RESUMO
While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.
Assuntos
Analgésicos Opioides , Fentanila , Receptores Opioides mu , Insuficiência Respiratória , Animais , Camundongos , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Ratos , Masculino , Fentanila/farmacologia , Fentanila/síntese química , Fentanila/química , Relação Estrutura-Atividade , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Piperazinas/uso terapêutico , Piperazinas/farmacocinética , Humanos , Ratos Sprague-Dawley , Distribuição Tecidual , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Naltrexona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/síntese química , Naltrexona/química , Naltrexona/uso terapêuticoRESUMO
From an analytical chemistry standpoint, determining the chemical attribution signatures (CAS) of synthetic reaction mixtures is an impurity profiling exercise. Identifying and understanding the impurity profile and CAS of these chemical agents would allow them to be exploited for chemical forensic information, such as how a particular chemical agent was synthesised. Being able to determine the synthetic route used to make a chemical agent allows for the possibility of batches of the agent, and individual incidents using that agent, to be forensically linked. This information is of particular benefit to agencies investigating the nefarious and illicit use of chemical agents. One such chemical agent of interest to law enforcement and national security agencies is fentanyl. In this study two acylation methods for the final step of fentanyl production, herein termed the Janssen and Siegfried methods, were investigated by liquid chromatography- high resolution mass spectrometry (LC-HRMS) and multivariate statistical analysis (MVA). From these data, fifty-five chemical impurities were identified. Of these, ten were specific CAS for the Janssen method, and five for the Siegfried method. Additionally, analytical data from four different literature methods for production of the fentanyl precursor 4-anilino-N-phenethylpiperidine (ANPP), were compared to the results obtained from the method of production (Valdez) used in this study. Comparison of the LC-HRMS data for these five methods allowed for four Valdez specific impurities to be identified. These may be useful CAS for the Valdez method of ANPP production.
Assuntos
Analgésicos Opioides/síntese química , Contaminação de Medicamentos , Fentanila/síntese química , Cromatografia Líquida , Humanos , Espectroscopia de Ressonância Magnética , Análise Multivariada , Espectrometria de Massas em TandemRESUMO
The constant evolution of the illicit drug market makes the identification of unknown compounds problematic. Obtaining certified reference materials for a broad array of new analogues can be difficult and cost prohibitive. Machine learning provides a promising avenue to putatively identify a compound before confirmation against a standard. In this study, machine learning approaches were used to develop class prediction and retention time prediction models. The developed class prediction model used a naïve Bayes architecture to classify opioids as belonging to either the fentanyl analogues, AH series or U series, with an accuracy of 89.5%. The model was most accurate for the fentanyl analogues, most likely due to their greater number in the training data. This classification model can provide guidance to an analyst when determining a suspected structure. A retention time prediction model was also trained for a wide array of synthetic opioids. This model utilised Gaussian process regression to predict the retention time of analytes based on multiple generated molecular features with 79.7% of the samples predicted within ±0.1 min of their experimental retention time. Once the suspected structure of an unknown compound is determined, molecular features can be generated and input for the prediction model to compare with experimental retention time. The incorporation of machine learning prediction models into a compound identification workflow can assist putative identifications with greater confidence and ultimately save time and money in the purchase and/or production of superfluous certified reference materials.
Assuntos
Analgésicos Opioides/análise , Cromatografia Líquida de Alta Pressão , Fentanila/análise , Aprendizado de Máquina , Espectrometria de Massas por Ionização por Electrospray , Detecção do Abuso de Substâncias , Espectrometria de Massas em Tandem , Analgésicos Opioides/síntese química , Animais , Fentanila/análogos & derivados , Fentanila/síntese química , Cavalos/sangue , Estrutura Molecular , Reprodutibilidade dos Testes , Relação Estrutura-AtividadeRESUMO
In this work, we studied a series of carfentanyl amide-based opioid derivatives targeting the mu opioid receptor (µOR) and the delta opioid receptor (δOR) heteromer as a credible novel target in pain management therapy. We identified a lead compound named MP135 that exhibits high G-protein activity at µ-δ heteromers compared to the homomeric δOR or µOR and low ß-arrestin2 recruitment activity at all three. Furthermore, MP135 exhibits distinct signaling profile, as compared to the previously identified agonist targeting µ-δ heteromers, CYM51010. Pharmacological characterization of MP135 supports the utility of this compound as a molecule that could be developed as an antinociceptive agent similar to morphine in rodents. In vivo characterization reveals that MP135 maintains untoward side effects such as respiratory depression and reward behavior; together, these results suggest that optimization of MP135 is necessary for the development of therapeutics that suppress the classical side effects associated with conventional clinical opioids.
