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Cayman NPS Metabolism Monograph Nathan K ISSUE 2 Cayman NPS Metabolism Monograph Nathan K. Layle, Ting Zhao, and Donna M. Iula N-butyl Pentylone Item No. 26701 Synthetic Cathinone O H O H HO N N O HO M1 A Amine group O Aryl ring O O H NH O N B O 2 N-butyl Pentylone is a synthetic cathinone O O first reported in 1960s German patent literature, M2 emerging on the recreational drug market Ketone C O in late 2018.1 Cathinone analogs have seen H O N widespread abuse since the mid-2000s and (A) Demethylenation O are derived from the alkaloid cathinone found OH 2 (B) N-Dealkylation M3 in khat. N-butyl Pentylone has been identified (C) Hydroxylation on illicit research chemical websites and in Observed phase I metabolites of N-butyl pentylone seized drug samples. While several similar detected using high mass accuracy fragments cathinone analogs are Schedule I controlled generated by LC-MS/MS. substances, N-butyl pentylone remains uncontrolled as of mid-2020. The goal of this monograph is to identify its probable phase I metabolites using HLM assays. This study can provide insights into the metabolic pathway of N-butyl pentylone, and by analysis with Need a Reference Standard for a high-resolution Orbitrap mass spectrometry, we Specific Metabolite? aim to provide forensic toxicologists with the key ions/fragments that can help identify this Have a Request for Future Studies? novel synthetic cathinone in biological samples. Contact Us at [email protected] Cayman Chemical · (800) 364-9897 www.caymanchem.com 1180 E. Ellsworth Road · Ann Arbor, MI · 48108 Mass Spectrum and Fragments of N-butyl Pentylone O O O O H H H H2 N N O N N O O O O O O O Exact Mass: 128.1434 Exact Mass: 149.0233 Exact Mass: 205.0859 Exact Mass: 230.1539 Exact Mass: 260.1645 Exact Mass: 278.1751 O O O O H H H H2 N N O N N O O O O O O O Exact Mass: 128.1434 Exact Mass: 149.0233 Exact Mass: 205.0859 Exact Mass: 230.1539 Exact Mass: 260.1645 Exact Mass: 278.1751 O O O O H H H H2 N N O N N O O O O O O O Exact Mass: 128.1434 Exact Mass: 149.0233 Exact Mass: 205.0859 Exact Mass: 230.1539 Exact Mass: 260.1645 Exact Mass: 278.1751 O O O O H H H H2 N N O N N O O O O O O O O O O H H O H H 2 N N O N N O O O Exact Mass:O 128.1434 Exact Mass: 149.0233 Exact Mass: 205.0859 Exact Mass: 230.1539 Exact Mass: 260.1645 Exact Mass: 278.1751 O O O Exact Mass: 128.1434 Exact Mass: 149.0233 Exact Mass: 205.0859 Exact Mass: 230.1539 Exact Mass: 260.1645 Exact Mass: 278.1751 Figure 1. High-resolution mass spectrum of the parent compound N-butyl pentylone with proposed fragment structures. N-butyl Pentylone Metabolite Formation and Detection The parent compound N-butyl pentylone was incubated with human liver microsomes (HLM) to form phase I metabolites. An aliquot from the incubation was quenched with acetonitrile, and the mixture was centrifuged at 13,200 rpm for 10 minutes. The obtained supernatant was injected onto a Dionex Ultra-High Performance Liquid Chromatography (UHPLC) system for metabolite separation. The eluted metabolites were detected using a high-resolution Orbitrap mass spectrometer (Thermo Scientific). For comparison, a control sample was prepared by incubating N-butyl pentylone with deactivated HLM. The total ion chromatogram (TIC) along with extracted ion chromatograms (EICs) of the incubation compared with those of the control were used to identify metabolites formed from the HLM assay with N-butyl pentylone. The TIC shows potential metabolites at 4.75 (M1), 4.80 (M2), and 5.09 (M3) min retention times (RT), as well as the parent, N-butyl pentylone, at 5.70 min. The EICs show the three main phase I metabolites by their exact masses, formed from our HLM incubation. All three metabolites gave masses consistent with the known ways 3,4-methylenedioxycathinones are metabolized: demethylenation, N-dealkylation, and oxidation (hydroxylation).3 In our study, we did not observe the possible hydrogenation metabolite that results from reduction of the β-ketone to the corresponding alcohol that can occur with some cathinones. This result agrees with the literature on the metabolism of 3,4-methylenedioxy-substituted cathinones.3 Interestingly, we observed two peaks at 5.38 min and 5.70 min in the metabolite incubation that correspond with the MS/MS spectrum of the parent compound. However, we only observed a single peak of the parent compound at 5.72 min in the control sample. The earlier 5.38 min peak displays no evidence of a mass shift, indicating that it results from a change in the parent N-butyl pentylone because of incubation and not as the result of metabolism. 