Accurate mass measurement at enhanced mass‐resolution on a triple quadrupole mass‐spectrometer for the identification of a reaction impurity and collisionally‐induced fragment ions of cabergoline

Paul, George; Winnik, Witold; Hughes, Nicola; Schweingruber, Hans; Heller, Rexford; Schoen, Alan

doi:10.1002/rcm.952

Cited by 23 publications

(18 citation statements)

References 9 publications

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“…Accurate mass data for the fragment ions at m/z ϭ 175, m/z ϭ 156, and m/z ϭ 147 were consistent with the calculated exact mass for the basic amino acids in RF, HF,°and°KV°(Table°1)° [35][36][37].…”

Section: Determination Of Exact Masssupporting

confidence: 71%

A study of b₁+H₂O and b₁-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues

Hiserodt

Brown

Swijter

et al. 2007

J. Am. Soc. Mass Spectrom.

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The product ion spectra of approximately 200 dipeptides were acquired under low-energy conditions using a triple quadrupole mass spectrometer. The spectra of dipeptides containing an N-terminal arginine (R), histidine (H), or lysine (K) were observed to yield a b 1 ϩ H 2 O ion corresponding to the protonated basic amino acid. This was equivalent to the y 1 -ion in the corresponding C-terminal isomer. The formation of a b 1 ϩ H 2 O ion was not a significant fragmentation channel in any dipeptides analyzed including those containing a C-terminal basic amino acid unless they also contained an N-terminal basic amino acid. Occurring simultaneously and under equal energy conditions an apparent b 1 -ion was formed, which has its corresponding C-terminal equivalent in the y 1 -H 2 O ion. Energy resolved mass spectrometry (ERMS), deuterium labeling, and accurate mass experiments as well as data reported were used to show the relationships between the b 1 ϩH 2 O and b 1 -ions in the dipeptides containing an N-terminal basic amino acid and the y 1 and y 1 -H 2 O ions in the corresponding C-terminal isomers. (J Am Soc Mass Spectrom 2007, 18, 1414 -1422) © 2007 American Society for Mass Spectrometry C ollision induced dissociation (CID) in a triple quadrupole mass spectrometer utilizing electrospray ionization (ESI) is a widely used technique for obtaining product ion spectra for the characterization of peptides. The spectrometric information in the product ion spectrum acquired at a single collision energy is limited and can be significantly enhanced utilizing energy resolved mass spectrometry (ERMS), where product ion spectra are acquired at increasingly greater collision cell energies. This results in an increase in the internal energy of the precursor ion, which leads to further dissociation. A plot of relative intensity versus collision energy of selected fragment ions leads to the generation of breakdown curves [1,2]. Evaluation of these breakdown curves can provide information on fragmentation mechanisms such as distinguishing between competitive and consecutive fragmentation pathways, the stability of product ions, and identification of first and subsequent generation product ions [3][4][5][6][7][8]; identification of isomers and tautomers [9 -11]; and development of library searchable product ion spectra [12,13]. Since the internal energy of the precursor ion is not rigorously known, breakdown curves provide a qualitative picture of a fragmentation mechanism.Using these analytical tools, our laboratory analyzed ϳ200 dipeptides and have made some noteworthy observations in the product ion spectra of dipeptides containing N-terminal arginine (R), histidine (H), and lysine (K) and their C-terminal isomers. We used the single letter abbreviations for amino acids in dipeptides throughout this paper.The first was the observation of a fragment ion that corresponded to the mass of the protonated molecule (M ϩ H) ϩ of the basic amino acid. This was observed at m/z ϭ 175 for arginine, m/z ϭ 156 for histidine, and m/z ϭ 147 fo...

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Section: Determination Of Exact Masssupporting

confidence: 71%

A study of b₁+H₂O and b₁-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues

Hiserodt

Brown

Swijter

et al. 2007

J. Am. Soc. Mass Spectrom.

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“…These values were determined in triplicate and were Յ0.5 mmu from the calculated mass taking into account the mass of an electron [35]. Complete details for the determination of the exact mass of a precursor or product ion can be found in references [36,37].…”

Section: Determination Of Exact Massmentioning

confidence: 99%

Proposed mechanisms for the fragmentation of doubly allylic alkenamides (tingle compounds) by low energy collisional activation in a triple quadrupole mass spectrometer

Hiserodt

Pope

Cossette

et al. 2004

J. Am. Soc. Mass Spectrom.

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Tingle compounds are a class of alkenamides with organoleptic properties that include a numbing or a pins and needles effect that is generally perceived on the lips and in the mouth when consumed. They occur in nature in a number of botanical species. Spilanthol and Pellitorine are important examples of tingle compounds. A number of homologs and analogs were synthesized to study the effect of chain length, double bond location, and amide moiety on the tingle effect. This also provided the opportunity to study the behavior of these compounds in the collision cell of a triple quadrupole mass spectrometer. The doubly allylic 2E,6Z-alkenamides, which made up the largest class studied, fragmented in a characteristic way to produce a distonic radical cation and a cyclopropene cation. Mechanisms for the formation of these ions are proposed. The mechanisms are supported by energy-resolved mass spectrometric data, the analysis of deuterated analogs and homologs that are not doubly allylic, and exact mass measurements. Exceptions to the proposed mechanisms are also presented. These data represent the first attempt to apply mechanistic principles to the product ions observed in the MS/MS spectra of these compounds. The authors believe the results of this study will facilitate the identification of these and similar compounds and contribute to the fundamental understanding of the behavior of alkenamides in the collision cell of a triple quadrupole mass

