The first reported fatality associated with the synthetic opioid 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis

The search for synthetic opioids as alternatives to opium-based derivatives has provided an important impulse to drug development around the globe. An important goal in the systematic evaluation of new drug candidates is the identification of compounds that provide a more favorable side-effect profile, which includes reduced dependence-producing properties and abuse liability. A rich source of information about these research efforts can be found in the scientific literature. However, the exploration of these important discoveries has also been increasingly mined by largescale producers of these materials, which are then offered for sale. These so-called ‘research chemicals’ or new psychoactive substances (NPS)[1] have created challenges to policy makers, clinicians, and law enforcement around the world.[2] Recent examples of synthetic opioids that emerged as NPS on the market, and which were associated with severe cases of adverse effects, include 3,4-dichloro-N- {[1-(dimethylamino)cyclohexyl]methyl}benzamide (AH-7921), 1-cyclohexyl-4-(1,2- diphenylethyl)piperazines (MT-45) and N-phenyl-N-[1-(2-phenylethyl)piperidin-4- yl]acetamide (acetylfentanyl), respectively (Figure 1). Following the recommendation provided by the World Health Organization’s Expert Committee on Drug Dependence (ECDD),[3] AH-7921 was placed in Schedule I of the 1961 Single Convention, as amended by the 1972 Protocol in 2015.[4] Furthermore, ECDD’s recommendation to place MT-45 into Schedule I and acetylfentanyl in Schedules I and IV of the same Convention[5] have been recently confirmed by the Commission on Narcotic Drugs.[6] -Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) (Figure 1) has recently emerged on the market and can be purchased from various Internet retailers and is a structural isomer of AH-7921 (Figure 1). The preparation of U- 47700 and other derivatives was disclosed by the Upjohn Company in the 1970s[7] followed by the recognition that U-47700 showed increased analgesic properties and morphine-like behavioural features in mice compared to morphine itself.[8,9] The presence of two chiral centres gives rise to a cis- and trans- racemic mixture with the trans-form being advertised for sale. Binding studies also revealed that U-47700 displayed an appreciable selectivity for the μ-opioid receptor over the −opioid receptor.[10,11] A variety of cyclohexyl trans-1,2-diamines have been found to be potent analgesics and the vicinal 1,2-diamine pattern has provided access to a large range of substances with diverse biological activities.[12-14] Since U-47700 did not progress to clinical trials, there is no direct clinical information pertaining to its effects. Keeping in mind the various limitations that may be associated with descriptions obtained from self-reporting users, its effects have been described with various positive and negative symptoms but appeared to be essentially comparable to other opioids. Specifically, euphoria was reported in individuals, sometimes being short-lived, as well as general lift in mood with these desired effects being experienced in waves. The negative effects were also opioid based, including nausea with some users describing respiratory depression. For some users, U-47700 had a shorter duration of action and the urge to keep re-dosing was stated as being very high