2 TIC M1 & M2 N-butyl Pentylone 5.70 min M3 4.75 4.80 M1 EIC M2 EIC 266.1751 m/z 222.1125 m/z 5.09 M3 EIC 294.1700 m/z 5.00 5.21 Figure 2. TIC (top) and EICs (bottom) of N-butyl pentylone post-incubation. EICs and corresponding exact masses for metabolites M1, M2, and M3 represent demethylenation, N-dealkylation, and hydroxylation, respectively. 3 Metabolite 1 (M1) The first eluting metabolite (4.75 min) yielded the MS/MS spectrum below with proposed major fragments. This demethylenation metabolite is consistent with literature metabolism data on structurally similar analog N-ethyl pentylone, which includes authentic human biological samples.4 Two key ions generated from fragmentation of this metabolite are 266.1743 m/z and 193.0857 m/z, both of which show the loss of the methylenedioxy methylene (CH2) group. O O H HO N O O H H2 H2 N N HO N HO O HO H3N + + Chemical Formula: C11H13O3 Chemical Formula: C15H20NO Exact Mass: 74.0964 Exact Mass: 128.1434 Exact Mass: 193.0859 Exact Mass: 230.1539 Exact Mass: 248.1645 Exact Mass: 266.1751 O O H HO N O O H H2 H2 N N HO N HO O HO H3N + + Chemical Formula: C11H13O3 Chemical Formula: C15H20NO Exact Mass: 74.0964 Exact Mass: 128.1434 Exact Mass: 193.0859 Exact Mass: 230.1539 Exact Mass: 248.1645 Exact Mass: 266.1751 O O H HO N O O H H2 H2 N N HO N HO O HO H3N O O O + O + H Chemical Formula: C11H13O3 Chemical Formula:H C15H20NO HO N HO N Exact Mass: 74.0964 Exact Mass: 128.1434 Exact Mass: 193.0859 O Exact Mass: 230.1539 O Exact Mass:O 248.1645 Exact Mass:O 266.1751 H H H2 H2 H2 H2 N N O O N HO N N HO N HO HO H HO O N O O O H HO H2 H2 HO H3N N + + N HO N ChemicalH3N Formula: C H O Chemical Formula: C H NO + + 11 13 3 HO Chemical15 20 Formula: C11H13O3 Chemical Formula: C15H20NO O Exact Mass: 74.0964 Exact Mass: 128.1434 ExactExact Mass: Mass: 74.0964 193.0859 Exact Mass:Exact 128.1434 Mass: 230.1539Exact Mass: 193.0859Exact Mass: 248.1645 Exact Mass: 230.1539Exact Mass: 266.1751Exact Mass: 248.1645 Exact Mass: 266.1751 HO H3N + + Chemical Formula: C11H13O3 Chemical Formula: C15H20NO Exact Mass: 74.0964 Exact Mass: 128.1434 Exact Mass: 193.0859 Exact Mass: 230.1539 Exact Mass: 248.1645 Exact Mass: 266.1751 Figure 3. High-resolution MS/MS spectrum of demethylenation metabolite M1 and proposed fragment structures. 4 Metabolite 2 (M2) The second eluting metabolite had a retention time of 4.80 min and yielded the MS/MS spectrum and fragments below. The key fragments that indicate N-dealkylation include 222.1120 m/z, 204.1016 m/z, and 174.0912 m/z. These fragments have proposed structures based on the fragmentation of similar cathinones. O O O NH2 NH2 O NH3 O NH2 O O H2N O Exact Mass: 72.0808 Exact Mass: 135.0441 Exact Mass: 146.0964 Exact Mass: 174.0913 Exact Mass: 204.1019 Exact Mass: 222.1125 O O O NH2 NH2 O NH3 O NH2 O O H2N O Exact Mass: 72.0808 Exact Mass: 135.0441 Exact Mass: 146.0964 Exact Mass: 174.0913 Exact Mass: 204.1019 Exact Mass: 222.1125 O O O NH2 ONH2 O NH3O O O O O O NH2 NH2 NH2 O NH3 O NH O O NH O NH O NH2 O 2 2 O 3 H N 2 O O NH2 NH2 O NH2 O O NH3 H N O Exact Mass: 72.0808 Exact Mass: 135.04412 Exact Mass:O 146.0964O Exact Mass: 174.0913NH2 Exact Mass: 204.1019 Exact Mass: 222.1O 125 H2N O Exact Mass: 72.0808 Exact Mass: 135.0441 Exact Mass: 146.0964 Exact Mass: 174.0913 O Exact Mass: 204.1019 O Exact Mass: 222.1125 H2N Exact Mass: 72.0808 O Exact Mass: 135.0441 Exact Mass: 146.0964 Exact Mass: 174.0913 Exact Mass: 204.1019 Exact Mass: 222.1125 Exact Mass: 72.0808 Exact Mass: 135.0441 Exact Mass: 146.0964 Exact Mass: 174.0913 Exact Mass: 204.1019 Exact Mass: 222.1125 Figure 4. High-resolution MS/MS spectrum of N-dealkylation metabolite M2 and proposed fragment structures. 5 Metabolite 3 (M3) The latest eluting metabolites had retention times of 5.00 min/5.09 min/5.21 min and yielded the averaged mass spectrum and proposed fragments below.
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