First Report on Brorphine: The Next Opioid on the Deadly New Psychoactive Substance Horizon?
Open accessAbstract
New psychoactive substances continue to appear on the drug market. Until recently, new synthetic opioids, which are among the most dangerous new psychoactive substances, primarily encompassed analogs of the potent analgesic fentanyl. Lately, also other new synthetic opioids have increasingly started to surface. This is the first report on the identification and full chemical characterization of brorphine, a novel potent synthetic opioid with a piperidine benzimidazolone structure. A powder, identified as brorphine, was obtained from a patient seeking medical help for detoxification. Brorphine was also found in a serum sample of the patient. Liquid chromatography-high-resolution mass spectrometry (LC-HRMS) identified an exact mass of m/z 400.1020 and 402.1005 for the compound, corresponding to both bromine isotopes. Further chemical characterization was performed by gas chromatography-mass spectrometry, liquid chromatography-diode array detection and Fourier-transform infrared spectroscopy analyses. Finally, the structure was confirmed by performing 1H-NMR and 13C-NMR spectroscopy. In vitro biological activity of brorphine was determined by a cell-based µ-opioid receptor activation assay, resulting in an EC50 of 30.9 nM (13.5 ng/mL) and an Emax of 209% relative to hydromorphone, confirming the high potency and efficacy of this compound. In a serum sample of the patient, brorphine and a hydroxy-metabolite were found using the LC-HRMS screening method. The presence of opioid activity in the serum was also confirmed via the activity-based opioid screening assay. The occurrence of brorphine is yet another example of how the illicit drug market is continuously evolving in an attempt to escape international legislation. Its high potency poses a serious and imminent health threat for any user.
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Brorphine is a synthetic piperidine benzimidazolone opioid that was first identified on the NPS market in 2019.
“Brorphine is a synthetic piperidine benzimidazolone opioid that was first identified on the NPS market in 2019 (Vandeputte et al., 2022a; Verougstraete et al., 2020).”
From Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization (2024) · cites this paper as Verougstraete et al., 2020
This apparent discrepancy may be due to involvement of other receptors and/or signaling pathways, differences in blood-brain barrier penetration, metabolic (in)activation, etc.
“This apparent discrepancy may be due to involvement of other receptors and/or signaling pathways, differences in blood-brain barrier penetration, metabolic (in)activation, etc. (Vandeputte et al., 2022d, 2022e; Verougstraete et al., 2020).”
From Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization (2024) · cites this paper as Verougstraete et al., 2020
While it is currently not known whether any of the brorphine metabolites retain clinically relevant opioid activity, metabolic (in)activation may contribute to some of the (unexpected) behavioral findings reported here.
“While it is currently not known whether any of the brorphine metabolites retain clinically relevant opioid activity (Verougstraete et al., 2020), metabolic (in)activation may contribute to some of the (unexpected) behavioral findings reported here.”
From Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization (2024) · cites this paper as Verougstraete et al., 2020
The ortho-chloro analogue of chlorphine has nanomolar affinity for the opioid receptor-like 1 (ORL1) receptor.
“In this context, it is interesting to note that the ortho -chloro analogue of chlorphine has nanomolar affinity for the opioid receptor-like 1 (ORL1) receptor (Kawamoto et al., 1999; Verougstraete et al., 2020).”
From Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization (2024) · cites this paper as Verougstraete et al., 2020
Cites
Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review
Armenian, P., Vo, K. T., Barr‐Walker, J., & Lynch, K. L. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.10.016 · Cited by 714 · see citing works
Morphine Side Effects in β-Arrestin 2 Knockout Mice
Raehal, K. M., Walker, J. K. L., & Bohn, L. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.087254 · Cited by 626 · see citing works
Bias factor and therapeutic window correlate to predict safer opioid analgesics
Schmid, C. L., Kennedy, N. M., Ross, N. C., Lovell, K. M., Yue, Z., Morgenweck, J., Cameron, M. D., Bannister, T. D., & Bohn, L. M. (2017) · Cell · doi:10.1016/j.cell.2017.10.035 · Cited by 567 · see citing works
