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Recently, thienyl derivatives of cathinones have appeared on the market as new psychoactive substances (NPS). In this study, identification and characterization of 2-(pyrrolidin-1-yl)-1-(thiophen-2-yl)pentan-1-one (α-PVT), 2-(pyrrolidin-1-yl)-1-(thiophen-2-yl)butan-1-one (α-PBT), and their bromothienyl analogs disclosed in illicit products are described. In our analysis, some analogous compounds of α-PVT, which had a bromine substitution on the thiophene ring, were identified in the samples containing α-PVT; 1-(4-bromothiophen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one, 1-(5-bromothiophen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one, and 1-(4,5-dibromothiophen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one by comparing the analytical data with synthetic reference standards. We also observed 1-(4-bromothiophen-2-yl)-2-(pyrrolidin-1-yl)butan-1-one and 1-(5-bromothiophen-2-yl)-2-(pyrrolidin-1-yl)butan-1-one from a powder product, in which α-PBT was detected. The brominated α-PVTs were also found when overbrominated 1-(thiophen-2-yl)pentan-1-one reacted with pyrrolidine, and they are suspected to be the by-products of α-PVT synthesis. In Japan, cathinone derivatives with a phenyl group as the aromatic ring have been widely controlled by generic scheduling. To escape from such a regulation, analogs with different aromatic groups such as α-PVT and α-PBT appeared on the illicit market of psychoactive compounds. To our knowledge, this is the first report describing identification of α-PBT, and bromothienyl analogs of both α-PVT and α-PBT in illicit drug products. The synthetic method and analytical data shown in this study will be useful for identification of the thienyl derivatives of cathinone analogs.

1-Phenyl-2-(pyrrolidin-1-yl)octan-1-one (PV9) and 16 metabolites, including diastereomers and conjugates, were identified or tentatively detected in human urine by gas chromatography–mass spectrometry and liquid chromatography–high-resolution tandem mass spectrometry. These urinary metabolites indicated that the metabolic pathways of PV9 include: (1) the reduction of ketone groups to their corresponding alcohols; (2) oxidation of the pyrrolidine ring to the corresponding pyrrolidone; (3) aliphatic oxidation of the terminal carbon atom to the corresponding carboxylate form, possibly through an alcohol intermediate (not detected); and (4) hydroxylation at the penultimate carbon atom to the corresponding alcohols followed by further oxidation to ketones, and combinations of these steps. In addition, results from the quantitative analyses of five phase-I metabolites using newly synthesized authentic standards suggested that the main metabolic pathway includes the aliphatic oxidation of terminal and/or penultimate carbons. Human metabolism of PV9 differed significantly from those of α-pyrrolidinovalerophenone and α-pyrrolidinobutiophenone, suggesting that the main metabolic pathways of α-pyrrolidinophenones significantly change depending on the alkyl chain length of the parent molecule.

Little information is available on the amounts of hypnotics incorporated into hair after a single administration and about effective analytical procedures to document cases like drug-facilitated sexual assaults. To obtain basic information, single-hair specimens from a volunteer who took a single dose of 10-mg zolpidem (ZP) were analyzed by a newly established liquid chromatography–tandem mass spectrometry procedure, using a one-pot pulverization extraction method. The detection limit of ZP was 50 fg/2-cm single hair, and ZP in each segment was determined for the single black hair specimens (n = 15). ZP was detectable in 14 hairs (positive for all the proximal 0–2 cm segments, negative for all 2–4 cm segments), but was not detected in a single hair (probably in the telogen stage). The amounts of ZP detected in each positive 2-cm segment of single hair ranged from 27 to 63 pg (average 43 pg). The estimated total incorporation of ZP in the scalp hair (black hair ~110,000 strands) was about 4.7 μg, which corresponds to about 0.06 % of the single 10-mg dose (8.03 mg as free ZP). In addition, the direct detection of single-dose ZP incorporated in hair and its imaging were successfully achieved by matrix-assisted laser desorption ionization-mass spectrometry. It is suggested that a combination of these methodologies will provide the highest-level evidence to document such exposure to a hypnotic drug.

Urinary metabolites of α-pyrrolidinovalerophenone (α-PVP) in humans were investigated by analyzing urine specimens obtained from abusers. Unambiguous identification and accurate quantification of major metabolites were realized using gas chromatography–mass spectrometry and liquid chromatography-tandem mass spectrometry with newly synthesized authentic standards. Two major metabolic pathways were revealed: (1) the reduction of the β-keto moiety to 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-ol (OH-α-PVP, diastereomers) partly followed by conjugation to its glucuronide, and (2) the oxidation at the 2″-position of the pyrrolidine ring to α-(2″-oxo-pyrrolidino)valerophenone (2″-oxo-α-PVP) via the putative intermediate α-(2″-hydroxypyrrolidino)valerophenone (2″-OH-α-PVP). Of the metabolites retaining the structural characteristics of the parent drug, OH-α-PVP was most abundant in most of the specimens examined.

Mass spectrometric differentiation of the six isomers of mono-methoxyethylamphetamines (MeO-EAs) and mono-methoxydimethylamphetamines (MeO-DMAs) by gas chromatography–electron ionization–tandem mass spectrometry (GC–EI–MS–MS) was investigated. Based on their EI-mass spectra, the fragment ions at m/z 121 and 72 were selected as precursor ions for their regioisomeric and structurally isomeric differentiation, respectively. Collision-induced dissociation provides intensity differences in product ions among the isomers, enabling mass spectrometric differentiation of the isomers. Furthermore, high reproducibility of the product ion spectra at the optimized collision energy was confirmed, demonstrating the reliability of the method. To our knowledge, this is the first report on mass spectrometric differentiation of the six isomers of MeO-EAs and MeO-DMAs by GC–EI–MS–MS. Isomeric differentiation by GC–EI–MS–MS has a high potential to discriminate isomers of newly encountered designer drugs, making GC–MS–MS a powerful tool in the forensic toxicology field.

Cathinone-derived designer drugs have recently grown to be popular as drugs of abuse. 3,4-Dimethylmethcathinone (DMMC) has recently been abused as one of the alternatives to controlled cathinones. In the present study, DMMC and its major metabolites, 3,4-dimethylcathinone (DMC), 1-(3,4-dimethylphenyl)-2-methylaminopropan-1-ol (β-OH-DMMC, diastereomers), and 2-amino-1-(3,4-dimethylphenyl)propan-1-ol (β-OH-DMC, diastereomers), have been identified and quantified in a DMMC user’s urine by gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry using newly synthesized authentic standards. Other putative metabolites including oxidative metabolites of the xylyl group and conjugated metabolites have also been detected in urine. The identified and putative phase I metabolites indicated that the metabolic pathways of DMMC include its reduction of the ketone group to the corresponding alcohols, N-demethylation to the primary amine, oxidation of the xylyl group to the corresponding alcohol and carboxylate forms, and combination of these steps. Concentrations of the identified metabolites were found to increase slightly after enzymatic hydrolysis, suggesting that these compounds are partially metabolized to the respective conjugates.