DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles

Abstract

Etonitazene and related 2-benzylbenzimidazoles are potent analgetics invented in the research laboratories of the Swiss pharmaceutical giant CIBA in the late 1950s. Though the unprecedented structure distinguishes this class of compounds from poppy-derived and other synthetic analgetics, a range of studies indicate that these drugs are selective μ opioid receptor agonists possessing morphine-like pharmaco­toxicological properties in animals as well as humans. Several unscheduled members of this synthetically readily accessible class of opioids that are not controlled under the international and national drug control systems have recently emerged on the illicit drug market. Among them, isotonitazene has been implicated in at least 200 fatalities in Europe and North America. None of the 2-benzylbenzimidazole derivatives have been developed into medicines, but etonitazene and some of its derivatives have been used as receptor probes and in addiction behavior studies in animals. The unique structure has inspired research on such benzimidazoles and related benzimidazolones of which “brorphine” made its debut as one of the newest psychoactive substance to emerge on the illicit opioid drug market in mid-2019. This in-depth review provides a historical introduction, an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience of the 2-benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.

Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of “Nitazene” 2-Benzylbenzimidazole Synthetic Opioids

“…[11][12][13]19,20,[46][47][48][49][50] While it is not clear which route(s) are used for their illicit manufacture, several methods are simple and cost-efficient, not requiring regulated precursors. 22,24 For this report, we applied a relatively simple generic route (Fig. 3).…”

“…13,18 While several benzimidazole derivatives were patented, [19][20][21] further development was halted and no benzimidazole analgesics have ever been clinically approved. [22][23][24] Apart from observational animal studies (primarily tail-flick; a detailed overview of these studies is given by Ujváry et al 24 , a summary is also included in S1), there are no studies that systematically evaluated the µ-opioid receptor (MOR) activation potential of this emerging class of synthetic opioids. As early as 1975, the chemist Alexander T. Shulgin warned for the potential misuse of benzimidazole opioids as heroin substitutes.…”

Metonitazene in the United States—Forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry

“…However, although new in recreational North American drug supplies, the drug itself is not "newly discovered" as its pharmacology was described in pharmaceutical patents dating back to the 1950s and 1960s together with a closely related analogue: etonitazene (Figure 1). [5][6][7][8] A report documents the powerful analgesic effects of metonitazene from human clinical studies. 9 Metonitazene (EC 50 8.14 nM) is a potent synthetic opioid, albeit less potent than etonitazene (EC 50 0.661 nM), with purported potency similar to fentanyl (EC 50 14.4 nM) based on in vitro studies.…”

“…Metonitazene was first reported in Europe (Germany) in September 2020 12 . A recent review provides additional information about the 2‐benzylbenzimidazole (“nitazene”) subclass of NSOs 8,10 . No additional cases involving metonitazene have been reported to the United Nations Office on Drugs and Crime (UNODC) Early Warning Advisory (EWS) on NPS as of April 2021 12 .…”

Non-fentanyl-derived synthetic opioids emerging during recent years

“…The fatalities involved in the benzimidazole opioids were reported mainly for in etonitazene [ 59 ], isotonitazene [ 60 , 61 ], and metonitazene [ 55 ]; top fatalities are found for isotonitazene (Table 4 ). On the “Human deaths” column of Table 4 , there are many compounds without fatality data available (“na”), implying that deaths involved in other compounds of benzimidazole opioids will appear in the near future.…”