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Off-target activity of NBOMes and NBOMe analogs at the mu opioid receptor

(2023) ARCHIVES OF TOXICOLOGY. 97(5). p.1367-1384
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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.
Keywords
SYNTHETIC CANNABINOIDS, POTENT HALLUCINOGENS, PROTEIN, 5-HT2A, PHARMACOLOGY, PHENETHYLAMINES, PHOTOPROTEINS, TOXICITIES, MOLECULES, MECHANISM, Bioassay, mu opioid receptor, NBOMe, Off-target, Psychedelics, Molecular docking

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Citation

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MLA
Deventer, Marie, et al. “Off-Target Activity of NBOMes and NBOMe Analogs at the Mu Opioid Receptor.” ARCHIVES OF TOXICOLOGY, vol. 97, no. 5, 2023, pp. 1367–84, doi:10.1007/s00204-023-03465-9.
APA
Deventer, M., Persson, M., Laus, A., Pottie, E., Cannaert, A., Tocco, G., … Stove, C. (2023). Off-target activity of NBOMes and NBOMe analogs at the mu opioid receptor. ARCHIVES OF TOXICOLOGY, 97(5), 1367–1384. https://doi.org/10.1007/s00204-023-03465-9
Chicago author-date
Deventer, Marie, Mattias Persson, Antonio Laus, Eline Pottie, Annelies Cannaert, Graziella Tocco, Henrik Green, and Christophe Stove. 2023. “Off-Target Activity of NBOMes and NBOMe Analogs at the Mu Opioid Receptor.” ARCHIVES OF TOXICOLOGY 97 (5): 1367–84. https://doi.org/10.1007/s00204-023-03465-9.
Chicago author-date (all authors)
Deventer, Marie, Mattias Persson, Antonio Laus, Eline Pottie, Annelies Cannaert, Graziella Tocco, Henrik Green, and Christophe Stove. 2023. “Off-Target Activity of NBOMes and NBOMe Analogs at the Mu Opioid Receptor.” ARCHIVES OF TOXICOLOGY 97 (5): 1367–1384. doi:10.1007/s00204-023-03465-9.
Vancouver
1.
Deventer M, Persson M, Laus A, Pottie E, Cannaert A, Tocco G, et al. Off-target activity of NBOMes and NBOMe analogs at the mu opioid receptor. ARCHIVES OF TOXICOLOGY. 2023;97(5):1367–84.
IEEE
[1]
M. Deventer et al., “Off-target activity of NBOMes and NBOMe analogs at the mu opioid receptor,” ARCHIVES OF TOXICOLOGY, vol. 97, no. 5, pp. 1367–1384, 2023.
@article{01H97TCMQ42DT0371GAPY656FZ,
  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.}},
  author       = {{Deventer, Marie and  Persson, Mattias and  Laus, Antonio and Pottie, Eline and Cannaert, Annelies and  Tocco, Graziella and  Green, Henrik and Stove, Christophe}},
  issn         = {{0340-5761}},
  journal      = {{ARCHIVES OF TOXICOLOGY}},
  keywords     = {{SYNTHETIC CANNABINOIDS,POTENT HALLUCINOGENS,PROTEIN,5-HT2A,PHARMACOLOGY,PHENETHYLAMINES,PHOTOPROTEINS,TOXICITIES,MOLECULES,MECHANISM,Bioassay,mu opioid receptor,NBOMe,Off-target,Psychedelics,Molecular docking}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{1367--1384}},
  title        = {{Off-target activity of NBOMes and NBOMe analogs at the mu opioid receptor}},
  url          = {{http://doi.org/10.1007/s00204-023-03465-9}},
  volume       = {{97}},
  year         = {{2023}},
}

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