In vitro structure–activity relationships and forensic case series of emerging 2‑benzylbenzimidazole ‘nitazene’ opioids
De Vrieze, L.M. et al. (2024) In vitro structure–activity relationships and forensic case series of emerging 2-benzylbenzimidazole ‘nitazene’ opioids. Arch. Toxicol. DOI:10.1007/s00204-024-03774-7
The study investigates the rising threat of 2-benzylbenzimidazole ‘nitazene’ opioids to public health. It systematically compares the effects of different structural modifications to the 2-benzylbenzimidazole core on μ-opioid receptor (MOR) activity. Researchers evaluated nine previously uncharacterized nitazenes along with known analogues, focusing on ‘ring’ substituted analogues, ‘desnitazene’ analogues (lacking the 5-nitro group), and N-desethyl analogues. Two in vitro MOR activation assays were used: β-arrestin2 recruitment and inhibition of cAMP accumulation. The results demonstrated that ‘ring’ modifications yield highly active drugs, with N-pyrrolidino substitutions generally more favorable for MOR activation than N-piperidine substitutions. Removal of the 5-nitro group resulted in a significant decrease in potency, while N-desethyl modifications showed notable MOR activity, with N-desethyl isotonitazene being exceptionally potent.
The study also included a forensic case series from North America and the UK, involving etodesnitazene, N-desethyl etonitazene, N-desethyl isotonitazene, N-pyrrolidino metonitazene, and N-pyrrolidino protonitazene. The low-to-sub ng/mL blood concentrations in most cases highlight the high potencies of these substances. The research bridges pharmacology and case data, aiming to increase awareness and guide legislative and public health efforts.
Keywords: New synthetic opioids (NSOs), 2-benzylbenzimidazole ‘nitazene’ opioids, forensic toxicology, μ-opioid receptor (MOR), bioassay
