The United Nations Office on Drugs and Crime (UNODC) defines “new psychoactive substances” (NPSs) as “substances of abuse, either in a pure form or a preparation, that are not controlled by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but which may pose a public health threat” [1]. NPS is generally available to drug users through offers on internet vendor sites, with shipments of small parcels complicating the monitoring of market evolutions of new recreational drugs. Fast identification of new molecules is necessary for efficient monitoring, information sharing, early warning, and risk awareness to respond efficiently to the potential health and social threats posed by the consumption of new substances [2]. The health effects of newly emerging NPS are generally unknown. In most cases, assumptions regarding their psychoactive effects are drawn from the similarity of their chemical structure with those of known substances. This paradigm has also been driving the production and design of new molecules for the recreational drug market: small modifications of core‐based chemical structures led to numerous synthetic cannabinoid receptor agonists (SCRAs) and synthetic cathinones present on the market of recreational synthetic drugs in Europe. The objective could be the replacement of a substance subject to control measures in certain countries or even enlarging the offer to satisfy a demand of customers with new “attractive” products [3]. While potential psychoactive effects can be attributed to new molecules on the basis of structural similarities with known substances for which such effects are known, ideally, experimental data becomes available to support these hypotheses.

This study presents the case of a new substance, not showing structural similarity with typical NPS, present in 5 g of white powder in a suspicious package labelled “5CP.” The parcel was sent from the Netherlands and seized by French customs in June 2022. Structure elucidation using various analytical techniques (discussed below) confirmed the identity of the substance as CH‐FUBBMPDORA (CHO‐4′Me‐5′Br‐FUBOXPYRA).

CH‐FUBBMPDORA (also referred to as 6TP/SGT and N‐[5‐bromo‐1‐(4‐fluorobenzyl)‐4‐methyl‐2‐oxo‐1,2‐dihydropyridin‐3‐yl)cyclohexanecarboxamide) (Figure 1) was introduced on the recreational drug market as a new addition to the SCRA family. Its name, CH‐FUBBMPDORA, was established in relation to the structure showing a cyclohexyl (CH) linked group, a fluorobenzyl (FUB) tail, a 5‐bromo‐4‐methylpyridin‐2(1H)‐one (BMPDO) core, and a retroamide (RA) linker [4]. SCRAs typically act on the central nervous system and have the cannabinoid 1 receptor (CB₁) as their prime target, and SCRA users aim to experience psychotropic effects such as relaxation and euphoria, similar to those exerted by Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC), the predominant psychoactive substance found in cannabis [5, 6]. However, due to their often higher potency, SCRA use has been associated with severe side effects such as cardiovascular, renal, and gastrointestinal toxicity, as well as respiratory depression, psychosis, seizures, stroke, coma, and even death [6, 7, 8, 9]. In addition, SCRAs often also act on the cannabinoid 2 receptor (CB₂), expressed at sites of active inflammation and present on cells of the immune system [10, 11].

Since the enactment of a seemingly blanket ban on SCRAs in China in mid‐2021, which controlled a wide array of current and potential future substances, the worldwide SCRA market has expanded and diversified even more [12, 13, 14]. Gradually moving away from the conventional head‐core‐tail building block structure, a plethora of new compounds have emerged on the SCRA scene, aiming to circumvent legislation by including several structural modifications such as the absence of features (e.g., the tail‐less precursor ADB‐INACA [15]), the presence of altered linkers (e.g., ADB‐FUBIATA [16]), the introduction of halogen atoms to the core moiety (e.g., ADB‐5′Br‐INACA [17]), and the overall inclusion of new core structures (e.g., BZO‐HEXOXIZID [18]) [19, 20, 21]. CH‐FUBBMPDORA can be classified as part of the latter group, carrying an oxo‐pyridyl structure, not mentioned as one of the seven core structures covered by the Chinese generic legislation. Interestingly, this substance also carries an additional bromine atom on the core, a structural modification also seen in other recently emerging SCRAs (e.g., ADB‐5′Br‐INACA, MDMB‐5′Br‐INACA, ADB‐5′Br‐PINACA, and ADB‐5′Br‐BINACA [17, 21, 22, 23, 24, 25]). Furthermore, a methyl substitution of the core moiety as a way to evade the generic ban on indazole‐carrying SCRAs has been noticed recently (MDMB‐5′Me‐INACA) and is also present in the structure of CH‐FUBBMPDORA [26]. It is the first SCRA reported to the EU Early Warning System of the European Drugs Agency (EUDA, formerly EMCDDA) with a BMPDO core.