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“…The TSQ Quantum AM instrument contains a thermally stabilized analyzer control board with a virtual digital-to-analog converter subsystem designed specifically for accurate mass measurement. 7 This innovation imparts accurate mass measurement capabilities to the triple-quadrupole mass spectrometer. For the mass spectral scan, product ion scan, neutral loss scan, and precursor ion scan experiments, the accurate mass function of the TSQ Quantum AM was not utilized.…”

Section: Mass Spectrometrymentioning

confidence: 99%

“…For accurate determination of the product ions by SRM, two different lock-mass schemes were used. The first one was based on using two product ions of the precursor [HO(CH 2 CH 2 O) 7 3 þH þ ], with exact mass of 133.0865 u, and this first scheme was used for one metabolite. The second scheme, applied for the drug and all other metabolites, was based on using the b2 ion (C 11 H 22 N 5 O 2 S þ , with exact mass of 288.1494 u) and y2 ion (C 12 H 17 N 2 O 3 þ , with exact mass of 237.1239 u) of Met-Arg-Phe-Ala (MRFA).…”

Section: Mass Spectrometrymentioning

confidence: 99%

A strategy for metabolite identification using triple‐quadrupole mass spectrometry with enhanced resolution and accurate mass capability

Jemal

Ouyang

Zhao

et al. 2003

Rapid Comm Mass Spectrometry

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Using a single platform of a triple-quadrupole mass spectrometer equipped with enhanced resolution and accurate mass capabilities, a strategy for metabolite identification of a drug in a biological matrix has been demonstrated. The strategy is based on first screening for metabolites via neutral loss and precursor ion scan schemes, devised as the result of the product ion spectrum of a matrixfree standard of the drug. The accurate masses of the precursor ions identified via the two scan schemes plus the precursor ions of structurally likely metabolites are then determined by enhanced resolution, accurate mass (AM) selected ion monitoring (SIM). The identities of the metabolites are further established by determining the accurate masses of the product ions via enhanced resolution AM selected reaction monitoring (SRM). The feasibility of the strategy was demonstrated using a liver microsome incubation sample of nefazodone, an antidepressant drug. The neutral loss and precursor ion screening runs were able to identify most of the metabolites of nefazodone. The subsequent SIM and SRM experiments gave mass accuracy of better than AE0.003 u for the masses of the precursor and product ions of nefazodone and all the metabolites. The ability to perform metabolite screening by using the scan features followed by accurate mass determinations on the same instrument is an attractive feature of using a triple-quadrupole mass spectrometer with enhanced resolution and accurate mass capability. Copyright # 2003 John Wiley & Sons, Ltd.Metabolite identification has become an integral part of drug discovery and development, and mass spectrometry has evolved as an essential component of strategies used for fast metabolite identification. 1-4 Different mass spectrometric platforms have been used for metabolite identification, including triple-quadrupole, quadrupole-ion trap, triple-quadrupole/linear quadrupole trap combination, and quadrupole/time of flight combination (Q-TOF). As part of such strategies, a triple-quadrupole mass spectrometer is considered essential as neutral loss and precursor ion scans can be easily achieved in addition to the full scan, product ion scan and selected reaction monitoring (SRM) features. The recent commercial availability of a triple-quadrupole mass spectrometer with enhanced resolution and accurate mass capability has provided the opportunity for performing neutral loss scans, precursor ion scans, and accurate mass determinations for precursor and product ions, on a single platform. In this paper we present our experience with a metabolite identification strategy based on this mass spectrometer using a nefazodone (Fig. 1) liver microsome incubation sample as a model test sample. Nefazodone, an antidepressant drug, was selected as a model drug since the metabolites of nefazodone have been reported previously. 5,6 EXPERIMENTAL Chemicals and reagentsNefazodone and three nefazodone metabolites were obtained from Bristol-Myers Squibb Research Institute. HPLC-grade acetonitrile, glacial acetic acid and ...

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Accurate mass measurement at enhanced mass‐resolution on a triple quadrupole mass‐spectrometer for the identification of a reaction impurity and collisionally‐induced fragment ions of cabergoline

Cited by 23 publications

References 9 publications

A study of b₁+H₂O and b₁-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues

A study of b₁+H₂O and b₁-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues

Proposed mechanisms for the fragmentation of doubly allylic alkenamides (tingle compounds) by low energy collisional activation in a triple quadrupole mass spectrometer

A strategy for metabolite identification using triple‐quadrupole mass spectrometry with enhanced resolution and accurate mass capability

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Accurate mass measurement at enhanced mass‐resolution on a triple quadrupole mass‐spectrometer for the identification of a reaction impurity and collisionally‐induced fragment ions of cabergoline

Cited by 23 publications

References 9 publications

A study of b1+H2O and b1-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues

A study of b1+H2O and b1-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues

Proposed mechanisms for the fragmentation of doubly allylic alkenamides (tingle compounds) by low energy collisional activation in a triple quadrupole mass spectrometer

A strategy for metabolite identification using triple‐quadrupole mass spectrometry with enhanced resolution and accurate mass capability

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A study of b₁+H₂O and b₁-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues

A study of b₁+H₂O and b₁-ions in the product ion spectra of dipeptides containing N-terminal basic amino acid residues