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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
Get PDFStudies on the tissue distribution of the new synthetic opioid U-47700 and its main
metabolite N-desmethyl-U-47700 revealed about sixfold higher metabolite concentrations in pig brain as compared with the parent compound. To better assess the
toxic potential of this drug, the aim of this study was to assess the in vitro μ-opioid
receptor (MOR) activation potential of the main metabolites of U-47700, Ndesmethyl-U-47700, and N,N-bisdesmethyl-U-47700, using a live cell-based reporter
assay based on NanoLuc Binary Technology®. Cells stably expressing human MOR
and β-arrestin 2 (βarr2), each fused via a flexible linker to two complementary inactive
subunits of the nanoluciferase, were seeded on poly-D-lysine-coated 96-well plates
and treated with N-desmethyl-U-47700, N,N-bisdesmethyl-U-47700, U-47700, or
hydromorphone as reference standard. MOR activation results in functional complementation of the nanoluciferase, which can be assessed via luminescence monitoring.
The potency of the metabolites is lower than that of U-47700 (EC50 of 186 nM for
U-47700, 3770 nM for N-desmethyl-U-47700, and >5 μM for N,N-bisdesmethylU-47700). The maximal efficacy (Emax) observed (relative to hydromorphone, set
arbitrarily at 100%) decreased from 183% to 127% and 39.2% for U-47700,
N-desmethyl-U-47700, and N,N-bisdesmethyl-U-47700, respectively. Thus, the loss
of one or two methyl groups reduced the MOR activation potential, which was more
pronounced if both methyl groups were removed. It is thus anticipated that the
impact on MOR exerted by the higher metabolite concentration in brain has only
little—if any relevance for the strong toxic effects of U-47700
Are the N-demethylated metabolites of U-47700 more active than their parent compound? In vitro mu-opioid receptor activation of N-desmethyl-U-47700 and N,N-bisdesmethyl-U-47700
No full textStudies on the tissue distribution of the new synthetic opioid U-47700 and its main metabolite N-desmethyl-U-47700 revealed about sixfold higher metabolite concentrations in pig brain as compared with the parent compound. To better assess the toxic potential of this drug, the aim of this study was to assess the in vitro mu-opioid receptor (MOR) activation potential of the main metabolites of U-47700, N-desmethyl-U-47700, and N,N-bisdesmethyl-U-47700, using a live cell-based reporter assay based on NanoLuc Binary Technology (R). Cells stably expressing human MOR and beta-arrestin 2 (beta arr2), each fused via a flexible linker to two complementary inactive subunits of the nanoluciferase, were seeded on poly-d-lysine-coated 96-well plates and treated with N-desmethyl-U-47700, N,N-bisdesmethyl-U-47700, U-47700, or hydromorphone as reference standard. MOR activation results in functional complementation of the nanoluciferase, which can be assessed via luminescence monitoring. The potency of the metabolites is lower than that of U-47700 (EC50 of 186 nM for U-47700, 3770 nM for N-desmethyl-U-47700, and >5 mu M for N,N-bisdesmethyl-U-47700). The maximal efficacy (E-max) observed (relative to hydromorphone, set arbitrarily at 100%) decreased from 183% to 127% and 39.2% for U-47700, N-desmethyl-U-47700, and N,N-bisdesmethyl-U-47700, respectively. Thus, the loss of one or two methyl groups reduced the MOR activation potential, which was more pronounced if both methyl groups were removed. It is thus anticipated that the impact on MOR exerted by the higher metabolite concentration in brain has only little-if any relevance for the strong toxic effects of U-47700
U-47700. An old opioid becomes a recent danger
No full textU-47700 is a synthetic opioid analgesic and a potent, short acting structural isomer of the earlier opioid AH-7921 that has recently invaded the drug arena in Europe and the Unites States. Although the drug was synthesized and patented in the 1970s, it was first identified in October 2014, as a powder sample that was seized by Swedish Customs. Sweden formally notified the European Union Early Warning System in January 2015. Animal studies proved that U-47700 is a strong μ-opioid receptor agonist and has a morphine-like analgesic action, being 7.5 times higher than morphine. The drug has a much lower affinity for the κ-opioid receptor. This newly appearing psychoactive substance has already led to more than 25 confirmed fatalities associated with U-47700 in Europe and the United States and to six non-fatal intoxications reported in the United States. The aim of this review is to summarize the current knowledge about this drug, regarding its chemistry, synthesis, pharmacology, toxicology and metabolism, as well as its international legal status. The existing analytical methods for the determination of U-47700 in biological samples are also presented. Published or reported U-47700 related cases, fatalities or intoxications, and self reports from drug users are reviewed. © 2016, Japanese Association of Forensic Toxicology and Springer Japan
Non-fatal overdose with U-47700: Identification in biological matrices
No full textBACKGROUND/OBJECTIVE:
We report on a case of severe intoxication after insufflation of U-47700, a synthetic opioid that acts as a selective agonist of the μ-opioid receptor, and is several times more potent than morphine. A man in his 30s was found irresponsive in his apartment and was brought to the emergency department of a local hospital. A comatose state and severe respiratory depression were present. Hetero anamnesis revealed that the patient could have taken the substance named "U-47700", bought on the Internet. After supportive care, the patient fully recovered.
