Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole 'nitazene' synthetic opioid
- Author
- Marthe Vandeputte (UGent) , Alex J. Krotulski, Donna Walther, Grant C. Glatfelter, Donna Papsun, Sara E. Walton, Barry K. Logan, Michael H. Baumann and Christophe Stove (UGent)
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- Project
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- Leave a light on: towards multiplexed luminometric characterization and detection of new psychoactive substances
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- Abstract
- Novel synthetic opioids continue to emerge on recreational drug markets worldwide. In response to legislative bans on fentanyl analogues, non-fentanyl structural templates, such as 2-benzylbenzimidazoles ('nitazenes' ), are being exploited to create new mu-opioid receptor (MOR) agonists. Here, we pharmacologically characterize an emerging cyclic analogue of etonitazene, called N-pyrrolidino etonitazene (etonitazepyne), using in vitro and in vivo methods. A series of analytically confirmed fatalities is described to complement preclinical findings. Radioligand binding assays in rat brain tissue revealed that N-pyrrolidino etonitazene has high affinity for MOR (Ki = 4.09 nM) over delta-opioid (Ki = 959 nM) and kappa-opioid (Ki = 980 nM) receptors. In a MOR-beta-arrestin2 activation assay, N-pyrrolidino etonitazene displayed high potency (EC50 = 0.348 nM), similar to etonitazene (EC50 = 0.360 nM), and largely exceeding the potencies of fentanyl (EC50 = 14.9 nM) and morphine (EC50 = 290 nM). When administered s.c. to male Sprague Dawley rats, N-pyrrolidino etonitazene induced opioid-like antino-ciceptive, cataleptic, and thermic effects. Its potency in the hot plate test (ED50 = 0.0017 mg/kg) was tenfold and 2,000-fold greater than fentanyl (ED50 = 0.0209 mg/kg) and morphine (ED50 =3.940 mg/kg), respectively. Twenty-one overdose fatalities associated with N-pyrrolidino etonitazene were found to contain low blood concentrations of the drug (median = 2.2 ng/mL), commonly in the context of polysubstance use. N-Pyrrolidino etonitazene was reported as a cause of death in at least two cases, demonstrating toxicity in humans. We demonstrate that N-pyrrolidino etonitazene is an extremely potent MOR agonist that is likely to present high risk to users. Continued vigilance is required to identify and characterize emergent 2-benzylbenzimidazoles, and other non-fentanyl opioids, as they appear in the marketplace.
- Keywords
- New synthetic opioids (NSOs), 2-benzylbenzimidazole 'nitazene' opioids, Forensic toxicology, mu-opioid receptor, In vitro and in vivo, characterization, New psychoactive substances (NPS), UND VERWANDTE HETEROCYCLEN, MORPHINE, SYSTEM
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01GS866C8Q94ZVNMPTG3CQCK3J
- MLA
- Vandeputte, Marthe, et al. “Pharmacological Evaluation and Forensic Case Series of N-Pyrrolidino Etonitazene (Etonitazepyne), a Newly Emerging 2-Benzylbenzimidazole ‘nitazene’ Synthetic Opioid.” ARCHIVES OF TOXICOLOGY, vol. 96, no. 6, 2022, pp. 1845–63, doi:10.1007/s00204-022-03276-4.
- APA
- Vandeputte, M., Krotulski, A. J., Walther, D., Glatfelter, G. C., Papsun, D., Walton, S. E., … Stove, C. (2022). Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole “nitazene” synthetic opioid. ARCHIVES OF TOXICOLOGY, 96(6), 1845–1863. https://doi.org/10.1007/s00204-022-03276-4
- Chicago author-date
- Vandeputte, Marthe, Alex J. Krotulski, Donna Walther, Grant C. Glatfelter, Donna Papsun, Sara E. Walton, Barry K. Logan, Michael H. Baumann, and Christophe Stove. 2022. “Pharmacological Evaluation and Forensic Case Series of N-Pyrrolidino Etonitazene (Etonitazepyne), a Newly Emerging 2-Benzylbenzimidazole ‘nitazene’ Synthetic Opioid.” ARCHIVES OF TOXICOLOGY 96 (6): 1845–63. https://doi.org/10.1007/s00204-022-03276-4.