Assuntos
Fentanila/análogos & derivados , Receptores Opioides delta/agonistas , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Linhagem Celular , Fentanila/síntese química , Fentanila/farmacologia , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Long-Evans , Receptores Opioides delta/metabolismoRESUMO
BACKGROUND: 4-Anilidopiperidine class of synthetic opioid analgesics, with it's representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of µ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity. METHODS: The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test. RESULTS: The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test. CONCLUSION: Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.
Assuntos
Analgésicos Opioides/síntese química , Analgésicos Opioides/farmacologia , Medição da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Fentanila/síntese química , Fentanila/farmacologia , Camundongos , Dor/patologia , Medição da Dor/métodosRESUMO
The identification of tert-butyl-4-anilinopiperidine-1-carboxylate (4-anilinopiperdine-t-BOC or 4-AP-t-BOC) in many seized falsified 'Xanax' tablets has been reported after being encountered in forensic casework in late 2019 and early 2020 in Ireland. This substance was also detected in a pink powder submitted for analysis in March 2020. The pink powder was part of a larger seizure comprising brown powders which contained morphine or diamorphine (heroin) or a type of counterfeit heroin or heroin adulterant (known as 'bash'). Novel benzodiazepines and other substances are being detected as ingredients in falsified benzodiazepine tablets more frequently on the illicit market. The detection of 4-AP-t-BOC in benzodiazepine tablets is noteworthy and 4-AP-t-BOC is added to the list of adulterants found in benzodiazepine tablets emerging in Europe. The presence of 4-AP-t-BOC in both falsified 'Xanax' and powdered seizures is unusual, and analytical data are presented to assist with the identification of this compound in suspected illicit substances. The presence of 4-AP-t-BOC in the tablets was confirmed using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses, and spectral fragmentation pathways were suggested. To the authors' best knowledge, information about the biological activity of 4-AP-t-BOC is not available. The removal of the t-BOC protecting group yields 4-anilinopiperidine which has been reported to be involved in the synthesis of fentanyl.
Assuntos
Alprazolam/análise , Contaminação de Medicamentos , Heroína/análise , Alprazolam/química , Cromatografia Líquida , Medicamentos Falsificados/análise , Fentanila/síntese química , Cromatografia Gasosa-Espectrometria de Massas , Heroína/química , Drogas Ilícitas/análise , Drogas Ilícitas/química , Irlanda , Espectrometria de Massas , ComprimidosRESUMO
INTRODUCTION: Illicitly manufactured fentanyl (IMF) is responsible for a growing number of deaths. Some case series have suggested that IMF overdoses require significantly higher naloxone doses than heroin overdoses. Our objective was to determine if the naloxone dose required to treat an opioid overdose is associated with the finding of fentanyl, opiates, or both on urine drug screen (UDS). METHODS: A retrospective chart review was conducted at a single emergency department and its affiliated emergency medical services (EMS) agency. The charts of all patients who received naloxone through this EMS from 1/1/2017 to 6/15/2018 were reviewed. The study included patients diagnosed with a non-suicidal opioid overdose whose UDS was positive for opiates, fentanyl, or both. Data collected included demographics, vital signs, initial GCS, EMS and ED naloxone administrations, response to treatment, laboratory findings, and ED disposition. The fentanyl-only and fentanyl + opiate groups were compared to the opiate-only group using the stratified (by ED provider) variant of the Mann-Whitney U test. RESULTS: Eight hundred and thirty-seven charts were reviewed, and 121 subjects were included in the final analysis. The median age of included subjects was 38 years and 75% were male. In the naloxone dose analysis, neither the fentanyl-only (median 0.8 mg, IQR 0.4-1.6; p = 0.68) nor the fentanyl + opiate (median 0.8 mg, IQR 0.4-1.2; p = 0.56) groups differed from the opiate-only group (median 0.58 mg, IQR 0.4-1.6). CONCLUSION: Our findings refute the notion that high potency synthetic opioids like illicitly manufactured fentanyl require increased doses of naloxone to successfully treat an overdose. There were no significant differences in the dose of naloxone required to treat opioid overdose patients with UDS evidence of exposure to fentanyl, opiates, or both. Further evaluation of naloxone stocking and dosing protocols is needed.