METHOD:
Urine, blood and a white powder found at his home were collected during his hospital stay and sent for testing using liquid chromatography-high resolution mass spectrometry (LC-HRMS) on an Orbitrap instrument. Later, his pubic hair was also collected. A standard comprehensive toxicology screening was performed.
RESULTS:
U-47700 was identified in all biological samples and in the seized white powder. Using liquid chromatography-high resolution mass spectrometry (LC-HRMS) the presence of U-47700 and its phase I and phase II metabolites in blood, urine and pubic hair was confirmed. U-47700 was determined at 94 ng/mL and 5.2 ng/mL in blood at the admission and the day after, respectively, and 3.02 ng/mg in pubic hair, together with its metabolites. No other opioid nor designer drug could be detected in blood and urine, while in pubic hair Cocaine, Benzoylecgonine, Norcocaine, Mephedrone, Ketamine, Norketamine, 3,4-Methylenedioxymethamphetamine, Tetrahydrocannabinol and Cannabinol were also detected.
CONCLUSION:
The toxicological findings confirmed the use of U-47700 in the intoxicated patient and also revealed a history of a poly-drug use. The use of LC-HRMS allowed the easy identification of the NPS and its metabolites in fluids and hai
U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market
Get PDFThe recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone products, adulterants in heroin, or ingredients in counterfeit drug preparations. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a prime example of a non-fentanyl NSO that is associated with numerous intoxications and fatalities. Here, we review the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and its analogs. An up-to-date summary of the human cases involving U-47700 intoxication and death are described. The evidence demonstrates that U-47700 is a potent μ-opioid receptor agonist, which poses a serious risk for overdosing and death. However, most analogs of U-47700 appear to be less potent and have been detected infrequently in forensic specimens. U-47700 represents a classic example of how chemical entities from the medicinal chemistry or patent literature can be diverted for use in recreational drug markets. Lessons learned from the experiences with U-47700 can inform scientists, clinicians, and policymakers who are involved with responding to the spread and impact of NSOs
A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700)
Get PDF<p>A 30-year old man was found dead in his home after inhaling fumes of a powder burned on aluminum foil. Blood and urine were taken by the medical examiner during the external body examination and submitted to the laboratory for a comprehensive systematic toxicological analysis. A toxic fentanyl level of 10.9μg/L was measured in the subclavian blood. Police investigation revealed that the man searched the internet for information on new psychotropic substances, among others including U-47700. A powder found in the victims' home was transferred to the laboratory for analysis, in which trace amounts of fentanyl (0.0035%, m/m) and U-47700 (0.0012%, m/m) were identified by gas chromatography mass spectrometry. U-47700 is an opioid analgesic drug, considered to have a potency of approximately 7.5 times that of morphine. A target analysis on U-47700 was performed using liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry operating in multiple reaction monitoring mode. The method validation was based on the Scientific Working Group of Forensic Toxicology document 'Standard Practices of Method Validation in Forensic Toxicology'. In blood and urine the U-47700 concentration was 13.8 and 71.0μg/L, respectively. To the author's knowledge, this is the first case report of a fatal intoxication involving U-47700 abused as a new psychotropic substance.</p></p
Near death from a novel synthetic opioid labeled U-47700: emergence of a new opioid class
Get PDFBackgroundIn the last decade there has been a worldwide surge in the recreational abuse of novel psychoactive substances, particularly amphetamine derivatives and synthetic cannabinoids. Synthetic opioids such as AH-7921, MT-45, and U-47700, with structures distinct from those ever used therapeutically or described recreationally, have also recently emerged.Case detailsWe report a patient who suffered respiratory failure and depressed level of consciousness after recreationally using a novel synthetic opioid labeled U-47700. A single dose of naloxone administered by paramedics completely reversed his opioid poisoning. Comprehensive laboratory analysis confirmed the presence of a novel synthetic opioid and excluded other drugs. The drug used appeared to have caused a false positive benzodiazepine result on the initial urine drugs of abuse panel.ConclusionThe case we describe of toxicity from the synthetic opioid labeled U-47700 highlights the emerging trend of novel synthetic opioid abuse
Intoxications involving methoxyacetylfentanyl and U-47700: a study of 3 polydrug fatalities
