DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles

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 mu 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 2benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.

Automated summary

Etonitazene and its derivatives, developed in the late 1950s by the Swiss pharmaceutical giant CIBA, are potent analgesics with morphine-like effects. Recently, unscheduled synthetic opioids have emerged on the illicit drug market, leading to fatalities. This class of compounds has inspired research and led to the emergence of new psychoactive substances, impacting chemical neuroscience.