| 1. |
- Deventer, Marie H., et al.
(författare)
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In vitro cannabinoid activity profiling of generic ban-evading brominated synthetic cannabinoid receptor agonists and their analogs
- 2024
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Ingår i: Drug Testing and Analysis. - : WILEY. - 1942-7603 .- 1942-7611. ; 16:6, s. 616-628
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Tidskriftsartikel (refereegranskat)abstract
- Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5 Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5 Br-INACA (ADMB-5Br-INACA), MDMB-5 Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (S)-enantiomers of these substances, as well as of two predicted analogs MDMB-5 Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5 F-BUTINACA (ADMB-B-5F-INACA), using CB1 and CB2 beta-arrestin 2 recruitment assays and a CB1 intracellular calcium release assay. Surprisingly, the tail-less (S)-ADB-5 Br-INACA and (S)-MDMB-5 Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (S)-ADB-5 Br-BUTINACA and (S)-MDMB-5 Br-BUTINACA, respectively, which were potent and efficacious CB1 agonists. Also, at CB2, tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((S)-ADB-INACA) resulted in a reduced activity at CB1; however, this effect was less prominent at CB2. Looking at tailed analogs, replacing the bromine with a fluorine substitution ((S)-ADB-5 F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5 Br-INACA and MDMB-5 Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB1 receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5 Br-INACA and MDMB-5 Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected. The enactment of the Chinese generic ban (2021) has majorly impacted the SCRA market, exemplified by the recent emergence of tail-less compounds and substances with a brominated core. CB1 and CB2 cannabinoid activity of six analogs was assessed using beta arr2 recruitment and Ca2+ release assays. Absence of a tail moiety still yielded cannabinoid activity albeit with lower potency, whereas tailed analogs were highly efficacious.image
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| 2. |
- Deventer, Marie H., et al.
(författare)
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Off-target activity of NBOMes and NBOMe analogs at the mu opioid receptor
- 2023
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Ingår i: Archives of Toxicology. - : SPRINGER HEIDELBERG. - 0340-5761 .- 1432-0738. ; 97:5, s. 1367-1384
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Tidskriftsartikel (refereegranskat)abstract
- New psychoactive substances (NPS) are introduced on the illicit drug market at a rapid pace. Their molecular targets are often inadequately elucidated, which contributes to the delayed characterization of their pharmacological effects. Inspired by earlier findings, this study set out to investigate the mu opioid receptor (MOR) activation potential of a large set of psychedelics, substances which typically activate the serotonin (5-HT2A) receptor as their target receptor. We observed that some substances carrying the N-benzyl phenethylamine (NBOMe) structure activated MOR, as confirmed by both the NanoBiT (R) beta arr2 recruitment assay and the G protein-based AequoScreen (R) Ca2+ release assay. The use of two orthogonal systems proved beneficial as some aspecific, receptor independent effects were found for various analogs when using the Ca2+ release assay. The specific off-target effects at MOR could be blocked by the opioid antagonist naloxone, suggesting that these NBOMes occupy the same common opioid binding pocket as conventional opioids. This was corroborated by molecular docking, which revealed the plausibility of multiple interactions of 25I-NBOMe with MOR, similar to those observed for opioids. Additionally, structure-activity relationship findings seen in vitro were rationalized in silico for two 25I-NBOMe isomers. Overall, as MOR activity of these psychedelics was only noticed at high concentrations, we consider it unlikely that for the tested compounds there will be a relevant opioid toxicity in vivo at physiologically relevant concentrations. However, small modifications to the original NBOMe structure may result in a panel of more efficacious and potent MOR agonists, potentially exhibiting a dual MOR/5-HT2A activation potential.
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| 3. |
- Norman, Caitlyn, et al.
(författare)
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Detection in seized samples, analytical characterization, and in vitro metabolism of the newly emerged 5-bromo-indazole-3-carboxamide synthetic cannabinoid receptor agonists
- 2023
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Ingår i: Drug Testing and Analysis. - : WILEY. - 1942-7603 .- 1942-7611.
