Comparative neuropharmacology of structurally distinct non-fentanyl opioids that are appearing on recreational drug markets worldwide

The United States (US) is experiencing an unprecedented opioid epidemic (CDC, 2022). While illicitly manufactured fentanyl is a major driving force (Ciccarone, 2019), the emergence of novel synthetic opioids (NSOs) has added a layer of complexity to the crisis (Prekupec et al., 2017). The number of NSOs continues to grow, with more than 70 identified by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and the United Nations Office on Drugs and Crime (UNODC) (EMCDDA, 2022a, UNODC, 2022). Particularly worrisome is the putative high potency of many NSOs, which portends risk for respiratory depression and death (Adamowicz and Nowak, 2022). The NSO market can be broadly categorized into fentanyl analogs (e.g., phenethylpiperidines) and non-fentanyl compounds of various chemical classes (e.g., cyclohexylbenzamides (Baumann et al., 2020, Kyei-Baffour and Lindsley, 2020), 2-benzylbenzimidazoles (Ujváry et al., 2021, Vandeputte et al., 2021), cinnamyl piperazines (Fogarty et al., 2022)). In 2017, 77% of NSOs reported to the EMCDDA were fentanyl analogs, but by 2021, all newly reported NSOs were structurally distinct from fentanyl (EMCDDA, 2022b, UNODC, 2020). The chemical structures of representative NSOs, as compared to morphine and fentanyl, are depicted in Fig. 1.

Beginning in 2015, the most prevalent non-fentanyl NSO was U-47700. This cyclohexylbenzamide compound was patented in the 1970s by the Upjohn company (Szmuszkovicz, 1978) as part of a series of novel antinociceptive agents, but was never approved for clinical use (Baumann et al., 2020, Kyei-Baffour and Lindsley, 2020, Sharma et al., 2019). U-47700 garnered worldwide attention due to its association with multiple fatalities (Kyei-Baffour and Lindsley, 2020). As a result, the drug was internationally scheduled in 2017 (CND, 2017), then gradually disappeared. The number of new fentanyl analogs and U-compounds declined from 2018 to 2019, though various NSOs with different chemical structures transiently appeared (UNODC, 2020, Vandeputte et al., 2022d). In 2019, the NSO market took a new turn with the emergence of isotonitazene, a 2-benzylbenzimidazole opioid structurally related to the internationally scheduled compound, etonitazene (Blanckaert et al., 2020, Ujváry et al., 2021).

2-Benzylbenzimidazole opioids (“nitazenes”) were originally studied in the late 1950s (Bromig, 1958, Gross and Turrian, 1957, Hunger et al., 1960a, Hunger et al., 1960b, Hunger et al., 1957), but were never marketed (Ujváry et al., 2021). Data from preclinical studies demonstrate that isotonitazene is a highly potent mu-opioid receptor (MOR) agonist (Hunger et al., 1960a, Vandeputte et al., 2021), and the drug has been linked to many intoxications and fatalities (Krotulski et al., 2019, Krotulski et al., 2020a). Isotonitazene dominated the NSO market for a little over a year (Vandeputte et al., 2022a), followed by its international scheduling (DEA, 2020, UNODC, 2021) and the appearance of the benzimidazolone compound, brorphine (Krotulski et al., 2020c, Verougstraete et al., 2020). First described in the scientific literature in 2018 (Kennedy et al., 2018), brorphine quickly spread into recreational markets (Krotulski et al., 2020b, Vandeputte et al., 2022a). Scheduling actions targeting brorphine (DEA, 2021) expedited its disappearance, which was followed by the emergence of several new nitazene analogs (e.g., N-pyrrolidino etonitazene) (Papsun et al., 2022, Vandeputte et al., 2022b, Vandeputte et al., 2022e). With the exception of fluorofentanyl, nitazene opioids now dominate the NSO market (EMCDDA, 2022a, Krotulski et al., 2023b). The most recent nitazene detected in confiscated drug material is N-desethyl isotonitazene, a known metabolite of isotonitazene (Krotulski et al., 2023a, Krotulski et al., 2022).

Limited information is available about the biological effects of NSOs when they first appear (Baumann et al., 2018b). Most preclinical studies have focused mainly on the in vitro pharmacological characterization of distinct classes of NSOs (i.e., fentanyl analogs (Åstrand et al., 2020, Eshleman et al., 2020, Hassanien et al., 2020, Kanamori et al., 2021, Vasudevan et al., 2020), U-compounds (Baumann et al., 2020, Hsu et al., 2019, Otte et al., 2022, Vasudevan et al., 2020), or nitazenes (De Luca et al., 2022, Kanamori et al., 2022, Vandeputte et al., 2021, Vandeputte et al., 2022b, Vandeputte et al., 2022e, Walton et al., 2022), and larger inter-class comparisons of NSOs are limited, hampering a direct evaluation of opioid activities across chemical scaffolds. Hence, the purpose of the present study was to carry out a side-by-side comparison of the pharmacology of recent, structurally diverse NSOs, and the classic opioid agonists morphine and fentanyl. In particular, we examined the effects of U-47700, isotonitazene, and brorphine, as prototypical examples of cyclohexylbenzamide, 2-benzylbenzimidazole, and benzimidazolone opioids. The parent nitazene compound, etonitazene, and the isotonitazene metabolite, N-desethyl isotonitazene, were also included (Fig. 1). In vitro radioligand binding and cyclic AMP (cAMP) functional assays were performed in rat brain tissue and in cells stably expressing human MOR, respectively. Furthermore, in vivo opioid effects in rats were studied and compared across the different compounds.

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