First Report on Brorphine: The Next Opioid on the Deadly New Psychoactive Substance Horizon?

Abstract

New psychoactive substances (NPS) continue to appear on the drug market. Until recently, new synthetic opioids, which are amongst the most dangerous NPS, primarily encompassed analogues 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. Brorphine was identified in a powder and in the serum of a patient seeking medical help for detoxification. 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 (GC–MS), LC–diode array detection (DAD) and Fourier-transform infrared (FT-IR) spectroscopy analyses. Finally, the structure was confirmed by performing 1H- and 13C-NMR spectroscopy. In vitro biological activity of brorphine was determined by a cell-based µ-opioid receptor (MOR) 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.

Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of “Nitazene” 2-Benzylbenzimidazole Synthetic Opioids

“…23 The above further stresses the high harm potential of even small quantities of material and emphasizes the need for highly sensitive detection methods -whether analytical or activity-based. 10,[60][61][62][63][64] In a recent report from Poland, undiluted etodesnitazene was identified in a powder. As also stated by the authors, the fact that a large amount (25.0 g) of highly pure powder was found, poses a particular threat.…”

“…Recent examples include the emergence of AP-237, piperidylthiambutene, brorphine and several 2benzylbenzimidazole opioids, also referred to as nitazenes. 2,3,[7][8][9][10] Structurally unrelated to traditional opiates or (the later synthesized) fentanyl (Fig. 1), the synthesis of a series of benzimidazole derivatives was first reported in the late 50s and early 60s by a Swiss company.…”

Trace Residue Identification, Characterization and Longitudinal Monitoring of the Novel Synthetic Opioid β-U10, from Discarded Drug Paraphernalia

“…Predominately, newly emerging NSO's are identified and characterized from intact samples seized by law enforcement agencies [17], obtained during online monitoring of drug markets [18], or provided by individuals presenting for medical care after experiencing adverse effects following consumption [19], using a range of analytical chemistry techniques including Fourier-transform infrared spectroscopy (FT-IR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography (LC-MS) using electrospray ionization (ESI), LC-tandem mass spectrometry (MS/MS) and Nuclear magnetic resonance (NMR). The sensitivity of GC-MS and LC-MS and -MS/MS methods also facilitate the use of these techniques for trace residue analysis of the contents of discarded drug paraphernalia (DDP), such as used syringes, where materials may be present in only microgram to nanogram quantities [20][21][22][23][24][25].…”

Brorphine—Investigation and quantitation of a new potent synthetic opioid in forensic toxicology casework using liquid chromatography‐mass spectrometry

“…Literature regarding prevalence and/or toxicity of brorphine is limited. Verougstraete et al detailed the first report of brorphine emerging on the NPS market in Europe [28]. This case from early to mid‐2020 involved a living individual admitted to the emergency department experiencing withdrawal symptoms.…”

“…Brorphine (#21 in their publication) was found to be one of the most potent compounds relative to morphine. Recent studies using in vitro receptor activation assays showed that brorphine presents efficacy and potency similar to fentanyl [27,28].…”