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

Baumann, Michael H.; Tocco, Graziella; Papsun, Donna M; Mohr, Amanda L A; Fogarty, Melissa F; Krotulski, Alex J

doi:10.3390/brainsci10110895

Cited by 35 publications

(58 citation statements)

References 99 publications

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“…Generally, synthetic opioids present stronger analgesic activity compared to morphine and classical opioid. Fentanyl and carfentanyl are approximately 50–100- and 10000-times respectively more potent than classical opioids [ 25 , 26 , 27 , 28 ]. Affinity to opioid receptors significantly differs between stereoisomers, e.g., only the trans form has opioid activity for U-47700 and U-50488 [ 27 ], and R-enantiomers are thought to be more potent than the S ones [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

Giorgetti

Pascali

Fais

et al. 2021

Life

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Novel psychoactive substances (NPS) represent a severe health risk for drug users. Even though the phenomenon has been growing since the early 2000s, the mechanisms of action of NPS at the receptors and beyond them are still scarcely understood. The aim of the present study was to provide a systematic review of the updated knowledge regarding the molecular mechanisms underlying the toxicity of synthetic opioids, cannabinoids, cathinones, and stimulants. The study was conducted on the PubMed database. Study eligibility criteria included relevance to the topic, English language, and time of publication (2010–2020). A combined Mesh and free-text protocols search was performed. Study selection was performed on the title/abstract and, in doubtful cases, on the full texts of papers. Of the 580 records identified through PubMed searching and reference checking, 307 were excluded by title/abstract and 78 additional papers were excluded after full-text reading, leaving a total of 155 included papers. Molecular mechanisms of synthetic opioids, synthetic cannabinoids, stimulants, psychedelics, and hallucinogens were reviewed and mostly involved both a receptor-mediated and non-receptor mediated cellular modulation with multiple neurotransmitters interactions. The molecular mechanisms underlying the action of NPS are more complex than expected, with a wide range of overlap among activated receptors and neurotransmitter systems. The peculiar action profile of single compounds does not necessarily reflect that of the structural class to which they belong, accounting for possible unexpected toxic reactions.

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Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

Giorgetti

Pascali

Fais

et al. 2021

Life

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“…The μ type receptor functions to provoke analgesia, physical dependence, respiratory depression, miosis, and euphoria; the κ type receptor functions to provoke analgesia, anticonvulsant effects, depression, dissociative/hallucinogenic effects, diuresis, miosis, and dysphoria; the δ type receptor functions to provoke analgesia, antidepressant effects, convulsant effects, physical dependence, and respiratory depression [ 18 , 19 ]. The most typical U-compound U-47700 largely acts on the μ opioids’ receptor [ 20 ]; its euphoric action and psychological and physical dependence are the causes for its repeated abuse, which lead many of its users to respiratory depression and deaths. U-48800, U-50488, and U-51754 have similar 2-phenylacetamide structures (see supplementary material Fig.…”

Section: U-compounds Including Ah-7921mentioning

confidence: 99%

“…AH-7921 1.7 [ 11 ], 0.9 [ 13 ] 26.9 [ 21 ] July 2012 in Norway and Sweden [ 11 ] At least 18 [ 14 ] LC–MS/MS [ 26 ] GC–MS [ 26 ] 2. U-47700 7.5 [ 11 , 12 ] 8.8 [ 21 ] Appearance on the recreational drug market in 2014, USA [ 20 ] At least 32 [ 20 ] (7.8–3040 ng/mL [ 20 ]) LC–MS/MS [ 26 , 28 ] LC–QTOF-MS [ 26 ] GC–MS [ 26 ] 3. U-49900 na [ 15 ] na Appearance in 2016 on a popular online forum [ 11 ] na (1.0–3.5 ng/mL [ 22 ]) UHPLC–HRMS/MS [ 23 , 24 ] GC–MS [ 24 ] 4.…”

Section: Introductionmentioning

confidence: 99%

“…U-47931E (bromadoline) na na Started to be sold on web sites in 2017 in Europe [ 16 ] na UPLC–MS/MS [ 22 ] 6. U-48800 7.5 [ 11 ] (acts on KOR [ 11 ]) na Included in seized material in 2018, USA [ 20 ] At least 8 [ 22 ] (0.27–6.2 ng/mL [ 22 ]) UPLC–MS/MS [ 22 ] 7. U-50488 na (acts on KOR [ 11 ]) na na na UPLC–MS/MS [ 25 ] 8.…”