Get PDFNovel synthetic opioids (NSOs) represent an emerging group of novel psychoactive substances, acting as agonists at the opioid receptors. NSOs include fentanyl-related compounds, e.g. methoxyacetylfentanyl (MeACF), and non-fentanyl analogs, e.g. "U compounds" including U-47700. Here we present three cases of death involving MeACF and U-47700, with particular reference to preliminary data on pharmacokinetics and tissue distribution.After a complete post-mortem examination, general unknown screenings and analysis of drugs of abuse were performed on postmortem samples by immunoassays, gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. To quantify the analytes of interest in post-mortem blood and tissues, the standard addition method was used. A toxicological significance score (TSS), weighing the role of the NSO in each death case, was assigned.Case 1 died at the hospital after consumption of U-47700, methadone (serum levels: 2,600 ng/ml and 37 ng/ml), tilidine and benzodiazepines. In case 2, U-47700 (204 ng/ml) together with methadone (290 ng/ml), flubromazepam (480 ng/ml) and diazepam (300 ng/ml) were detected in peripheral blood. In case 3, methoxyacetylfentanyl (266 ng/ml), furanylfentanyl (4.3 ng/ml) 4-ANPP (15 ng/ml) and alprazolam (69 ng/ml) were quantified in femoral blood. In all cases, the NSO likely contributed to the death (TSS = 3).NSOs appear to be often consumed in the setting of polydrug intoxications, especially in combination with other opioids and benzodiazepines, which often exert synergistic effects. The standard addition method remains the most reliable in post-mortem analysis and toxicological results should always be evaluated together with circumstantial and autopsy data
U-47700: The new emerging opioid drug
No full textIntroductionThe trans-3;4-dichloro-N-(2-(dimethylamine) cyclohexyl) labelled as U-47700 has a high affinity with the selective receptor, considered to have 7.5 times the binding affinity of morphine; as a result, it is sold as a recreational drug because of its analgesic and euphoric effects. Several toxicity cases and some fatalities have been reported during 2016.ObjectivesTo describe the presence of trans-3;4-dichloro-N-(2-(dimethylamine) cyclohexyl) in samples delivered to Energy Control during 2016 in Barcelona.MethodsFrom January 2016 to October 2016, 4031 samples were delivered and only those samples containing trans-3;4-dichloro-N-(2-(dimethylamine) cyclohexyl) were studied, 6 of them were analysed as U-47700 (0.148%). Samples were analysed by energy control, a Spanish harm-reduction NGO that offers users the possibility of analysing the substances they intend to consume. Analysis was done by gas chromatography–mass spectrometry.ResultsFrom the 6 samples that were analysed as trans-3;4-dichloro-N-(2-(dimethylamine) cyclohexyl), the presentation of 4 of them was white powder and the rest were not described. The procedence of the samples was Canada (2), USA (1), Sweden (1), Holland (1) and the remaining sample was not described. All samples were received during 2016.ConclusionsThe use of trans-3;4-dichloro-N-(2-(dimethylamine)cyclohexyl) is progressively increasing in Barcelona. Its harmful effects are being reported in recent medical literature and consumption represents an emerging issue, gaining popularity among recreational opioid users. It is potentially lethal when mixed with depressants like alcohol or benzodiazepines and overdose risk is higher compared to other opioids. This drug is not being detected by routine in medical test.Disclosure of interestThe authors have not supplied their declaration of competing interest.</jats:sec
Intoxications involving methoxyacetylfentanyl and U-47700: a study of 3 polydrug fatalities
Get PDFNovel synthetic opioids (NSOs) represent an emerging group of novel psychoactive substances, acting as agonists at the opioid receptors. NSOs include fentanyl-related compounds, e.g. methoxyacetylfentanyl (MeACF), and non-fentanyl analogs, e.g. “U compounds” including U-47700. Here we present three cases of death involving MeACF and U-47700, with particular reference to preliminary data on pharmacokinetics and tissue distribution.
After a complete post-mortem examination, general unknown screenings and analysis of drugs of abuse were performed on postmortem samples by immunoassays, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry. To quantify the analytes of interest in post-mortem blood and tissues, the standard addition method was used. A toxicological significance score (TSS), weighing the role of the NSO in each death case, was assigned.
Case 1 died at the hospital after consumption of U-47700, methadone (serum levels: 2,600 ng/ml and 37 ng/ml), tilidine and benzodiazepines. In case 2, U-47700 (204 ng/ml) together with methadone (290 ng/ml), flubromazepam (480 ng/ml) and diazepam (300 ng/ml) were detected in peripheral blood. In case 3, methoxyacetylfentanyl (266 ng/ml), furanylfentanyl (4.3 ng/ml) 4-ANPP (15 ng/ml) and alprazolam (69 ng/ml) were quantified in femoral blood. In all cases, the NSO likely contributed to the death (TSS = 3).
NSOs appear to be often consumed in the setting of polydrug intoxications, especially in combination with other opioids and benzodiazepines, which often exert synergistic effects. The standard addition method remains the most reliable in post-mortem analysis and toxicological results should always be evaluated together with circumstantial and autopsy data
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