New psychoactive substances: challenges for drug surveillance, control, and public health responses
Peacock, A., Bruno, R., Gisev, N., Degenhardt, L. J., Hall, W., Sedefov, R., White, J. M., Thomas, K. V., Farrell, M., & Griffiths, P. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32231-7 · Cited by 372 · see citing works
Morphine‐induced respiratory depression is independent of β‐arrestin2 signalling
Kliewer, A., Gillis, A., Hill, R., Schmiedel, F., Bailey, C. P., Kelly, E., Henderson, G., Christie, M. J., & Schulz, S. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15004 · Cited by 249 · see citing works
Böcker, S., & Dührkop, K. (2016) · Journal of Cheminformatics · doi:10.1186/s13321-016-0116-8 · Cited by 208 · see citing works
Kawamoto, H., Ozaki, S., Itoh, Y., Miyaji, M., Arai, S., Nakashima, H., Kato, T., Ohta, H., & Iwasawa, Y. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm990517p · Cited by 204 · see citing works
The Fentanyl Epidemic and Evolution of Fentanyl Analogs in the United States and the European Union
Jannetto, P. J., Helander, A., Garg, U. C., Janis, G. C., Goldberger, B. A., & Ketha, H. (2018) · Clinical Chemistry · doi:10.1373/clinchem.2017.281626 · Cited by 162 · see citing works
Isotonitazene Quantitation and Metabolite Discovery in Authentic Forensic Casework
Krotulski, A. J., Papsun, D. M., Kacinko, S. L., & Logan, B. K. (2020) · Journal of Analytical Toxicology · doi:10.1093/jat/bkaa016 · Cited by 146 · see citing works
Blanckaert, P., Cannaert, A., Van Uytfanghe, K., Hulpia, F., Deconinck, E., Van Calenbergh, S., & Stove, C. (2020) · Drug Testing and Analysis · doi:10.1002/dta.2738 · Cited by 116 · see citing works
Self-citationMardal, M., Andreasen, M. F., Mollerup, C. B., Stockham, P. C., Telving, R., Τhomaidis, Ν. S., Diamanti, K. S., Línnet, K., & Dalsgaard, P. W. (2019) · Journal of Analytical Toxicology · doi:10.1093/jat/bkz030 · Cited by 115 · see citing works
Helfer, A. G., Michely, J. A., Weber, A. A., Meyer, M. R., & Maurer, H. H. (2017) · Analytica Chimica Acta · doi:10.1016/j.aca.2017.03.002 · Cited by 74 · see citing works
Optimization of a series of mu opioid receptor (MOR) agonists with high G protein signaling bias
Kennedy, N. M., Schmid, C. L., Ross, N. C., Lovell, K. M., Yue, Z., Chen, Y. T., Cameron, M. D., Bohn, L. M., & Bannister, T. D. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01136 · Cited by 71 · see citing works
Sharma, K. K., Hales, T. G., Rao, V. J., NicDaéid, N., & McKenzie, C. (2018) · Forensic Toxicology · doi:10.1007/s11419-018-0454-5 · Cited by 58 · see citing works
In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances
Vandeputte, M. M., Cannaert, A., & Stove, C. P. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02855-7 · Cited by 58 · see citing works
Self-citationVasudevan, L., Vandeputte, M., Deventer, M., Wouters, E., Cannaert, A., & Stove, C. P. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113910 · Cited by 55 · see citing works
Control of fentanyl-related substances in China
Bao, Y., Meng, S., Shi, J., & Lü, L. (2019) · The Lancet Psychiatry · doi:10.1016/s2215-0366(19)30218-4 · Cited by 42 · see citing works
Gampfer, T. M., Wagmann, L., Park, Y. M., Cannaert, A., Herrmann, J. E., Fischmann, S., Westphal, F., Müller, R., Stove, C. P., & Meyer, M. R. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02726-1 · Cited by 36 · see citing works
Self-citationHide and Seek: Overcoming the Masking Effect of Opioid Antagonists in Activity-Based Screening Tests
Cannaert, A., Deventer, M. H., Fogarty, M. F., Mohr, A. L. A., & Stove, C. P. (2019) · Clinical Chemistry · doi:10.1373/clinchem.2019.309443 · Cited by 21 · see citing works
Self-citationCannaert, A., Fernández, M. D. M. R., Theunissen, E. L., Ramaekers, J. G., Wille, S. M. R., & Stove, C. P. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.0c00484 · Cited by 8 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Vandeputte, M. M., Van Uytfanghe, K., Layle, N. K., St. Germaine, D. M., Iula, D. M., & Stove, C. P. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00064 · Cited by 161 · see citing works
Self-citationDARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles
Ujváry, I., Christie, R., Evans-Brown, M., Gallegos, A., Jorge, R., de Morais, J., & Sedefov, R. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00037 · Cited by 141 · see citing works
The Rise and Fall of Isotonitazene and Brorphine: Two Recent Stars in the Synthetic Opioid Firmament