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Tidskriftsartikel (refereegranskat)abstract
- Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS) and new structural scaffolds have emerged on the recreational drug market since the enactment of Chinese SCRA analog controls in 2021. This study reports the first SCRAs to be detected with a bromide at the 5 position (5 ' Br) on the phenyl ring of the indazole core and without a tail moiety. ADB-5 ' Br-INACA (ADMB-5 ' Br-INACA) and MDMB-5 ' Br-INACA were detected in seized samples from Scottish prisons, Belgian customs, and US forensic casework. The brominated analog with a tail moiety, ADB-5 ' Br-BUTINACA (ADMB-5 ' Br-BUTINACA), was also detected in Scottish prisons and US forensic casework. The metabolites of these compounds and the predicted compound MDMB-5 ' Br-BUTINACA were identified through incubation with primary human hepatocytes to aid in their toxicological identification. The bromide on the indazole remains intact on metabolites, allowing these compounds to be easily distinguished in toxicological samples from their non-brominated analogs. Glucuronidation was more common for tail-less analogs than their butyl tail-containing counterparts. Forensic toxicologists are advised to update their analytical methods with the characteristic ions for these compounds, as well as their anticipated urinary markers: amide hydrolysis and monoOH at tert-butyl metabolites (after beta-glucuronidase treatment) for ADB-5 ' Br-INACA; monoOH at tert-butyl and amide hydrolysis metabolites for ADB-5 ' Br-BUTINACA; and ester hydrolysis metabolites with additional metabolites for MDMB-5 ' Br-INACA and MDMB-5 ' Br-BUTINACA. Toxicologists should remain vigilant to the emergence of new SCRAs with halogenation of the indazole core and tail-less analogs, which have already started to emerge. This study reports the detection of the new synthetic cannabinoids ADB-5 ' Br-INACA and MDMB-5 ' Br-INACA in Scotland, Belgium, and the US, and ADB-5 ' Br-BUTINACA in Scotland and the US. These compounds, along with the predicted compound MDMB-5 ' Br-BUTINACA, were incubated with primary human hepatocytes to examine metabolic pathways and aid in toxicological identification.image
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| 4. |
- Vandeputte, Marthe M., et al.
(författare)
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Characterization of recent non-fentanyl synthetic opioids via three different in vitro µ-opioid receptor activation assays
- 2022
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Ingår i: Archives of Toxicology. - : SPRINGER HEIDELBERG. - 0340-5761 .- 1432-0738. ; 96, s. 877-897
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Tidskriftsartikel (refereegranskat)abstract
- New synthetic opioids (NSOs) are one of the fastest growing groups of new psychoactive substances. Amid this dynamic landscape, insight into the pharmacology of NSOs is important to estimate the harm potential of newly emerging drugs. In this work, we determined the mu-opioid receptor (MOR) affinity and activation potential of seven poorly characterized non-fentanyl NSOs (N-ethyl-U-47700, 3,4-difluoro-U-47700, U-47931E/bromadoline, 2,4-difluoro-U-48800, U-62066/spiradoline, 2F-viminol, ketobemidone) and a panel of nine reference opioids. MOR affinity was determined via [H-3]-DAMGO binding in rat brain tissue homogenates, and was found to correlate well with different functional parameters. MOR activation potential was studied at different levels of receptor signaling using three distinct assays (NanoBiT (R) MOR-beta-arrestin2/mini-G(alpha i) and AequoScreen (R)). The most active compounds were ketobemidone (EC50 32.8-528 nM; E-max 105-271%, relative to hydromorphone) and N-ethyl-U-47700 (EC50 241-767 nM; E-max 139-247%). The same opioids showed the strongest MOR affinity. As most of the other NSOs only weakly activated MOR in the three assays (EC50 values in the high nM-mu M range), they likely do not pose a high overdose risk. 2F-viminol (EC50 2.2-4.5 mu M; E-max 21.2-61.5%) and U-47931E/bromadoline (EC50 0.55-2.9 mu M; E-max 52.8-85.9%) were partial agonists compared to hydromorphone, and maximum receptor activation was not reached for 2,4-difluoro-U-48800 (EC50 > 22 µM). We further highlight the importance of considering specific assay characteristics upon interpretation of potencies, efficacies and biased agonism. As absolute values may greatly differ between assays with varying experimental set-ups, a comparison of functional parameters to those of well-characterized reference agonists is considered the most informative.
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