Pharmacological Evaluation and Forensic Case Series of N-pyrrolidino Etonitazene (etonitazepyne), a Newly Emerging 2-benzylbenzimidazole 'Nitazene' Synthetic Opioid

• NCJ Number: 304811
• Journal: Archives of Toxicology Volume: 96 Dated: April 2022 Pages: 1845–1863
• Author(s): Marthe M. Vandeputte; Alex J. Krotulski; Donna Walther; Grant C. Glatfelter; Donna Papsun; Sara E. Walton; Barry K. Logan; Michael H. Baumann; Christophe P. Stove
• Date Published: April 2022
• Length: 19 pages
• Grant Number(s): 2020-DQ-BX-0007
• Agencies: NIJ-Sponsored
• Publication Type: Research (Applied/Empirical)
• Award: Real-Time Sample-Mining and Data-Mining Approaches for the Discovery of Novel Psychoactive Substances (NPS)

Annotation

Here, we pharmacologically characterize an emerging cyclic analogue of etonitazene, called N-pyrrolidino etonitazene (etonitazepyne), using in vitro and in vivo methods.

Abstract

Novel synthetic opioids continue to emerge on recreational drug markets worldwide. In response to legislative bans on fentanyl analogues, non-fentanyl structural templates, such as 2-benzylbenzimidazoles (‘nitazenes’), are being exploited to create new μ-opioid receptor (MOR) agonists. In the current study, a series of analytically confirmed fatalities is described to complement preclinical findings. Radioligand binding assays in rat brain tissue revealed that N-pyrrolidino etonitazene has high affinity for MOR (Ki = 4.09 nM) over δ-opioid (Ki = 959 nM) and κ-opioid (Ki = 980 nM) receptors. In a MOR-β-arrestin2 activation assay, N-pyrrolidino etonitazene displayed high potency (EC50 = 0.348 nM), similar to etonitazene (EC50 = 0.360 nM), and largely exceeding the potencies of fentanyl (EC50 = 14.9 nM) and morphine (EC50 = 290 nM). When administered s.c. to male Sprague Dawley rats, N-pyrrolidino etonitazene induced opioid-like antinociceptive, cataleptic, and thermic effects. Its potency in the hot plate test (ED50 = 0.0017 mg/kg) was tenfold and 2,000-fold greater than fentanyl (ED50 = 0.0209 mg/kg) and morphine (ED50 = 3.940 mg/kg), respectively. Twenty-one overdose fatalities associated with N-pyrrolidino etonitazene were found to contain low blood concentrations of the drug (median = 2.2 ng/mL), commonly in the context of polysubstance use. N-Pyrrolidino etonitazene was reported as a cause of death in at least two cases, demonstrating toxicity in humans. We demonstrate that N-pyrrolidino etonitazene is an extremely potent MOR agonist that is likely to present high risk to users. Continued vigilance is required to identify and characterize emergent 2-benzylbenzimidazoles, and other non-fentanyl opioids, as they appear in the marketplace. (Publisher Abstract Provided)