The characterization of isobaric product ions of fentanyl using multi‐stage mass spectrometry, high‐resolution mass spectrometry and isotopic labeling

Davidson, J. Tyler; Sasiene, Zachary J.; Jackson, Glen P.

doi:10.1002/dta.2758

Cited by 23 publications

(53 citation statements)

References 23 publications

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“…[97], and the third structure has a unique elemental composition and structure but the same nominal mass of m/z 188. The previous study also provided compelling evidence for an R-group transfer of the amide moiety to the N-atom of the piperidine ring during fragmentation [121]. The current study provides additional support for this unusual mechanism and shows that the mechanism is conserved for a range of FRCs.…”

Section: Resultssupporting

confidence: 71%

“…which, like fentanyl, is comprised of at least two isobaric product ions (Figure 5.3a). The primary product ions observed at m/z 260 and m/z 232 correspond with the loss of aniline (C6H7N) and phenethylamine (C8H11N), which have been shown to be primary fragmentation pathways for fentanyl analogs [97,121]. It is noteworthy that the primary product ion expected at m/z 281 is not groups on the phenylalkylamide moiety eliminated the formation of this intermediate [122].…”

Section: Resultsmentioning

confidence: 95%

“…The first phase of this project established several fragmentation pathways for protonated fentanyl and its main synthetic precursor 4-ANPP using tandem MS on a Q-TOF and a LIT [121].…”

Section: Resultsmentioning

confidence: 99%

“…The HRMS instrument allows the resolution of ions that are nominal isobars but have different exact masses. Examples are the product ions at m/z 188.1439 for C13H18N + and m/z 188.1075 for C12H14NO + [97,121], which appear at the same nominal m/z 188 in the LIT. For the purpose of this work, primary product ions are defined as product ions formed directly from the precursor ion without any intermediate ion between the precursor ion and primary product ion.…”

Section: Resultsmentioning

confidence: 99%

“…The conserved fragmentation behavior of FRCs can be very beneficial for the identification of novel FRCs, if the underlying fragmentation mechanisms can be understood. Examples of mechanistic interpretation for the generation of characteristic fentanyl fragmentation include Thevis et al [94], Wichitnithad et al [97] and our previous work on common intermediates in the tandem MS of FRCs [121]. However, these examples are focused on either fentanyl or specific FRCs, and as such do not provide a broad, generalized approach for the identification of the location of substitutions to the core fentanyl structure.…”

Section: Introductionmentioning

confidence: 99%

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Structural Characterization of Emerging Synthetic Drugs

Davidson¹

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Structural Characterization of Emerging Synthetic Drugs J. Tyler Davidson The identification of well-characterized seized drugs is performed thousands of times a day in the United States; however, the expanding use of emerging synthetic drugs is creating a growing problem for both toxicological and seized drug analyses. Two of the most rapidly growing areas of emerging synthetic drugs are synthetic cathinones and fentanyl-related compounds (FRCs). In this work we demonstrate the combination of multi-stage mass spectrometry (MS n), accurate mass measurements with high-resolution mass spectrometry (HRMS), and isotopic labeling for the structural characterization of synthetic cathinones and fentanyl analogs. The deliverables of this research include the identification of conserved fragmentation pathways for synthetic cathinones and fentanyl analogs, proposed mechanisms for the formation of characteristic ions through both protonated tandem mass spectrometry (MS/MS) and electron ionization mass spectrometry (EI-MS), and a discussion about how to apply the broadened understanding of the fragmentation behavior to the identification of novel synthetic cathinones and fentanyl analogs. The first major finding about the fragmentation behavior of synthetic cathinones is that the tropylium ion (m/z 91), or substituted derivative thereof, forms through different oxygencontaining intermediates that do not contain a formal C=O bond but instead contain a phthalanelike core structure. The phthalane-like intermediates were elucidated through gas-phase ion spectroscopy measurements and density functional theory (DFT) calculations. Likewise, the use of stable isotope labeling revealed the unprecedented finding that, during collision-induced dissociation (CID) of α-pyrrolidinophenone synthetic cathinones, the α-carbon is retained almost exclusively in the tropylium ion and the carbonyl carbon is not retained in the tropylium ion. Isotope labeling also identified competitive pathways for the loss of CO and ethylene (C2H4) from a primary intermediate ion, which provides support for the direct loss of CO from the alkyl side chain. A second major finding was the identification of characteristic protonated MS/MS fragmentation pathways and proposed mechanistic origins for both protonated MS/MS and EI-MS fragmentation for α-pyrrolidinophenone and N-alkylated synthetic cathinones. For MS/MS spectra of protonated α-pyrrolidinophenone synthetic cathinones the dominant fragmentation pathways are through 4-center hydrogen rearrangements to produce pyrrolidine ring cleavage, characteristic iminium ions and diagnostic ions at m/z 91 and m/z 105. For EI mass spectra, radical-directed αcleavages result in dominant iminium ions. In contrast to α-pyrrolidinophenone synthetic cathinones, MS/MS of protonated N-alkylated synthetic cathinones provided abundant radical losses from both the N-alkylated and aliphatic side chains, a dominant loss of H2O for 2° amines and the formation of abundant alkylphenones for 3° amines. These findings help advance our cu...