Assuntos
Analgésicos Opioides/efeitos adversos , Overdose de Drogas/tratamento farmacológico , Fentanila/efeitos adversos , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Adolescente , Adulto , Idoso , Analgésicos Opioides/síntese química , Analgésicos Opioides/urina , Cálculos da Dosagem de Medicamento , Overdose de Drogas/diagnóstico , Overdose de Drogas/urina , Serviço Hospitalar de Emergência , Feminino , Fentanila/síntese química , Fentanila/urina , Humanos , Masculino , Pessoa de Meia-Idade , Naloxona/efeitos adversos , Naloxona/farmacocinética , Antagonistas de Entorpecentes/efeitos adversos , Antagonistas de Entorpecentes/farmacocinética , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/urina , Estudos Retrospectivos , Detecção do Abuso de Substâncias , Resultado do Tratamento , Urinálise , Adulto JovemRESUMO
Human exposures to fentanyl analogs, which significantly contribute to the ongoing U.S. opioid overdose epidemic, can be confirmed through the analysis of clinical samples. Our laboratory has developed and evaluated a qualitative approach coupling liquid chromatography and quadrupole time-of-flight mass spectrometry (LC-QTOF) to address novel fentanyl analogs and related compounds using untargeted, data-dependent acquisition. Compound identification was accomplished by searching against a locally-established mass spectral library of 174 fentanyl analogs and metabolites. Currently, our library can identify 150 fentanyl-related compounds from the Fentanyl Analog Screening (FAS) Kit), plus an additional 25 fentanyl-related compounds from individual purchases. Plasma and urine samples fortified with fentanyl-related compounds were assessed to confirm the capabilities and intended use of this LC-QTOF method. For fentanyl, 8 fentanyl-related compounds and naloxone, lower reportable limits (LRL100), defined as the lowest concentration with 100 % true positive rate (n = 12) within clinical samples, were evaluated and range from 0.5 ng/mL to 5.0 ng/mL for urine and 0.25 ng/mL to 2.5 ng/mL in plasma. The application of this high resolution mass spectrometry (HRMS) method enables the real-time detection of known and emerging synthetic opioids present in clinical samples.
Assuntos
Analgésicos Opioides/sangue , Analgésicos Opioides/urina , Cromatografia Líquida de Alta Pressão , Fentanila/sangue , Fentanila/urina , Espectrometria de Massas por Ionização por Electrospray , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem , Analgésicos Opioides/síntese química , Cromatografia Líquida de Alta Pressão/normas , Fentanila/análogos & derivados , Fentanila/síntese química , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/normas , Detecção do Abuso de Substâncias/normas , Espectrometria de Massas em Tandem/normasAssuntos
Analgésicos Opioides/efeitos adversos , Overdose de Drogas/epidemiologia , Epidemias/prevenção & controle , Fentanila/análogos & derivados , Drogas Ilícitas/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/economia , Overdose de Drogas/tratamento farmacológico , Overdose de Drogas/etiologia , Overdose de Drogas/mortalidade , Fentanila/efeitos adversos , Fentanila/síntese química , Fentanila/economia , Heroína/uso terapêutico , Humanos , Drogas Ilícitas/legislação & jurisprudência , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/mortalidade , Estados Unidos/epidemiologiaRESUMO
The purpose of this Policy Watch column is to provide a brief overview of the global problems associated with the illicit production and trafficking of synthetic opioids as well as international efforts and policy approaches designed to curb them. An in-depth evaluation of drug control efforts of many different nations is important for a comprehensive analysis. However, because of the vast amount of information available, this column is limited to cooperative global control efforts, not efforts specific to any one nation. A great deal of information about production methods, clandestine laboratories, international trafficking methods, and online sales over the dark Web has been omitted. It is important to understand key issues regarding the illicit cultivation and distribution of plant-based opioids derived from natural compounds found in opium poppies (heroin, opium, morphine, codeine) or other drugs (cocaine, methamphetamines, etc.), but the scope of this column is limited to discussion about synthetic opioids including fentanyl, fentanyl analogues, and fentanyl precursor chemicals. Issues about human rights and ethical considerations for nurses and other addictions professionals are also discussed.
