The search for the “next” euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning

Abstract

PurposeA detailed review on the chemistry and pharmacology of non-fentanil novel synthetic opioid receptor agonists, particularly N-substituted benzamides and acetamides (known colloquially as U-drugs) and 4-aminocyclohexanols, developed at the Upjohn Company in the 1970s and 1980s is presented.MethodPeer-reviewed literature, patents, professional literature, data from international early warning systems and drug user fora discussion threads have been used to track their emergence as substances of abuse.ResultsIn terms of impact on drug markets, prevalence and harm, the most significant compound of this class to date has been U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide), reported by users to give short-lasting euphoric effects and a desire to re-dose. Since U-47700 was internationally controlled in 2017, a range of related compounds with similar chemical structures, adapted from the original patented compounds, have appeared on the illicit drugs market. Interest in a structurally unrelated opioid developed by the Upjohn Company and now known as BDPC/bromadol appears to be increasing and should be closely monitored.ConclusionsInternational early warning systems are an essential part of tracking emerging psychoactive substances and allow responsive action to be taken to facilitate the gathering of relevant data for detailed risk assessments. Pre-emptive research on the most likely compounds to emerge next, so providing drug metabolism and pharmacokinetic data to ensure that new substances are detected early in toxicological samples is recommended. As these compounds are chiral compounds and stereochemistry has a large effect on their potency, it is recommended that detection methods consider the determination of configuration.

Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene

“…4,10,11 Because of the relatively simple synthesis, in addition to excellent online precursor availability, the large majority of NPS opioids appearing until the end of 2018 were derivatives of fentanyl (marked in blue and with horizontal stripes in Figure 1). 12 From 2018 onwards, these numbers dropped and only one novel fentanyl analog was identified in 2019. This strong reduction was most probably a result of the introduction of new legislation in China in 2018.…”

Toxicokinetics and analytical toxicology of the abused opioid U‐48800 — in vitro metabolism, metabolic stability, isozyme mapping, and plasma protein binding

“…Both chemical structures are given in Figure . U‐48800 receptor affinity studies were not yet performed, but based on the analogy to U‐51754, comparable pharmacological effects are likely . Due to a higher affinity to the κ‐receptor in comparison to the μ‐receptor, analgesia with fewer unwanted pharmacological effects such as respiratory depression could be expected.…”

“…6 Together with its regioisomer U-51754 (methene-U-47700), which was also described as an NSO, 7,8 it belongs to the so-called U-drugs and is structurally non-related to classical opioids such as morphine and fentanyl. 6,9 Both chemical structures are given in Figure 1. U-48800 receptor affinity studies were not yet performed, but based on the analogy to U-51754, comparable pharmacological effects are likely.…”

“…U-48800 receptor affinity studies were not yet performed, but based on the analogy to U-51754, comparable pharmacological effects are likely. 6,7 Due to a higher affinity to the κ-receptor in comparison to the μ-receptor, analgesia with fewer unwanted pharmacological effects such as respiratory depression could be expected. Solimini et al recently reviewed the pharmacotoxicology of non-fentanylderived NSOs and found U-48800 available as a "research chemical" of the opioid analgesic class to replace U-47700 and that conventional drug tests do not detect such compounds.…”

“…(parallel tube model with 6 [BW] = liver weight normalized by body weight = 26, 16 and SF = scaling factor S9 protein per gram of liver = 121, 17 CL h = hepatic clearance, Q = hepatic blood flow rate in human = 20 mL/min/kg, 18 f u = free fraction in plasma.…”