Identifying cytochrome P450s involved in oxidative metabolism of synthetic cannabinoid <i>N</i>‐(adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1<i>H</i>‐indole‐3‐carboxamide (STS‐135)

Jones, Stanley; Yarbrough, Azure; Fantegrossi, William E.; Prather, Paul L.; Bush, John; Radominska‐Pandya, Anna; Fujiwara, Ryoichi

doi:10.1002/prp2.561

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…Whilst the number of substances detected by toxicology in SCRA-related decedents dramatically increased from 2012 to 2019, evidence for SCRA drug-drug interactions remains scarce. Studies indicate that some SCRA types interact with cytochrome P450 pathways, which may negatively impact the pharmacodynamics of other co-administered substances leading to adverse events (61)(62)(63)(64)(65)(66)(67)(68)(69)(70). However, these studies used older SCRA types, which differ substantially in terms of molecular structure to those which are currently prevalently used (42).…”

Section: Knowledge Of Scra-disease/drug Interactions Is Scarcementioning

confidence: 99%

Synthetic Cannabinoid-Related Deaths in England, 2012–2019

Yoganathan

Claridge

Chester

et al. 2022

Cannabis and Cannabinoid Research

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Instruments to conduct in vivo electrophysiology and imaging experiments. CSC sits on the Novel Psychoactive Substances sub-group of the Home Office's independent Advisory Council on the Misuse of Drugs (ACMD) as the NPSAD representative.The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.The analysis undertaken in this project was not pre-registered. The results should therefore be considered exploratory.

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Section: Knowledge Of Scra-disease/drug Interactions Is Scarcementioning

confidence: 99%

Synthetic Cannabinoid-Related Deaths in England, 2012–2019

Yoganathan

Claridge

Chester

et al. 2022

Cannabis and Cannabinoid Research

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“…The substrate (final concentration 1-400 µM) was added to each tube (50 µL) along with protein, water, and buffer (final concentration 0.1 M KPO 4 , pH 7.4); the reactions were started with the addition of an NADPH-regenerating system (1 mM NADP + , 3 mM glucose 6-phosphate, 3 mM MgCl 2 ; 1 U/mL glucose 6-phosphate dehydrogenase) to ensure the saturation of NADPH, thus enabling cytochrome P450mediated reactions. As described previously in Jones et al (2020) [29], we used up to 50 µg of enzyme sources for each incubation tube. We confirmed that we observed the enzyme activity in a protein amount-dependent manner.…”

Section: Metabolism Of Jwh-019 In Hlms and Recombinant P450smentioning

confidence: 99%

Identification of Cytochrome P450 Enzymes Responsible for Oxidative Metabolism of Synthetic Cannabinoid (1-Hexyl-1H-Indol-3-yl)-1-naphthalenyl-methanone (JWH-019)

et al. 2023

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(1-Hexyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-019) is one of the second-generation synthetic cannabinoids which as a group have been associated with severe adverse reactions in humans. Although metabolic activation can be involved in the mechanism of action, the metabolic pathway of JWH-019 has not been fully investigated. In the present study, we aimed to identify the enzymes involved in the metabolism of JWH-019. JWH-019 was incubated with human liver microsomes (HLMs) and recombinant cytochrome P450s (P450s or CYPs). An animal study was also conducted to determine the contribution of the metabolic reaction to the onset of action. Using an ultra-performance liquid chromatography system connected to a single-quadrupole mass detector, we identified 6-OH JWH-019 as the main oxidative metabolite in HLMs supplemented with NADPH. JWH-019 was extensively metabolized to 6-OH JWH-019 in HLMs with the KM and Vmax values of 31.5 µM and 432.0 pmol/min/mg. The relative activity factor method estimated that CYP1A2 is the primary contributor to the metabolic reaction in the human liver. The animal study revealed that JWH-019 had a slower onset of action compared to natural and other synthetic cannabinoids. CYP1A2 mediates the metabolic activation of JWH-019, contributing to the slower onset of its pharmacological action.