Assuntos
Analgésicos Opioides/efeitos adversos , Tráfico de Drogas/prevenção & controle , Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Fentanila/efeitos adversos , Saúde Global , Regulamento Sanitário Internacional , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Adolescente , Adulto , Idoso , Analgésicos Opioides/síntese química , Tráfico de Drogas/legislação & jurisprudência , Feminino , Fentanila/análogos & derivados , Fentanila/síntese química , Direitos Humanos/legislação & jurisprudência , Humanos , Masculino , Pessoa de Meia-Idade , Papel do Profissional de Enfermagem , Transtornos Relacionados ao Uso de Opioides/enfermagem , Adulto JovemRESUMO
Background: In the last decade there has been a progressive increase in the use of new psychoactive substances (NPSs) that are not yet under international control. In particular, novel synthetic opioids (NSOs) have reappeared on the recreational drug market in the last few years. As a result, the use of NSOs has increased rapidly. This poses an emerging and demanding challenge to public health. Aim: To raise awareness among clinicians and other professionals about NPSs, especially NSOs, to summarize current knowledge about pharmacological properties, forms of NSO on the market, pattern of use, effects and consequences of use. Methods: An electronic search was carried out on the Medline/PubMed and Google Scholar databases to find selected search terms. Results: Some NPSs are already controlled, while others can be legally sold directly on the drug market (mainly via internet, less so by drug dealers) or be used as precursors for the synthesis of other designer drugs that mimic the psychoactive effects of controlled substances. Potential side-effects of NSOs include miosis, sedation, respiratory depression, hypothermia, inhibition of gastrointestinal propulsion, death (from opioid overdose). Conclusions: The severity of the opioid crisis has intensified with the introduction of highly potent NSOs on the drug market. As long as addicts are dying from overdose or similar causes, there is something more constructive to do than waiting for addicts to overdose on heroin at a place located near a remedy, as if to say, within reach of naloxone.
Assuntos
Analgésicos Opioides/síntese química , Analgésicos Opioides/intoxicação , Drogas Ilícitas/síntese química , Drogas Ilícitas/intoxicação , Transtornos Relacionados ao Uso de Opioides/etiologia , Overdose de Drogas/tratamento farmacológico , Overdose de Drogas/epidemiologia , Overdose de Drogas/etiologia , Fentanila/análogos & derivados , Fentanila/síntese química , Fentanila/intoxicação , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Saúde PúblicaRESUMO
A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce ß-arrestin2 recruitment. Compound 12 is a potent µ-opioid (MOP) receptor agonist, a potent κ-opioid (KOP) receptor antagonist with weak ß-arrestin2 recruitment activity. Compounds 10 and 11 are potent MOP receptor agonists with weak δ-opioid (DOP) receptor antagonist activity and moderate KOP receptor antagonist activity as well as weak ß-arrestin2 recruitment activity at the MOP receptor. These compounds are promising leads for discovery of potent opioid analgesics with reduced side effects relative to clinically available strong opioid analgesics.
