order and extent of them and often relied on problematic “semi-quantitative” mass spectroscopic (MS) approaches. We capitalized on 5F-APINACA absorbance for quantitation while leveraging MS to characterize metabolite structures for measuring 5F-APINACA steady-state kinetics. We demonstrated the reliability of absorbance and not MS for inferring metabolite levels. Human liver microsomal reactions yielded eight metabolites by MS but only five by absorbance. Subsequent kinetic studies on primary and secondary metabolites revealed highly efficient mono- and dihydroxylation of the adamantyl group and much less efficient oxidative defluorination at the N-pentyl terminus. Based on regiospecificity and kinetics, we constructed pathways for competing and intersecting steps in 5F-APINACA metabolism. Overall efficiency for adamantyl oxidation was 17-fold higher than that for oxidative defluorination, showing significant bias in metabolic flux and subsequent metabolite profile compositions. Lastly, our analytical approach provides a powerful new strategy to more accurately assess metabolic kinetics for other understudied synthetic cannabinoids possessing the indazole chromophore.

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Significance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics

et al. 2020

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Enzymatic synthesis of fluorinated compounds

Cheng

2021

Appl Microbiol Biotechnol

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Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the introduction of fluorine atoms into organic compound molecules can give these compounds new functions and make them have better performance. Therefore, the synthesis of fluorides has attracted more and more attention from biologists and chemists. Even so, achieving selective fluorination is still a huge challenge under mild conditions. In this review, the research progress of enzymatic synthesis of fluorinated compounds is summarized since 2015, including cytochrome P450 enzymes, aldolases, fluoroacetyl coenzyme A thioesterases, lipases, transaminases, reductive aminases, purine nucleoside phosphorylases, polyketide synthases, fluoroacetate dehalogenases, tyrosine phenol-lyases, glycosidases, fluorinases, and multienzyme system. Of all enzyme-catalyzed synthesis methods, the direct formation of the C-F bond by fluorinase is the most effective and promising method. The structure and catalytic mechanism of fluorinase are introduced to understand fluorobiochemistry. Furthermore, the distribution, applications, and future development trends of fluorinated compounds are also outlined. Hopefully, this review will help researchers to understand the significance of enzymatic methods for the synthesis of fluorinated compounds and find or create excellent fluoride synthase in future research. Key points • Fluorinated compounds are distributed in plants and microorganisms, and are used in imaging, medicine, materials science . • Enzyme catalysis is essential for the synthesis of fluorinated compounds . • The loop structure of fluorinase is the key to forming the C-F bond . Supplementary Information The online version contains supplementary material available at 10.1007/s00253-021-11608-0.

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An Internet Snapshot Survey Assessing the sale of Synthetic Cannabinoid Receptor Agonists for use with Electronic Vaping Devices

Gould,

Dargan,

Wood

2024

J. Med. Toxicol.

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Introduction Synthetic cannabinoid receptor agonists (SCRAs) are associated with significant toxicity and are increasingly used in electronic vaping devices. We assessed the availability of SCRA vaping products to UK purchasers on the surface web. Methods An internet snapshot survey was performed between October 2022 and January 2023 on ‘google.com’ using the search terms “buy c-liquid vape”, “buy herbal incense vape liquid”, “buy cannabis vape liquid”, “buy hashish vape liquid”, “buy K2 vape liquid”. Results 62 websites selling 128 SCRA vaping brands were identified. Most were purportedly based in the USA (41 websites, 66%) and most sold other controlled substances. Purchase incentives offered included discreet packaging (38, 61%), discounts for bulk purchase (34, 55%) and tracked delivery (30, 48%). Many websites stated SCRA products were: not for human consumption (41, 66%), for research purposes only (15, 24%), or legal (28, 45%). Websites sold a median (IQR) of 16 (7–25) SCRA vaping brands. Almost all were bottles of vaping liquid (1220/1225, 99.6%). The most common bottle size was 5mL (60%), the median (IQR) total volume of SCRA liquid per sale was 50mL (10–200mL). Median (IQR) price was £3.39/mL (£2.01/mL– £5.29/mL). Price decreased with increasing volume purchased (£6.58/mL for ≤ 5mL, £1.60/mL for > 200mL). Conclusion SCRA vaping products are easily obtainable online, in both small and bulk quantities. Information provided to purchasers on safety and legality is lacking or misleading. Further studies are needed to confirm the chemistry of these products. Policymakers should consider steps to limit the potential harm caused by the purchase and use of these products.

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Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity

Cited by 17 publications

References 37 publications

Significance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics

Significance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics

Enzymatic synthesis of fluorinated compounds

An Internet Snapshot Survey Assessing the sale of Synthetic Cannabinoid Receptor Agonists for use with Electronic Vaping Devices

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