Pharmacological and metabolic characterization of the novel synthetic opioid brorphine and its detection in routine casework. (October 2021)

• Record Type: Journal Article
• Authors: Grafinger, Katharina Elisabeth; Wilde, Maurice; Otte, Lorina; Auwärter, Volker
• Is Part Of: Forensic science international. Volume 327(2021)
• Publication Date: 2021-10
• Subjects: NSO -- Brorphine -- Metabolism -- PHLM -- [35S]-GTPγS -- MOR -- KOR; Medical jurisprudence -- Periodicals; Chemistry, Forensic -- Periodicals; Forensic Medicine -- Periodicals; Médecine légale -- Périodiques; Chimie légale -- Périodiques; Gerechtelijke geneeskunde; Gerechtelijke chemie; Gerechtelijke psychiatrie; Chemistry, Forensic; Medical jurisprudence; Electronic journals; Periodicals; Electronic journals; 614.1
• DOI: 10.1016/j.forsciint.2021.110989
• Languages: English
• ISSNs: 0379-0738

Abstract

Highlights: In vitro and in vivo metabolism of brorphine. Pharmacological characterization of brorphine at the µ- and κ-opioid receptors. Main in vivo metabolite formed by N-hydroxylation. Main in vitro metabolite formed by hydroxylation at the benzimidazol-2-one moiety. Brorphine to be a potent µ-opioid receptor agonist and a weak, partial κ-opioid receptor agonist. Abstract: After their first emergence in 2009, Novel synthetic opioids (NSO) have become an emerging class of New Psychoactive Substances (NPS) on the market for these new drugs. So far, 67 NSO have been reported to the Early Warning system of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). It is presumed that NSO mainly target the four known opioid receptors, i.e . the μ-opioid (MOR), the δ-opioid (DOR), the κ-opioid (KOR) and nociceptin receptors and that their consumption can result in serious adverse effects such as massive respiratory depression or death. In the present study we investigated the in vivo and in vitro metabolism of brorphine, a NSO that was first identified on the NPS market in August 2019 in the United States, using both a pooled human liver microsome assay and real forensic case samples. For the detection of metabolites LC-HR-MS/MS was used and quantification of brorphine was performed using an LC-MS/MS method. Additionally, we pharmacologically characterized brorphine regarding its activation of the MOR and KOR via G protein recruitment using the [ 35 S]-GTPγS assay. In forensic urine samples, 14 distinct metabolites were identified, whereas in blood only four metabolites could be found. The pooled human liver microsome assay generated six distinct in vitro phase I metabolites. The most prominent in vivo metabolite was formed by N -oxydation, whereas the main in vitro metabolite was formed by hydroxylation. The pharmacological characterization at the MOR and KOR revealed brorphine to be a potent MOR agonist and a weak, partial KOR agonist in the [ 35 S]-GTPγS assay.