Identification and analytical characterization of four synthetic cathinone derivatives iso‐4‐BMC, β‐TH‐naphyrone,mexedrone, and 4‐MDMC

New psychoactive substances (NPS) have gained much popularity on the global market over the last number of years. The synthetic cathinone family is one of the most prominent groups and this paper reports on the analytical properties of four synthetic cathinone derivatives: ( 1 ) 1‐(4‐bromophenyl)‐1‐(methylamino)propan‐2‐one (iso‐4‐BMC or iso‐brephedrone), ( 2 ) 2‐(pyrrolidin‐1‐yl)‐1‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)pentan‐1‐one (β ‐TH‐naphyrone), ( 3 ) 3‐methoxy‐2‐(methylamino)‐1‐(4‐methylphenyl)propan‐1‐one (mexedrone), and ( 4 ) 2‐(dimethylamino)‐1‐(4‐methylphenyl)propan‐1‐one (4‐MDMC). These identifications were based on liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometry (LC‐QTOF‐MS), gas chromatography‐mass spectrometry (GC‐MS) and nuclear magnetic resonance (NMR) spectroscopy. To our knowledge, no chemical or pharmacological data about compounds 1–3 have appeared until now, making this the first report on these compounds. The Raman and GC‐MS data of 4 have been reported, but this study added the LC‐MS and NMR data for additional characterization. Copyright © 2016 John Wiley & Sons, Ltd.     

Identification of three cannabimimetic indazole and pyrazole derivatives,APINACA 2H‐indazole analogue,AMPPPCA, and 5F‐AMPPPCA

This paper reports analytical properties of three cannabimimetic indazole and pyrazole derivatives seized from a clandestine laboratory. These three new synthetic cannabinoids include N ‐(1‐adamantyl)‐2‐pentyl‐2H ‐indazole‐3‐carboxamide (APINACA 2H ‐indazole analogue, 1 ), N ‐(1‐adamantyl)‐4‐methyl‐1‐pentyl‐5‐phenyl‐1H ‐pyrazole‐3‐carboxamide (AMPPPCA, 2 ), and N ‐(1‐adamantyl)‐1‐(5‐fluoropentyl)‐4‐methyl‐5‐phenyl‐1H ‐pyrazole‐3‐carboxamide (5F‐AMPPPCA, 3 ). These compounds were identified by liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometry (LC‐QTOF‐MS), gas chromatography‐time‐of‐flight‐mass spectrometry (GC‐TOF‐MS), and nuclear magnetic resonance (NMR) spectroscopy. No analytical properties and pharmacological activities about compounds 1–3 have appeared until now, making this the first report on these compounds. Copyright © 2016 John Wiley & Sons, Ltd.     

Identification and analytical characterization of four synthetic cannabinoids ADB‐BICA,NNL‐1, NNL‐2, and PPA(N)‐2201

Since the first appearance as psychotropic drugs in illegal markets in 2008, the spread of synthetic cannabinoids is becoming a serious problem in many countries. This paper reports on the analytical properties and structure elucidation of four cannabimimetic derivatives in seized material: 1‐benzyl‐N ‐(1‐carbamoyl‐2,2‐dimethylpropan‐1‐yl)‐1H ‐indole‐3‐carboxamide (ADB‐BICA, 1 ), N ‐(1‐carbamoylpropan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H ‐pyrrolo[2,3‐b]pyridine‐3‐carboxamide (NNL‐1, 2 ), (4‐benzylpiperazin‐1‐yl)(1‐(5‐fluoropentyl)‐1H ‐indol‐3‐yl)methanone (NNL‐2, 3 ), and N ‐(1‐carbamoyl‐2‐phenylethyl)‐1‐(5‐fluoropentyl)‐1H ‐indazole‐3‐carboxamide (PPA(N)‐2201, 4) . The identifications were based on liquid chromatography‐quadrupole‐time‐of‐flight‐mass spectrometry (LC‐QTOF‐MS), gas chromatography‐mass spectrometry (GC‐MS), Fourier transform infrared spectroscopy (FT‐IR), and nuclear magnetic resonance (NMR) spectroscopy. No chemical or pharmacological data about compounds 1–3 have appeared until now, making this the first report on these compounds. The GC‐MS data of 4 has been reported, but this study added the LC‐MS, FT‐IR, and NMR data for additional characterization. Copyright © 2016 John Wiley & Sons, Ltd.     