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“…134, Exclusive use of human liver microsomes has been used to study the metabolism of, MMB022, 3,5-AB-CHMFUPPYCA, ADB-FUBINACA, 5F-ADB, CUMYL-PINACA, CUMYL-4CN-B7AICA, CUMYL-4CN-BINACA, 5F-CUMYL-PINACA, AKB-48, STS-135, MAM-2201 and XLR-11 among others. 136,[164][165][166][167][168][169][170][171] The following synthetic cannabinoids have been studied using only hepatocytes, BB-22, 5C-AKB48, EG-018, PB-22, 5F-PB-22 SDB-006, AKB-48 and XLR-11 among others. [172][173][174][175][176][177][178] Several metabolism studies of synthetic cannabinoids in urine have been carried out, including of ADB-FUBINACA, AM-694, AM-2201, JWH-007, JWH-019, JWH-203, JWH-307, MAM-2201, UR-144, XLR-11, APINAC, BB-22, EG-018, EG-2201, MDMB-CHMCZCA, MDMB-FUBINACA and 5Cl-THJ-018.…”

Section: Synthetic Cannabinoidsmentioning

confidence: 99%

An insight into the metabolism of New Psychoactive Substances : Structural elucidation of urinary metabolites of synthetic cannabinoids and fentanyl analogues using synthesized reference standards

Wallgren

2020

Linköping Studies in Science and Technology. Dissertations

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New Psychoactive Substances (NPS) is an umbrella term covering hundreds of substances across different drug groups. Many of these substances were originally developed for therapeutic use but have later appeared on the recreational drug market. The use of NPS has been associated with many outbreaks leading to hospitalizations and has been implicated in numerous fatalities worldwide. To be able to analytically detect drugs in a forensic setting is vital in the fight against the abuse of NPS. One of the most notable challenges in detection of NPS is the identification of major urinary metabolites for use as biomarkers. Furthermore, given the lack of reference standards in most metabolism studies, the major urinary metabolites can often only be tentatively determined. Docent Johan Dahlén, my main supervisor, for allowing me the opportunity to carry out my research as a PhD student. Thank you for your positive attitude, support, encouragement and for your ability to turn problems into opportunities. Professor Peter Konradsson, my co-supervisor, for accepting me as a PhD student and for encouraging me to strive forward. Thank you for your guidance in chemistry as well as for your enjoyable music and sports analogies. Doctor Xiongyu Wu, my co-supervisor, for being an exceptional person and a master chemist. Thank you for always being there for me when I needed support or advice, never making me feel like a nuisance. You will always have my utmost admiration and appreciation. The people currently or previously working at the National Board of Forensic Medicine, Svante, Martin, Henrik, Anna, Robert, Ariane and Shimpei for excellent collaboration. Thank you for letting me partake in your fascinating research, it was the highlight of my time as a PhD student. Katriann Arja, for being a truly genuine and caring friend as well as an excellent life coach. Thank you for being a beacon of positivity and for lifting the spirits of everyone around you. Lastly, for our running sessions and discussions about happiness, Aitäh! Linda Lantz, my big sister at work, for taking me under your wing and making me feel at home. Thank you for trying to teach me everything from how to speak to how to run. Very few things make me as happy as baking pastries and treating you to them. Marcus Bäck, my brother from another mother, for your perpetual support, encouragement and most enjoyable company. Few people can relate to or understand me on a personal level as well as you can. VI Mathias Elgland, my doppelganger, for sharing all my peculiar interests. I have thoroughly enjoyed all our time together, from listening to Ludde to throwing flat circular objects around and everything in between. Anders Rexander, my former brother in arms, for all the enjoyable banter and hard-fought duels in various racket sports. The lab was never the same without you. Caroline Eriksson, my dear friend, for helping me break out of my shell. Few people have had such a positive impact on me as a person as you have. Tobias Abrahamsson for being around since the beginning...

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Identifying cytochrome P450s involved in oxidative metabolism of synthetic cannabinoid N‐(adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H‐indole‐3‐carboxamide (STS‐135)

Cited by 6 publications

References 30 publications

Synthetic Cannabinoid-Related Deaths in England, 2012–2019

Synthetic Cannabinoid-Related Deaths in England, 2012–2019

Identification of Cytochrome P450 Enzymes Responsible for Oxidative Metabolism of Synthetic Cannabinoid (1-Hexyl-1H-Indol-3-yl)-1-naphthalenyl-methanone (JWH-019)

An insight into the metabolism of New Psychoactive Substances : Structural elucidation of urinary metabolites of synthetic cannabinoids and fentanyl analogues using synthesized reference standards

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