Brorphine

Brorphine is a piperidine-based opioid analgesic compound. Some of its structural analogs, originally described in 2018, are functionally biased μ-opioid receptor agonists, showing reduced side effects, especially lacking respiratory depression, when administered in high doses in mice. Importantly, however, this brominated member of the series, while it is a potent μ-opioid agonist, lacks the safety margin seen for several other analogs and shows only limited functional bias, with an EC50 of 4.8nM for GTPγS binding and 182nM for β-arrestin recruitment.[1] Brorphine can instead be regarded as a typical opioid agonist, based upon its performance under various assay conditions, including robust arrestin recruitment. Brorphine is therefore not preferable, from a safety perspective, to common street opioids. Moreover, its safety profile in any animal model has never been established. In addition to respiratory risks, it is expected to be cardiotoxic because it is a potent hERG potassium ion channel inhibitor, a mechanism that can prompt deadly cardiac arrhythmias, similar to dextropropoxyphene, a previously approved opioid medication which was withdrawn from sale because of this side effect. Despite the potential safety issues and lack of animal studies, it has been sold as a designer drug since mid-2019, initially being identified in the US Midwest, though it has since been found in 2020 in Belgium. Given its potency, lack of functional bias, and hERG inhibition, it can be expected to be a comparatively toxic opioid, and indeed multiple deaths from its abuse have been reported. It is related in chemical structure to compounds such as benzylfentanyl and bezitramide, though it is sufficiently structurally distinct to fall outside the formal definition of a "fentanyl analogue" in jurisdictions such as the US and New Zealand which have Markush structure controls over this family of drugs.[2][3]

Brorphine
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChEMBL
Chemical and physical data
FormulaC20H22BrN3O
Molar mass400.320 g·mol−1
3D model (JSmol)

Brorphine was first identified in the U.S. recreational drug supply in July 2020 by the Center for Forensic Science Research and Education (CFSRE) through its NPS Discovery program; however, earlier identifications by the Drug Enforcement Administration (DEA) may have come as early as late 2019. The rise of brorphine in the U.S. can be directly linked to the decline of isotonitazene due to scheduling by the DEA. Brorphine was first implicated in 20 deaths in the U.S., primarily in cases originating from midwest states. Brorphine was commonly found with fentanyl and flualprazolam, a drug combination verified by drug product testing. Brorphine has also been identified in counterfeit opioid pills and tablets. Recently data from CFSRE and NMS Labs show that brorphine has been detected in more than 100 cases as of October 2020.[4]

See also

References
  1. Kennedy NM, Schmid CL, Ross NC, Lovell KM, Yue Z, Chen YT, et al. (October 2018). "Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias". Journal of Medicinal Chemistry. 61 (19): 8895–8907. doi:10.1021/acs.jmedchem.8b01136. PMC 6386185. PMID 30199635.
  2. Vandeputte MM, Cannaert A, Stove CP (November 2020). "In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances". Archives of Toxicology. 94 (11): 3819–3830. doi:10.1007/s00204-020-02855-7. PMID 32734307.
  3. Verougstraete N, Vandeputte MM, Lyphout C, Cannaert A, Hulpia F, Van Calenbergh S, et al. (August 2020). "First report on brorphine: the next opioid on the deadly new psychoactive substances' horizon?". Journal of Analytical Toxicology. doi:10.1093/jat/bkaa094. PMID 32744605.
  4. Krotulski AJ, Papsun DM, Kacinko SL, Nobel C, Logan BK (November 2020). "Brorphine—Investigation and quantitation of a new potent synthetic opioid in forensic toxicology casework using liquid chromatography‐mass spectrometry". Journal of Forensic Sciences. doi:10.1111/1556-4029.14623.


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