
In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole 'nitazene' opioids
- Author
- Liam De Vrieze (UGent) , Sara E. Walton, Eline Pottie (UGent) , Donna Papsun, Barry K. Logan, Alex J. Krotulski, Christophe Stove (UGent) and Marthe Vandeputte (UGent)
- Organization
- Project
-
- MOR(e) partners in crime: a bioassay approach to study µ-opioid receptor dimerization by new synthetic opioids
- Looks don’t matter, it’s what you do that counts*: Deployment of innovative bio-assays for screening and elucidation of the mechanism of action of new psychoactive substances
- Leave a light on: towards multiplexed luminometric characterization and detection of new psychoactive substances
- True colors are shining through: Flow cytometric biosensors as a new concept in forensic toxicology
- Shining a new light on psychedelics: set-up and application of novel 5-HT2AR bio-assays
- Abstract
- 2-Benzylbenzimidazole 'nitazene' opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects of different structural modifications to the 2-benzylbenzimidazole core structure on mu-opioid receptor (MOR) activity are limited. Here, we assessed in vitro structure-activity relationships of 9 previously uncharacterized nitazenes alongside known structural analogues. Specifically, we focused on MOR activation by 'ring' substituted analogues (i.e., N-pyrrolidino and N-piperidinyl modifications), 'desnitazene' analogues (lacking the 5-nitro group), and N-desethyl analogues. The results from two in vitro MOR activation assays (beta-arrestin 2 recruitment and inhibition of cAMP accumulation) showed that 'ring' modifications overall yield highly active drugs. With the exception of 4 '-OH analogues (which are metabolites), N-pyrrolidino substitutions were generally more favorable for MOR activation than N-piperidine substitutions. Furthermore, removal of the 5-nitro group on the benzimidazole ring consistently caused a pronounced decrease in potency. The N-desethyl modifications showed important MOR activity, and generally resulted in a slightly lowered potency than comparator nitazenes. Intriguingly, N-desethyl isotonitazene was the exception and was consistently more potent than isotonitazene. Complementing the in vitro findings and demonstrating the high harm potential associated with many of these compounds, we describe 85 forensic cases from North America and the United Kingdom involving etodesnitazene, N-desethyl etonitazene, N-desethyl isotonitazene, N-pyrrolidino metonitazene, and N-pyrrolidino protonitazene. The low-to-sub ng/mL blood concentrations observed in most cases underscore the drugs' high potencies. Taken together, by bridging pharmacology and case data, this study may aid to increase awareness and guide legislative and public health efforts.
- Keywords
- New synthetic opioids (NSOs), 2-Benzylbenzimidazole 'nitazene' opioids, Forensic toxicology, mu-Opioid receptor (MOR), Bioassay, UND VERWANDTE HETEROCYCLEN
Downloads
-
In vitro structure–activity relationships and forensic case series of emerging 2-benzylbenzimidazole ‘nitazene’ opioids.pdf
- full text (Published version)
- |
- open access
- |
- |
- 3.38 MB
Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01J69V9K4W902R3PDS2BR2D2Z9
- MLA
- De Vrieze, Liam, et al. “In Vitro Structure-Activity Relationships and Forensic Case Series of Emerging 2-Benzylbenzimidazole ‘nitazene’ Opioids.” ARCHIVES OF TOXICOLOGY, vol. 98, no. 9, 2024, pp. 2999–3018, doi:10.1007/s00204-024-03774-7.
- APA
- De Vrieze, L., Walton, S. E., Pottie, E., Papsun, D., Logan, B. K., Krotulski, A. J., … Vandeputte, M. (2024). In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole “nitazene” opioids. ARCHIVES OF TOXICOLOGY, 98(9), 2999–3018. https://doi.org/10.1007/s00204-024-03774-7
- Chicago author-date
- De Vrieze, Liam, Sara E. Walton, Eline Pottie, Donna Papsun, Barry K. Logan, Alex J. Krotulski, Christophe Stove, and Marthe Vandeputte. 2024. “In Vitro Structure-Activity Relationships and Forensic Case Series of Emerging 2-Benzylbenzimidazole ‘nitazene’ Opioids.” ARCHIVES OF TOXICOLOGY 98 (9): 2999–3018. https://doi.org/10.1007/s00204-024-03774-7.