Assuntos
Analgésicos Opioides/metabolismo , Fentanila/análogos & derivados , Fentanila/metabolismo , Receptores Opioides/metabolismo , Analgésicos Opioides/síntese química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/análogos & derivados , Ala(2)-MePhe(4)-Gly(5)-Encefalina/síntese química , Ala(2)-MePhe(4)-Gly(5)-Encefalina/metabolismo , Fentanila/síntese química , Células HEK293 , Humanos , Antagonistas de Entorpecentes/síntese química , Antagonistas de Entorpecentes/metabolismo , Ligação Proteica/fisiologiaRESUMO
Fentanyl, and the numerous drugs derived from it, are contributing to the opioid overdose epidemic currently underway in the USA. To identify human exposure to these growing public health threats, an LC-MS-MS method for 5 µL dried blood spots (DBS) was developed. This method was developed to detect exposure to 3-methylfentanyl, alfentanil, α-methylfentanyl, carfentanil, fentanyl, lofentanil, sufentanil, norcarfentanil, norfentanyl, norlofentanil, norsufentanil, and using a separate LC-MS-MS injection, cyclopropylfentanyl, acrylfentanyl, 2-furanylfentanyl, isobutyrylfentanyl, ocfentanil and methoxyacetylfentanyl. Preparation of materials into groups of compounds was used to accommodate an ever increasing need to incorporate newly identified fentanyls. This protocol was validated within a linear range of 1.00-100 ng/mL, with precision ≤12% CV and accuracy ≥93%, as reported for the pooled blood QC samples, and limits of detection as low as 0.10 ng/mL. The use of DBS to assess fentanyl analog exposures can facilitate rapid sample collection, transport, and preparation for analysis that could enhance surveillance and response efforts in the ongoing opioid overdose epidemic.
Assuntos
Analgésicos Opioides/sangue , Teste em Amostras de Sangue Seco/métodos , Overdose de Drogas/sangue , Overdose de Drogas/epidemiologia , Fentanila/análogos & derivados , Fentanila/sangue , Detecção do Abuso de Substâncias/métodos , Analgésicos Opioides/síntese química , Autopsia , Cromatografia Líquida , Confiabilidade dos Dados , Fentanila/síntese química , Furanos/sangue , Hematócrito , Humanos , Umidade/prevenção & controle , Drogas Ilícitas/sangue , Espectrometria de Massas em Tandem , Estados Unidos/epidemiologiaRESUMO
Novel synthetic opioids include various analogs of fentanyl and emerging non-fentanyl compounds with different chemical structures, such as AH-7921, MT-45 and U-47700. In recent years, these drugs have rapidly emerged on the drug market, and their abuse has been increasing worldwide. The motivations for use of these new compounds include their legal status, ready availability, low cost, users' curiosity or preference for their particular pharmacological properties and the intention to avoid detection. Furthermore, more common drugs like heroin are now increasingly being replaced or cut with fentanyl or new designer opioids; thus, many drug users are unintentionally or unknowingly using synthetic fentanyl analogs. In this scenario, the detection of new psychoactive substances in hair can provide insight into their current diffusion among the population and social characteristics of these synthetic drug users. In this manuscript, we describe a simple, fast, specific and sensitive UHPLC-MS-MS method able to detect 13 synthetic opioids (including fentanyl analogs) and metabolites in hair samples. Furthermore, the method includes the detection of 4-anilino-N-phenethyl-piperidine (4-ANPP), which is considered both a precursor and a metabolite of several fentanyl analogs. The method was applied to 34 real hair samples collected in New York City from subjects who had reported past-year non-medical opioid and/or heroin use. In total, 17 samples tested positive for at least one target analyte, with oxycodone (nine samples) and tramadol (eight samples) being the most common. Among these, the method was able to quantify furanyl-fentanyl and fentanyl in the pg/mg range in two samples. Simultaneously, also 4-ANPP was detected, giving evidence for the first time that this compound can be selected as a marker of fentanyl analogs use via hair testing. In conclusion, this study confirmed the increasing diffusion of new synthetic opioids and "fentalogs" with high potency among non-medical opioid users.