Section: Introductionmentioning

confidence: 99%

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Non-fentanyl-derived synthetic opioids emerging during recent years

2022

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Purpose Since the appearance of fentanyl followed by its many kinds of analogues around 1988, North America has been exposed to fierce synthetic opioid pandemic resulting in more than 130,000 deaths due to their overdoses until May 2019, when China declared to prohibit the licit fentanyl analog production. However, the Chinese announcement did not go into force in USA due to the adroit strategies of tough traffickers. Thus, contrary to the expectation, the number of synthetic opioid products and their poisoning cases in USA has increased by about 30%; especially, various benzimidazole synthetic opioids have revived on the illicit drug market during a recent few years. In this article, the recent abrupt changes in the situations of illicit synthetic opioid market and their current abuses are described. Methods Various databases, such as SciFinder, Google, and Google Scholar, were utilized to collect relevant reports referring old but newly appearing synthetic opioids. Results At the present time, there are several families of new synthetic opioids, which are not fentanyl derivatives; MT-45 and its analogs, benzamide and 2-phenylacetamide opioids (U-series opioids), and benzimidazole opioids. Most of the above substances had been developed in 1950s to 1970s, but had never been used as analgesic medicines, because of their severe adverse effects, such as respiratory depression, physical dependence, and resulting deaths. However, there is possibility that these drugs will become main illicit synthetic opioids in place of the fentanyl analogs during coming several years from this time. Conclusions All of the above non-fentanyl-derived families had been developed 50–70 years ago to establish them as analgesic medicines, but had been unsuccessful. These drugs largely appeared in the illicit drug markets in North America, Europe, and Australia, during recent years. Pharmacological, toxicological, and metabolic studies are insufficient for benzamide and 2-phenylacetamide opioids, and are very scant especially for benzimidazole opioids. This time we should start studying pharmacotoxicology of the newly emerging synthetic opioids to alert forensic toxicologists in the world and to suppress their rapid and wide spread in the world. Supplementary Information The online version contains supplementary material available at 10.1007/s11419-022-00624-y.

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“…U-47700 is a potent μ-opioid receptor agonist, reported to be 7.5 times more potent than morphine (in animal models), while U-50488 is a κ-opioid receptor agonist [6]. Originating from the Allen and Hanburys [10,11] and Upjohn Companies [12] in the 1970's, the AH-and Useries of drugs have never been brought to market for therapeutic use, but have increasingly appeared in the illicit drug market since the early 2010's, with numerous fatalities reported worldwide [6,8,[13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Trace Residue Identification, Characterization and Longitudinal Monitoring of the Novel Synthetic Opioid β-U10, from Discarded Drug Paraphernalia

West

Fitzgerald

Hopkins

et al. 2022

Preprint

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Empirical data regarding dynamic alterations in illicit drug supply markets in response to the COVID-19 pandemic, including the potential for introduction of novel drug substances and/or increased poly-drug combinations at the ‘street’ level (i.e., directly proximal to the point of consumption), is currently lacking. Here, a high-throughput strategy employing ambient ionization-mass spectrometry is described for the trace residue identification, characterization and longitudinal monitoring of illicit drug substances found within >6,600 discarded drug paraphernalia (DDP) samples collected during a pilot study of an early warning system for illicit drug use in Melbourne, Australia from August 2020-February 2021, while significant COVID-19 lockdown conditions were imposed. The utility of this approach is demonstrated for the de novo identification and structural characterization of β-U10, a previously unreported naphthamide analogue within the ‘U-series’ of synthetic opioid drugs, including differentiation from its α-U10 isomer without need for sample preparation or chromatographic separation prior to analysis. Notably, β-U10 was observed with 23 other drug substances, most commonly in temporally distinct clusters with heroin, etizolam and diphenhydramine, and in a total of 182 different poly-drug combinations. Finally, longitudinal monitoring of the number and weekly ‘average signal intensity’ (ASI) values of identified substances, developed here as a semi-quantitative proxy indicator of changes in availability, relative purity and compositions of street level drug samples, revealed that increases in the number of identifications and ASI for β-U10 and etizolam coincided with a 50% decrease in the number of positive detections and an order of magnitude decrease in the ASI for heroin.

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

Cited by 35 publications

References 99 publications

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

Non-fentanyl-derived synthetic opioids emerging during recent years

Trace Residue Identification, Characterization and Longitudinal Monitoring of the Novel Synthetic Opioid β-U10, from Discarded Drug Paraphernalia

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