- Chicago author-date (all authors)
- De Vrieze, Liam, Sara E. Walton, Eline Pottie, Donna Papsun, Barry K. Logan, Alex J. Krotulski, Christophe Stove, and Marthe Vandeputte. 2024. “In Vitro Structure-Activity Relationships and Forensic Case Series of Emerging 2-Benzylbenzimidazole ‘nitazene’ Opioids.” ARCHIVES OF TOXICOLOGY 98 (9): 2999–3018. doi:10.1007/s00204-024-03774-7.
- Vancouver
- 1.De Vrieze L, Walton SE, Pottie E, Papsun D, Logan BK, Krotulski AJ, et al. In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole “nitazene” opioids. ARCHIVES OF TOXICOLOGY. 2024;98(9):2999–3018.
- IEEE
- [1]L. De Vrieze et al., “In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole ‘nitazene’ opioids,” ARCHIVES OF TOXICOLOGY, vol. 98, no. 9, pp. 2999–3018, 2024.
@article{01J69V9K4W902R3PDS2BR2D2Z9, abstract = {{2-Benzylbenzimidazole 'nitazene' opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects of different structural modifications to the 2-benzylbenzimidazole core structure on mu-opioid receptor (MOR) activity are limited. Here, we assessed in vitro structure-activity relationships of 9 previously uncharacterized nitazenes alongside known structural analogues. Specifically, we focused on MOR activation by 'ring' substituted analogues (i.e., N-pyrrolidino and N-piperidinyl modifications), 'desnitazene' analogues (lacking the 5-nitro group), and N-desethyl analogues. The results from two in vitro MOR activation assays (beta-arrestin 2 recruitment and inhibition of cAMP accumulation) showed that 'ring' modifications overall yield highly active drugs. With the exception of 4 '-OH analogues (which are metabolites), N-pyrrolidino substitutions were generally more favorable for MOR activation than N-piperidine substitutions. Furthermore, removal of the 5-nitro group on the benzimidazole ring consistently caused a pronounced decrease in potency. The N-desethyl modifications showed important MOR activity, and generally resulted in a slightly lowered potency than comparator nitazenes. Intriguingly, N-desethyl isotonitazene was the exception and was consistently more potent than isotonitazene. Complementing the in vitro findings and demonstrating the high harm potential associated with many of these compounds, we describe 85 forensic cases from North America and the United Kingdom involving etodesnitazene, N-desethyl etonitazene, N-desethyl isotonitazene, N-pyrrolidino metonitazene, and N-pyrrolidino protonitazene. The low-to-sub ng/mL blood concentrations observed in most cases underscore the drugs' high potencies. Taken together, by bridging pharmacology and case data, this study may aid to increase awareness and guide legislative and public health efforts.}}, author = {{De Vrieze, Liam and Walton, Sara E. and Pottie, Eline and Papsun, Donna and Logan, Barry K. and Krotulski, Alex J. and Stove, Christophe and Vandeputte, Marthe}}, issn = {{0340-5761}}, journal = {{ARCHIVES OF TOXICOLOGY}}, keywords = {{New synthetic opioids (NSOs),2-Benzylbenzimidazole 'nitazene' opioids,Forensic toxicology,mu-Opioid receptor (MOR),Bioassay,UND VERWANDTE HETEROCYCLEN}}, language = {{eng}}, number = {{9}}, pages = {{2999--3018}}, title = {{In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole 'nitazene' opioids}}, url = {{http://doi.org/10.1007/s00204-024-03774-7}}, volume = {{98}}, year = {{2024}}, }
- Altmetric
- View in Altmetric
- Web of Science
- Times cited: