DARK Classics in Chemical Neuroscience: U-47700

Abstract

U-47700, 3,4-dichloro-N-((1R,2R)-2-(dimethylamino)­cyclohexyl)-N-methyl benzamide, is a novel synthetic opioid (NSO), discovered by the Upjohn company in the late 1970s. With potent in vivo activity, ∼10-times greater than that of morphine, U-47700 has become a drug of widespread abuse due to its ease of synthesis and, until recently, lack of robust detection methods by law enforcement. U-47700 has been found in counterfeit oxycodone tablets and is a key ingredient in “gray death.” Due to its emergence worldwide in the past 5 years, it is now a Schedule I drug in the United States and similarly designated around the world; moreover, at autopsy, U-47700 was found to have contributed to the death of the pop artist Prince. This Review will capture the >40 year history of U-47700 and go in-depth regarding the synthesis, medicinal chemistry, in vitro/in vivo pharmacology, drug metabolism (from postmortem overdose cases), and societal impact of this DARK Classic in chemical neuroscience.

Are the N‐demethylated metabolites of U‐47700 more active than their parent compound? In vitro μ‐opioid receptor activation of N‐desmethyl‐U‐47700 and N,N‐bisdesmethyl‐U‐47700

“…7 Nevertheless, functional in vitro activity assays showed a lower in vitro potency (EC 50 of 140 nM) at MOR than that of morphine (EC 50 of 31 nM), and radioligand-binding assays also showed a lower in vitro affinity to MOR (K i of 57 nM) than morphine (K i of 5 nM). 7 Thus, concerning brain tissue with a high density of opioid receptors, 19 the elucidation of MOR activity of the N-demethylated metabolites of U-47700 is essential to assess their potential toxicity. However, our in vitro MOR activation analysis of U-47700 and its metabolites revealed a negative impact of the loss of the methyl group(s) on the MOR activation potential.…”

“…Although the number of new releases is declining and NSOs constitute only a relatively small subgroup of illicitly marketed substances, 2 their hazardous potential has been responsible for a dramatic rise in NSO‐caused poisoning or fatal cases, especially in the United States, in the last years 3 . 3,4‐Dichloro‐ N ‐[2‐(dimethylamino)cyclohexyl]‐ N ‐methylbenzamide (U‐47700, Figure 1) is one of the most famous non‐fentanyl‐derived NSO and was involved in many intoxication cases reported in literature 4–7 . The structural arrangement of the basic nitrogen and the aromatic ring system allows U‐47700 to assume a spatial orientation comparable with that of morphine, resulting in a selective agonism at the μ‐opioid receptor (MOR), 8 which mediates the major pharmacological effects, such as analgesia, euphoria, sedation, and respiratory depression 9 …”

U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market

“…It is hypothesized that U-compounds emerged as NSOs due to their desirable opioid-mediated effects (i.e., euphoria and pain relief), together with ease of synthesis and availability of precursor chemicals or starting materials [ 20 , 21 ]. Clandestine drug products containing U-47700 are nicknamed “pink”, “U4”, or “pink heroin” by drug distributors and consumers, and more recently this drug was identified as a constituent in the potent opioid cocktail “gray death” [ 22 ].…”

“…Studies using laboratory animals show that U-47700 is about 10-times more potent than morphine as an analgesic agent [ 23 ], and this enhanced potency could be responsible for the intoxications and mortality associated with the compound [ 24 , 25 , 26 , 27 ]. Published reviews about U-47700 have covered its history and diversion [ 20 ], synthetic schemes and structure activity relationships (SAR) [ 21 ], as well as clinical symptoms [ 28 ]. Here, we provide an updated review of the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and selected analogs.…”

Fatal intoxication with U-47700 in combination with other NPS (N-ethylhexedrone, adinazolam, 4-CIC, 4-CMC) confirmed by identification and quantification in autopsy specimens and evidences

“…Particularly dangerous one seems to be a drug called 'Gray Death', which appeared on the streets in the Southeastern United States in 2019. Actually, 'Gray Death' is a random combination (depending on each mixture) of U-47700 with fentanyl, carfentanil, furanyl fentanyl, heroin, or other illicit opiates [11]. Nikolau et al [12] also paid attention to scientific papers describing cases of intoxication or deaths related to U-47700 alone, or in combination with alcohol, medicinal, controlled drugs, new psychoactive substances (NPS; especially fentanyl or its analogues).…”