Following its first identification in Europe (FIE) (presented in this study), CH‐FUBBMPDORA has been detected in several countries in Europe and in the United States (Table 1). It was identified for the first time in France, Germany, and Italy in 2022 and in Romania in 2023, according to information from EUDA [27]. As of November 2022, the substance has been added to the 1971 Schedule I of the Convention on Psychotropic Substances in Lithuania [28]; however, in 2023, it was seized in a Lithuanian prison. Following this, the Belarusian monitoring platform AIPSIN reported CH‐FUBBMPDORA as a substance with high potential for use in June of 2023 [29]. In March 2023, the Slovenian National Forensic Laboratory (NFL) included the substance in their NPS database as a detection based on a test purchase [30]. Also in March 2023, the US‐based Center for Forensic Science Research & Education (CFSRE) received a white powder containing the substance and reported the finding in June 2023 through their NPS Discovery program [31]. Furthermore, the compound was included as a Tier 2 (“Recommend”) substance in their Q4 2023 testing scope recommendations [32] (but was classified as a Tier 3 substance (“Consider”) at the beginning of 2024 and later removed from the scope recommendations [33, 34]). Still in 2023, by means of a decree on August 2, 2023, issued by the Ministry of Health in Italy, CH‐FUBBMPDORA was included in Table 1 of prohibited NPSs [35]. Also in August, the Swedish Public Health Agency received a request from the unit for drug prevention to declare the substance as a narcotic or health hazard [36] after it had been detected in an airport seizure in June 2023. After this, CH‐FUBBMPDORA has been seized again in Italy and Spain.

In this study, seized powder (indicated in gray in Table 1) was analyzed for structure identification by high‐field nuclear magnetic resonance (HF‐NMR), gas chromatography–mass spectrometry (GC–MS), Fourier transform infrared spectrometry (FTIR), liquid chromatography coupled to time‐of‐flight mass spectrometry (LC‐QTOF‐MS), Raman spectroscopy, and benchtop low‐field nuclear magnetic resonance (LF‐NMR), as discussed below. In particular, the potential of LF‐NMR for chemical elucidation was investigated. Modern LF‐NMR instruments use compact permanent magnets with magnetic fields typically below 2.5 Tesla. The high magnetic fields (typically above 7 Tesla) of HF‐NMR are produced in cryomagnets, making use of the phenomenon of supraconductivity. Higher magnetic fields allow for achieving higher resolution and better sensitivity, facilitating the structural analysis of complex molecules. On the other hand, HF‐NMR is an expensive technology. It requires the use of cryofluids and poses several technical constraints to the laboratory premises and infrastructure for the location of large‐dimension cryomagnets and electronic consoles. In contrast, LF‐NMR instruments are much more affordable, do not require cryofluids, and their small dimensions are comparable to those of most routine instruments used in analytical laboratories. Consequently, the LF‐NMR technique is becoming increasingly attractive to enforcement laboratories. Despite lower sensitivity and resolution, it is expected that LF‐NMR can be applied for the quantitative determination of certain controlled substances and, in combination with other analytical techniques, may contribute to the chemical identification of illicit unknown seized materials such as NPS [37, 38]. This topic is of high interest to enforcement customs and forensic laboratories. In this work, the spectra measured by LF‐NMR in the customs laboratory of Paris were used as a “challenge” to assess whether the information provided by this technique could allow partial or complete elucidation of the chemical structure. We present and discuss the interpretation of LF‐NMR data and the reasoning supporting the elucidation of the chemical structure of this new SCRA, CH‐FUBBMPDORA, which was established together with the customs laboratories of Paris and Rome, which are both equipped with such benchtop LF‐NMR instruments.

Despite the structural similarity of CH‐FUBBMPDORA with compounds described in the literature, the cannabinoid receptor activation potential of CH‐FUBBMPDORA itself was previously not investigated, leaving users (and legislators) unaware of the effects and potential harms associated with this substance, a topic that has been discussed on social media websites such as Reddit [39]. Although relatively new in the recreational drug landscape, oxopyridine structures were already described in a patent published in 2003 as compounds with an affinity for CB₂ [40]. Of relevance is that, in 2018, Chicca et al. studied the cannabinoid receptor affinity and activity of a series of oxopyridine carboxamides for future potential therapeutic purposes. One of the investigated compounds (“B2,” Figure 1) resembles CH‐FUBBMPDORA, as its retroamide, with the CH carboxamide moiety being switched to a cycloheptyl carboxamide. B2 showed nanomolar activity and affinity at both cannabinoid receptors [41]. Similarly, in 2019 and 2021, Gado et al. published the synthesis of “C2” (Figure 1), reportedly the first synthetic allosteric CB₂ modulator, which only differs from CH‐FUBBMPDORA in that it carries a cycloheptyl instead of a CH moiety. Furthermore, this compound displayed antinociceptive activity in an in vivo mouse model for neuropathic pain [42, 43]. Of relevance here is that it is not uncommon for clandestine labs or manufacturers to draw inspiration from (older) published literature describing research compounds for therapeutic purposes, as was seen before for nitazenes, a potent class of opioids [44]. At this point, it is unclear whether this was also the case for CH‐FUBBMPDORA.

To gain more insight into the pharmacological properties of CH‐FUBBMPDORA, in vitro CB₁ and CB₂ β‐arrestin 2 (βarr2) recruitment assays were performed using a reference standard as well as a sample of the seized powder. Moreover, metabolite studies via human liver microsome (HLM) incubation were carried out to facilitate the detection of use of this new SCRA, should it (further) emerge on recreational drug markets. Although CH‐FUBBMPDORA has not been detected in biological samples to this day, it is unclear whether this is due to a low prevalence of the substance, the absence of serious intoxication cases, or the inability of laboratories to detect the use of this compound because it—and its metabolites—are not included in the utilized targeted mass spectral libraries. Identifying the most plausible potential metabolites may thus aid in a more accurate mapping and monitoring of the use of this new SCRA.