Synthesis and identifications of potential metabolites as biomarkers of the synthetic cannabinoid AKB-48

Wallgren, Jakob; Vikingsson, Svante; Åstrand, Anna; Josefsson, Martin; Gréen, Henrik; Dahlén, Johan; Wu, Xiongyu; Konradsson, Peter

doi:10.1016/j.tet.2018.04.026

Cited by 13 publications

(17 citation statements)

References 14 publications

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“…Conversely, as we have earlier reported (Honrao et al, 2015;Honrao et al, 2016), we now provide detailed evidence that secondary adamantyl carbons can also be the primary site for oxidative metabolism. Parallel to our work, similar findings were also recently reported for AKB48 using synthetically derived monohydroxylated adamantyl metabolite (Wallgren et al, 2017;Wallgren et al, 2018). These monohydroxylated adamantyl metabolites can also further undergo oxidation to dihydroxy metabolites in vitro and in vivo extensively.…”

Section: Introductionsupporting

confidence: 90%

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

Honrao

Kulkarni

et al. 2020

Front. Pharmacol.

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Adamantyl groups are key structural subunit commonly used in many marketed drugs targeting diseases ranging from viral infections to neurological disorders. The metabolic disposition of adamantyl compounds has been mostly studied using LC-MS based approaches. However, metabolite quantities isolated from biological preparations are often insufficient for unambiguous structural characterization by NMR. In this work, we utilized microcoil NMR in conjunction with LC-MS to characterize liver microsomal metabolites of an adamantyl based CB2 agonist AM9338, 1-(3-(1H-1,2,3-triazol-1-yl) propyl)-N-(adamantan-1-yl)-1H-indazole-3-carboxamide, a candidate compound for potential multiple sclerosis treatment. We have identified a total of 9 oxidative metabolites of AM9338 whereas mono- or di-hydroxylation of the adamantyl moiety is the primary metabolic pathway. While it is generally believed that the tertiary adamantyl carbons are the preferred sites of CYP450 oxidation, both the mono- and di-hydroxyl metabolites of AM9338 show that the primary oxidative sites are located on the secondary adamantyl carbons. To our knowledge this di-hydroxylated metabolite is a novel adamantyl metabolite that has not been reported before. Further, the stereochemistry of both mono- and di-hydroxyl adamantyl metabolites has been determined using NOE correlations. Furthermore, docking of AM9338 into the CYP3A4 metabolic enzyme corroborates with our experimental findings, and the modelling results also provide a possible mechanism for the unusual susceptibility of adamantyl secondary carbons to metabolic oxidations. The novel dihydroxylated AM9338 metabolite identified in this study, along with the previously known adamantyl metabolites, gives a more complete picture of the metabolic disposition for adamantyl compounds.

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Section: Introductionsupporting

confidence: 90%

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

Honrao

Kulkarni

et al. 2020

Front. Pharmacol.

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“…Adapted from Wallgren et al Tetrahedron 2018, 74 (24), 2905-2913, with permission. 240 Compounds 13 and 14 were purchased. However, they can also be synthesized using hydroboration-oxidation.…”

Section: Compoundmentioning

confidence: 99%

“…(24), 2905-2913, with permission. 240 Hydroboration-oxidation of compound 16 was achieved by treatment with BH3•THF followed by NaOH (aq) and H2O2 (Scheme 4). 243 The reaction gave a mixture of compounds 18 and 19 in a ratio of 9:1.…”

Section: Compoundmentioning

confidence: 99%

“…Adapted from Wallgren et al Tetrahedron 2018, 74 (24), 2905-2913, with permission. 240 Given the low yields of compounds 19 and 25, a better synthetic route should be to reduce the ketones of compounds 20 and 21 using NaBH4 (Scheme 6). Furthermore, hydroboration-oxidation was also used to add water over the alkene of compound 26 to achieve compounds 28 and 29 (Scheme 5).…”

Section: Compoundmentioning

confidence: 99%

“…Adapted from Wallgren et al Tetrahedron 2018, 74 (24), 2905-2913, with permission. 240 The synthesis of compounds 6, 7, 8 and 9 was covered in paper I (Scheme 2). Compounds 30 and 31 were achieved through reduction of compound 6 using NaBH4 in methanol (MeOH) for one hour (Scheme 7).…”

Section: Compoundmentioning

confidence: 99%

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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

Self Cite

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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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Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB‐4en‐PICA, MDMB‐4en‐PINACA, ADB‐4en‐PINACA, and MMB‐4CN‐BUTINACA using a combination of binding and different CB₁ receptor activation assays: Part I—Synthesis, analytical characterization, and binding affinity for human CB₁ receptors

Pike

Grafinger

Cannaert

et al. 2021

Drug Testing and Analysis

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Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances (NPS). Despite this, pharmacological data are often lacking following the identification of a new SCRA in drug markets. In this first of a three-part series, we describe the synthesis, analytical characterization, and binding affinity of a proactively generated, systematic library of 30 indole, indazole, and 7-azaindole SCRAs related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA featuring a 4-pentenyl (4en-P), butyl (B/BUT), or 4-cyanobutyl (4CN-B/BUT) tail and a methyl L-valinate (MMB), methyl L-tert-leucinate (MDMB), methyl L-phenylalaninate (MPP), L-valinamide (AB), L-tert-leucinamide (ADB), L-phenylalaninamide (APP), adamantyl (A), or cumyl head group. Competitive radioligand binding assays demonstrated that the indazole core conferred the highest CB 1 binding affinity (K i = 0.17-39 nM), followed by indole-(K i = 0.95-160 nM) and then 7-azaindole-derived SCRAs (K i = 5.4-271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and methyl esters (K i = 0.17-14 nM) generally showing the greatest affinities, followed by valine derivatives (K i = 0.72-180 nM), and then phenylalanine derivatives (K i = 2.5-271 nM). Adamantyl head groups (K i = 8.8-59 nM)

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Synthesis and identifications of potential metabolites as biomarkers of the synthetic cannabinoid AKB-48

Cited by 13 publications

References 14 publications

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

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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