Assuntos
Analgésicos Opioides/análise , Biomarcadores/análise , Fentanila/análogos & derivados , Fentanila/análise , Cabelo/química , Piperidinas/análise , Detecção do Abuso de Substâncias/métodos , Adolescente , Adulto , Analgésicos Opioides/síntese química , Benzamidas/análise , Cromatografia Líquida , Drogas Desenhadas/análise , Fentanila/síntese química , Furanos/análise , Humanos , Drogas Ilícitas/análise , Oxicodona/análise , Espectrometria de Massas em Tandem , Tramadol/análise , Adulto JovemAssuntos
Analgésicos Opioides/efeitos adversos , Medicamentos Falsificados/efeitos adversos , Fentanila/análogos & derivados , Drogas Ilícitas/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/história , Analgésicos Opioides/síntese química , Medicamentos Falsificados/síntese química , Fentanila/efeitos adversos , Fentanila/síntese química , História do Século XX , História do Século XXI , Humanos , Drogas Ilícitas/síntese química , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/etiologia , Estados Unidos/epidemiologiaAssuntos
Overdose de Drogas/mortalidade , Fentanila/síntese química , Fentanila/toxicidade , Alcaloides Opiáceos/síntese química , Alcaloides Opiáceos/toxicidade , Transtornos Relacionados ao Uso de Opioides/mortalidade , Centers for Disease Control and Prevention, U.S. , China , Crime , Governo Federal , Feminino , Fentanila/administração & dosagem , Fentanila/análogos & derivados , Heroína/toxicidade , Humanos , Drogas Ilícitas/síntese química , Drogas Ilícitas/toxicidade , Masculino , Ohio/epidemiologia , Alcaloides Opiáceos/administração & dosagem , Estados UnidosRESUMO
[11 C]Carfentanil ([11 C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the µ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [11 C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [11 C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [11 C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol.
Assuntos
Radioisótopos de Carbono , Fentanila/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Receptores Opioides mu/metabolismo , Técnicas de Química Sintética , Fentanila/síntese química , Fentanila/química , RadioquímicaRESUMO
Attribution of the origin of an illicit drug relies on identification of compounds indicative of its clandestine production and is a key component of many modern forensic investigations. The results of these studies can yield detailed information on method of manufacture, starting material source, and final product, all critical forensic evidence. In the present work, chemical attribution signatures (CAS) associated with the synthesis of the analgesic fentanyl, N-(1-phenylethylpiperidin-4-yl)-N-phenylpropanamide, were investigated. Six synthesis methods, all previously published fentanyl synthetic routes or hybrid versions thereof, were studied in an effort to identify and classify route-specific signatures. A total of 160 distinct compounds and inorganic species were identified using gas and liquid chromatographies combined with mass spectrometric methods (gas chromatography/mass spectrometry (GC/MS) and liquid chromatography-tandem mass spectrometry-time of-flight (LC-MS/MS-TOF)) in conjunction with inductively coupled plasma mass spectrometry (ICPMS). The complexity of the resultant data matrix urged the use of multivariate statistical analysis. Using partial least-squares-discriminant analysis (PLS-DA), 87 route-specific CAS were classified and a statistical model capable of predicting the method of fentanyl synthesis was validated and tested against CAS profiles from crude fentanyl products deposited and later extracted from two operationally relevant surfaces: stainless steel and vinyl tile. This work provides the most detailed fentanyl CAS investigation to date by using orthogonal mass spectral data to identify CAS of forensic significance for illicit drug detection, profiling, and attribution.
Assuntos
Fentanila/análise , Cromatografia Gasosa , Cromatografia Líquida , Fentanila/síntese química , Espectrometria de Massas , Estrutura Molecular , Análise MultivariadaRESUMO
The development of 2-isocyanopyridines as novel convertible isocyanides for multicomponent chemistry is reported. Comparison of 12 representatives of this class revealed 2-bromo-6-isocyanopyridine as the optimal reagent in terms of stability and synthetic efficiency. It combines sufficient nucleophilicity with good leaving group capacity of the resulting amide moiety under both basic and acidic conditions. To demonstrate the practical utility of this reagent, an efficient two-step synthesis of the potent opioid carfentanil is presented.