When a Prophecy Comes True: Ethyleneoxynitazene as a 'Prophetic' Member of the Emerging Class of 2-Benzylbenzimidazole 'Nitazene' Synthetic Opioids

• Published in: Drug and alcohol dependence 2024-07, Vol.260, p.109969, Article 109969
• Main Authors: Vandeputte, Marthe, Glatfelter, Grant, Walther, Donna, Ujváry, István, Iula, Donna, Baumann, Michael, Stove, Christophe
• Format: Article
• Language: English
• ISSN: 0376-8716
• DOI: 10.1016/j.drugalcdep.2023.109969

Select Drug Category Opiates/Opioids Topic Molecular Pharmacology Abstract Detail Preclinical - In Vitro Abstract Category Original Research New synthetic opioids continue to emerge on recreational drug markets. Recently, opioids with a 2-benzylbenzimidazole core (‘nitazenes’, e.g. isotonitazene) have become increasingly prevalent, the potency of some members dwarfing that of fentanyl. The aim of our work is to in vitro and in vivo characterize existing, as well as 'prophetic' nitazenes, to allow risk prioritization based on structure activity relationships. As a case example, the pharmacological characterization of ethyleneoxynitazene, which we predicted to emerge, and which was first found in January 2023, will be presented. In vitro pharmacological characterization (experiments performed in quintuplicate) encompassed assessment of mu opioid receptor (MOR) activation via a β-arrestin2 recruitment assay to derive the potency and efficacy, as well as radioligand binding assays performed in rat brain tissue. Pharmacodynamic effects were evaluated in male Sprague Dawley rats and included assessment of antinociceptive, cataleptic, and thermic effects. Radioligand binding assays revealed a Ki of 57.9nM at MOR; only slightly higher than the Ki of etonitazene (38.4nM), the most potent nitazene. Despite a similar affinity, ethyleneoxynitazene had a >100-fold lower potency in the MOR-β-arrestin2 recruitment assay (EC50 etonitazene 0.588nM; ethyleneoxynitazene 70nM). Also its efficacy (relative to the reference hydromorphone) was lower than that of etonitazene (Emax 187% vs. 254%). The strongly reduced MOR activation potential was also evident from the in vivo antinociception (mouse hot plate) assay, with an ED50 of 0.0223mg/kg and 11.1mg/kg for etonitazene and ethyleneoxynitazene, repectively. The hypothermia and catalepsy assays revealed the same pattern. The a priori availability of pharmacological (in vitro and in vivo) data by the time the 'prophetic' opioid ethyleneoxynitazene hit the recreational drug market allowed us to predict that, compared to several other nitazenes, this is not the opioid of highest concern. Similarly, pharmacological data for other 'prophetic' nitazenes are now readily available.