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 95%

“…The first phase of this project established several fragmentation pathways for protonated fentanyl and its main synthetic precursor 4-ANPP using tandem MS on a Q-TOF and a LIT [121].…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural Characterization of Emerging Synthetic Drugs

Davidson¹

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The influence of chemical modifications on the fragmentation behavior of fentanyl and fentanyl‐related compounds in electrospray ionization tandem mass spectrometry

Davidson

Sasiene

Jackson

2020

Drug Testing and Analysis

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Fentanyl is a synthetic opioid that has been approved by the FDA as a general anesthetic because of its rapid onset and high potency. However, since 2013 an opioid epidemic involving fentanyl or fentanyl‐related compounds (FRCs) has swept the United States and caused numerous deaths in every state. The identification of novel FRCs is complicated by the rapid turnover of modifications to the core fentanyl structure. In this study, a series of 16 FRCs were analyzed using electrospray ionization tandem mass spectrometry (ESI‐MS/MS) to gain a deeper understanding of the conserved and unique fragmentation behaviors associated with substitution to the core fentanyl structure. This work provides an approach, based on the product ions from ESI‐MS/MS, to identify the modification site(s) on the core fentanyl structure for FRCs. Five common locations of substitution to the core fentanyl structure were used to assess the effect of substitution on the fragmentation behavior of FRCs. The proposed fragmentation pathways are supported through the combination of isotopic labeling, multi‐stage mass spectrometry (MSn), and accurate mass measurements with high‐resolution mass spectrometry (HRMS). The identification of primary product ions specific to regions of substitution provides an additional tool for the identification of the location of substitution to the core fentanyl structure, which ultimately will assist toxicologists and seized drug analysts in the identification of emerging FRCs.

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The metabolism of valerylfentanyl using human liver microsomes and zebrafish larvae

Cooman

Hoover

Sauvé

et al. 2022

Drug Testing and Analysis

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Valerylfentanyl, a novel synthetic opioid less potent than fentanyl, has been reported in biological samples, but there are limited studies on its pharmacokinetic properties.The goal of this study was to elucidate the metabolism of valerylfentanyl using an in vitro human liver microsome (HLM) model compared with an in vivo zebrafish model. Nineteen metabolites were detected with N-dealkylation-valeryl norfentanyl and hydroxylation as the major metabolic pathways. The major metabolites in HLMs were also detected in 30 day postfertilization zebrafish. An authentic liver specimen that tested positive for valerylfentanyl, among other opioids and stimulants, revealed the presence of a metabolite that shared transitions and retention time as the hydroxylated metabolite of valerylfentanyl but could not be confirmed without an authentic standard. 4-Anilino-N-phenethylpiperidine (4-ANPP), a common metabolite to other fentanyl analogs, was also detected. In this study, we elucidated the metabolic pathway of valerylfentanyl, confirmed two metabolites using standards, and demonstrated that the zebrafish model produced similar metabolites to the HLM model for opioids.

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The characterization of isobaric product ions of fentanyl using multi‐stage mass spectrometry, high‐resolution mass spectrometry and isotopic labeling

Cited by 23 publications

References 23 publications

Structural Characterization of Emerging Synthetic Drugs

Structural Characterization of Emerging Synthetic Drugs

The influence of chemical modifications on the fragmentation behavior of fentanyl and fentanyl‐related compounds in electrospray ionization tandem mass spectrometry

The metabolism of valerylfentanyl using human liver microsomes and zebrafish larvae

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