The analytical challenges of cyclopropylfentanyl and crotonylfentanyl: An approach for toxicological analysis

Maher, Sam; Elliott, Simon; George, Steve

doi:10.1002/dta.2417

Cited by 28 publications

(26 citation statements)

References 8 publications

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“…The reasons for this deplorable popularity renaissance include relatively facile and cheap syntheses as well as high potencies of fentanyl derivatives. From the point of view of chemical sciences, the fentanyl crisis increases the demand for analytical capabilities to identify illicit substances [26,27,28,29,30,31,32,33,34], in particular novel derivatives. This is due to not only the requirements of forensic medicine, but it is also important for regulatory, preventive and, law enforcement purposes.…”

Section: Introductionmentioning

confidence: 99%

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

et al. 2019

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Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the μOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

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Section: Introductionmentioning

confidence: 99%

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

et al. 2019

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“…Hydroxylation of the cyclopropyl moiety or amide hydrolysis has not been detected in this study. The main metabolite norcyclopropylfentanyl has also been detected by Maher et al (2018) in urine samples of two death cases and Palaty et al (2018) in several urine samples of patients with a substance use disorder from two canadian provinces.…”

Section: Fentanyl and Fentanyl Analogsmentioning

confidence: 97%

Metabolic Pathways and Potencies of New Fentanyl Analogs

et al. 2019

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Up to now, little is known about the metabolic pathways of new fentanyl analogs that have recently emerged on the drug markets worldwide with high potential for producing addiction and severe adverse effects including coma and death. For some of the compounds, limited information on the metabolism has been published, however, for others so far no information is available. Considering the well characterized metabolism of the pharmaceutically used opioid fentanyl and the so far available data, the metabolism of the new fentanyl analogs can be anticipated to generally involve reactions like hydrolysis, hydroxylation (and further oxidation steps), N - and O -dealkylation and O -methylation. Furthermore, phase II metabolic reactions can be expected comprising glucuronide or sulfate conjugate formation. When analyzing blood and urine samples of acute intoxication cases or fatalities, the presence of metabolites can be crucial for confirmation of the uptake of such compounds and further interpretation. Here we present a review on the metabolic profiles of new fentanyl analogs responsible for a growing number of severe and fatal intoxications in the United States, Europe, Canada, Australia, and Japan in the last years, as assessed by a systematic search of the scientific literature and official reports.

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“…CycP‐F presents the same empirical formula (C 23 H 28 N 2 O) as another fentanyl analogue, crotonylfentanyl (Cro‐F) . Analytical differentiation of these compounds has proven difficult . One group has reported the differention of CycP‐F and two isomers of Cro‐F utilising GC–MS .…”

Section: Introductionmentioning

confidence: 99%

“…CycP-F presents the same empirical formula (C 23 H 28 N 2 O) as another fentanyl analogue, crotonylfentanyl (Cro-F). 16,17 Analytical differentiation of these compounds has proven difficult. 17 One group has reported the differention of CycP-F and two isomers of Cro-F utilising GC-MS. 18 However, spectrally only minor differences in ion ratios were observed between CycP-F and the two Cro-F isomers, and additional analysis with FTIR or NMR was recommended to support identification.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 Analytical differentiation of these compounds has proven difficult. 17 One group has reported the differention of CycP-F and two isomers of Cro-F utilising GC-MS. 18 However, spectrally only minor differences in ion ratios were observed between CycP-F and the two Cro-F isomers, and additional analysis with FTIR or NMR was recommended to support identification. As such, it has been recommended that findings be reported as CycP-F/Cro-F. 19 The same approach will be taken in this study as has been reported previously 16 ; while the CycP-F notation will be utilised, identification in biological samples will represent CycP-F/Cro-F.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In vitro metabolism of the novel synthetic opioid agonist cyclopropylfentanyl and subsequent confirmation in authentic human samples using liquid chromatography‐high resolution mass spectrometry

Cutler¹,

Hudson²

2019

Drug Testing and Analysis

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Novel synthetic opioids (NSOs) are a class of novel psychoactive substances (NPS) that are growing in popularity and presenting a significant public health risk. Included in this class are derivatives of the highly potent analgesic, fentanyl. Cyclopropylfentanyl (CycP‐F) was first reported to the EU Early Warning System in August 2017, and was subsequently linked to more than 100 deaths in the US alone. Limited pharmacological, pharmacokinetic or toxicological data is available for many emerging NSOs; however we can expect novel fentanyl analogues to present limited detection windows, short onset, narrow therapeutic indices and the potential for very high potency. Knowledge of the metabolism of these drugs is essential for the identification of analytical targets for their detection. Therefore in vitro metabolites of CycP‐F were produced using human liver microsomal incubations. Metabolites formed were elucidated using liquid chromatography‐high resolution accurate mass analysis (LC‐HRAM). Identified metabolites were added to our accurate mass screening database for NPS which was utilised for subsequent screening analysis. CycP‐F and metabolites were identified in two human blood case samples. Eleven metabolites were identified in vitro, with the major metabolites produced via N‐dealkylation, monohydroxylation and N‐oxidation. Analysis of the positive case samples identified four in vivo metabolites, all of which were observed in vitro. The major metabolite identified in vitro and in vivo was the N‐dealkylated nor‐metabolite; two further mono‐hydroxylated and one dihydroxylated metabolite were detected in vivo.

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The analytical challenges of cyclopropylfentanyl and crotonylfentanyl: An approach for toxicological analysis

Cited by 28 publications

References 8 publications

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

Metabolic Pathways and Potencies of New Fentanyl Analogs

In vitro metabolism of the novel synthetic opioid agonist cyclopropylfentanyl and subsequent confirmation in authentic human samples using liquid chromatography‐high resolution mass spectrometry

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