Vandeputte, M. M., Krotulski, A. J., Papsun, D. M., Logan, B. K., & Stove, C. P. (2022) · Journal of Analytical Toxicology · doi:10.1093/jat/bkab082 · Cited by 71 · see citing works
Self-citationNon-Fentanyl New Synthetic Opioids—An Update
Zawilska, J. B., Adamowicz, P., Kurpeta, M., & Wojcieszak, J. (2023) · Forensic Science International · doi:10.1016/j.forsciint.2023.111775 · Cited by 55 · see citing works
Papsun, D. M., Krotulski, A. J., & Logan, B. K. (2022) · American Journal of Forensic Medicine & Pathology · doi:10.1097/paf.0000000000000787 · Cited by 51 · see citing works
Dahan, A., Franko, T. S., Carroll, J. W., Craig, D. S., Crow, C., Galinkin, J. L., Garrity, J. C., Peterson, J., & Rausch, D. B. (2024) · Frontiers in Public Health · doi:10.3389/fpubh.2024.1346109 · Cited by 49 · see citing works
Palmquist, K. B., Truver, M. T., Shoff, E. N., Krotulski, A. J., & Swortwood, M. J. (2023) · Journal of Forensic Sciences · doi:10.1111/1556-4029.15282 · Cited by 39 · see citing works
Vandeputte, M. M., Tsai, M.-H. M., Chen, L., Glatfelter, G. C., Walther, D., Stove, C. P., Shi, L., & Baumann, M. H. (2023) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2023.109939 · Cited by 39 · see citing works
Self-citationVandeputte, M. M., Glatfelter, G. C., Walther, D., Layle, N. K., St. Germaine, D. M., Ujváry, I., Iula, D. M., Baumann, M. H., & Stove, C. P. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107503 · Cited by 35 · see citing works
Self-citationNew Psychoactive Substances Intoxications and Fatalities during the COVID-19 Epidemic
Lo Faro, A., Berardinelli, D., Cassano, T., Dendramis, G., Montanari, E., Montana, A., Berretta, P., Zaami, S., Busardò, F., & Huestis, M. (2023) · Biology · doi:10.3390/biology12020273 · Cited by 33 · see citing works
Norman, C., Marland, V., McKenzie, C., Ménard, H., & Nic Daéid, N. (2023) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2023.104102 · Cited by 25 · see citing works
Grafinger, K. E., Wilde, M., Otte, L., & Auwärter, V. (2021) · Forensic Science International · doi:10.1016/j.forsciint.2021.110989 · Cited by 21 · see citing works
Vandeputte, M. M., Bilel, S., Tirri, M., Corli, G., Bassi, M., Layle, N. K., Fantinati, A., Walther, D., Iula, D. M., Baumann, M. H., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110113 · Cited by 19 · see citing works
Self-citationDeath associated with brorphine, an emerging novel synthetic opioid
Vohra, V., King, A. M., Jacobs, E., & Aaron, C. (2021) · Clinical Toxicology · doi:10.1080/15563650.2021.1879111 · Cited by 16 · see citing works
Activity-based detection of synthetic cannabinoid receptor agonists in plant materials
Timmerman, A., Balcaen, M., Coopman, V., Degreef, M., Pottie, E., & Stove, C. P. (2024) · Harm Reduction Journal · doi:10.1186/s12954-024-01044-4 · Cited by 8 · see citing works
Self-citationBehavioural Effects and Naloxone Effectiveness With New Synthetic Opioids
Nielsen, S., Silva, J. P., Jones, J. D., Krotulski, A., Poovendran, D., Muzangizi, D., Forte, G., White, J., & Comer, S. D. (2026) · Drug and Alcohol Review · doi:10.1111/dar.70040 · Cited by 6 · see citing works
- Authors
- Verougstraete, N., Vandeputte, M. M., Lyphout, C., Cannaert, A., Hulpia, F., Van Calenbergh, S., Verstraete, A. G., & Stove, C.
- Affiliations
- Ghent University Hospital (BE)
- Ghent University (BE)
- Laboratory for Medicinal Chemistry, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
- Corresponding author
- Stove, Christophe
- ORCID
- Venue
- Journal of Analytical Toxicology
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-08-03
- Volume
- 44
- Issue
- 9
- Pages
- 937-946
- ISSN
- 0146-4760 (ISSN-L)
- 1945-2403
- OpenAlex
- W3047168661
- Cited by
- 44
- References
- 20
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 2
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Analytical Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Funders
- Bijzonder Onderzoeksfonds UGent (01J15517)
- Fonds Wetenschappelijk Onderzoek (12Y9520N, 1703320N, 3S038719)
- Herculesstichting (AUGE/17/22 ‘Pharm-NMR’)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
- Keywords
- synthetic opioids, new psychoactive substances, fentanyl analogs, hydroxy metabolites, illicit drug markets, drug identification, chemical characterization, opioid potency
- MeSH terms
- Analgesics, Opioid, Chromatography, Liquid, Fentanyl, Humans, Imidazoles, Gas Chromatography-Mass Spectrometry, Piperidines, Psychotropic Drugs, Illicit Drugs, Designer Drugs, Substance Abuse Detection, Tandem Mass Spectrometry
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