- Chicago author-date (all authors)
- Vandeputte, Marthe, Alex J. Krotulski, Donna Walther, Grant C. Glatfelter, Donna Papsun, Sara E. Walton, Barry K. Logan, Michael H. Baumann, and Christophe Stove. 2022. “Pharmacological Evaluation and Forensic Case Series of N-Pyrrolidino Etonitazene (Etonitazepyne), a Newly Emerging 2-Benzylbenzimidazole ‘nitazene’ Synthetic Opioid.” ARCHIVES OF TOXICOLOGY 96 (6): 1845–1863. doi:10.1007/s00204-022-03276-4.
- Vancouver
- 1.Vandeputte M, Krotulski AJ, Walther D, Glatfelter GC, Papsun D, Walton SE, et al. Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole “nitazene” synthetic opioid. ARCHIVES OF TOXICOLOGY. 2022;96(6):1845–63.
- IEEE
- [1]M. Vandeputte et al., “Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole ‘nitazene’ synthetic opioid,” ARCHIVES OF TOXICOLOGY, vol. 96, no. 6, pp. 1845–1863, 2022.
@article{01GS866C8Q94ZVNMPTG3CQCK3J,
abstract = {{Novel synthetic opioids continue to emerge on recreational drug markets worldwide. In response to legislative bans on fentanyl analogues, non-fentanyl structural templates, such as 2-benzylbenzimidazoles ('nitazenes' ), are being exploited to create new mu-opioid receptor (MOR) agonists. Here, we pharmacologically characterize an emerging cyclic analogue of etonitazene, called N-pyrrolidino etonitazene (etonitazepyne), using in vitro and in vivo methods. A series of analytically confirmed fatalities is described to complement preclinical findings. Radioligand binding assays in rat brain tissue revealed that N-pyrrolidino etonitazene has high affinity for MOR (Ki = 4.09 nM) over delta-opioid (Ki = 959 nM) and kappa-opioid (Ki = 980 nM) receptors. In a MOR-beta-arrestin2 activation assay, N-pyrrolidino etonitazene displayed high potency (EC50 = 0.348 nM), similar to etonitazene (EC50 = 0.360 nM), and largely exceeding the potencies of fentanyl (EC50 = 14.9 nM) and morphine (EC50 = 290 nM). When administered s.c. to male Sprague Dawley rats, N-pyrrolidino etonitazene induced opioid-like antino-ciceptive, cataleptic, and thermic effects. Its potency in the hot plate test (ED50 = 0.0017 mg/kg) was tenfold and 2,000-fold greater than fentanyl (ED50 = 0.0209 mg/kg) and morphine (ED50 =3.940 mg/kg), respectively. Twenty-one overdose fatalities associated with N-pyrrolidino etonitazene were found to contain low blood concentrations of the drug (median = 2.2 ng/mL), commonly in the context of polysubstance use. N-Pyrrolidino etonitazene was reported as a cause of death in at least two cases, demonstrating toxicity in humans. We demonstrate that N-pyrrolidino etonitazene is an extremely potent MOR agonist that is likely to present high risk to users. Continued vigilance is required to identify and characterize emergent 2-benzylbenzimidazoles, and other non-fentanyl opioids, as they appear in the marketplace.}},
author = {{Vandeputte, Marthe and Krotulski, Alex J. and Walther, Donna and Glatfelter, Grant C. and Papsun, Donna and Walton, Sara E. and Logan, Barry K. and Baumann, Michael H. and Stove, Christophe}},
issn = {{0340-5761}},
journal = {{ARCHIVES OF TOXICOLOGY}},
keywords = {{New synthetic opioids (NSOs),2-benzylbenzimidazole 'nitazene' opioids,Forensic toxicology,mu-opioid receptor,In vitro and in vivo,characterization,New psychoactive substances (NPS),UND VERWANDTE HETEROCYCLEN,MORPHINE,SYSTEM}},
language = {{eng}},
number = {{6}},
pages = {{1845--1863}},
title = {{Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole 'nitazene' synthetic opioid}},
url = {{http://doi.org/10.1007/s00204-022-03276-4}},
volume = {{96}},
year = {{2022}},
}
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