Identification and analytical characterization of six synthetic cannabinoids NNL‐3, 5F–NPB‐22‐7N, 5F–AKB‐48‐7N, 5F–EDMB‐PINACA,EMB‐FUBINACA,and EG‐018

Clinical and forensic toxicology laboratories are continuously confronted by analytical challenges when dealing with the new psychoactive substances phenomenon. The number of synthetic cannabinoids, the chemical diversity, and the speed of emergence make this group of compounds particularly challenging in terms of detection, monitoring, and responding. Three indazole 7N positional isomer synthetic cannabinoids, two ethyl 2‐amino‐3‐methylbutanoate‐type synthetic cannabinoids, and one 9H –carbazole substituted synthetic cannabinoid were identified in seized materials. These six synthetic cannabinoid derivatives included: 1H –benzo[d ] [1,2,3]triazol‐1‐yl 1‐(5‐fluoropentyl)‐1H –pyrrolo[2,3‐b ]pyridine‐3‐carboxylate (NNL‐3, 1 ), quinolin‐8‐yl 1‐(5‐fluoropentyl)‐1H –pyrrolo[2,3‐b ]pyridine‐3‐carboxylate (5F–NPB‐22‐7N , 2 ), N ‐((1 s,3 s)‐adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H –pyrrolo[2,3‐b ]pyridine‐3‐carboxamide (5F–AKB‐48‐7N , 3 ), ethyl 2‐(1‐(5‐fluoropentyl)‐1H –indazole‐3‐carboxamido)‐3,3‐dimethylbutanoate (5F–EDMB‐PINACA, 4 ), ethyl 2‐(1‐(4‐fluorobenzyl)‐1H –indazole‐3‐carboxamido)‐3‐methylbutanoate (EMB‐FUBINACA, 5 ), and naphthalen‐1‐yl(9‐pentyl‐9H ‐carbazol‐3‐yl)methanone (EG‐018, 6 ). The identification was based on ultra‐high‐performance liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometry (UHPLC‐QTOF‐MS), gas chromatography–mass spectrometry (GC–MS), and nuclear magnetic resonance spectroscopy (NMR). The analytical characterization of these six synthetic cannabinoids was described, so as to assist forensic laboratories in identifying these compounds or other substances with similar structure in their case work. To our knowledge, no analytical data about the compounds 1 – 5 have appeared until now, making this the first report on these compounds. The GC–MS data of 6 has been reported, but this study added the LC–MS, NMR, and Fourier transform infrared (FTIR), data to render the analytical data collection process more complete. Copyright © 2017 John Wiley & Sons, Ltd.     

Development of a high‐speed MALDI‐triple quadrupole mass spectrometric method for the determination of 3,4‐methylenedioxymethamphetamine (MDMA) in oral fluid

3,4‐Methylenedioxymethamphetamine (MDMA, ecstasy) is still a widely used illicit designer drug and its detection in different matrices is of major importance for forensic purposes (e.g. driving under the influence) as well as for workplace drug testing or abstinence control. Established analytical methods for the determination of MDMA are mainly employing high performance liquid chromatography (HPLC) or gas chromatography (GC) coupled to mass spectrometric detection. Matrix assisted laser desorption/ionization‐triple quadrupole‐tandem mass spectrometry (MALDI‐QqQ‐MS/MS) is so far rarely used in forensics and offers an ultrafast high‐throughput platform. The Quantisal? Oral Fluid Collection Device was used for sample collection. After addition of the deuterated internal standard and a carbonate buffer (0.75 M Na₂CO₃), oral fluid samples were liquid‐liquid extracted (ButOAc/EtOAc, 1:1). As little as 1 microlitre of a mixture of this extract and the MALDI matrix (alpha‐cyano‐4‐hydroxycinnamic acid) was spotted onto the MALDI plate and could directly be analyzed. With MALDI omitting chromatographic separation, very short analysis times of about 10 s per sample were possible. The method was developed and validated according to international guidelines including specificity, recovery, matrix effects, accuracy and precision, stabilities and limit of quantification. All validation criteria were fulfilled except for ion suppression/enhancement. Comparison with a routine liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method showed good agreement of the results. Applicability of the method was shown by analyzing about 250 oral fluid samples collected after controlled administration of 125 mg MDMA in a pharmacokinetic study. The whole lot of samples could be analyzed in less than 1 h, proving the ultra‐high‐speed of the method. Copyright © 2015 John Wiley & Sons, Ltd.     

Preventive effects of fructose and N‐acetyl‐L‐cysteine against cytotoxicity induced by the psychoactive compounds N‐methyl‐5‐(2‐aminopropyl)benzofuran and 3,4‐methylenedioxy‐N‐methamphetamine in isolated rat hepatocytes

Psychoactive compounds, N‐methyl‐5‐(2‐aminopropyl)benzofuran (5‐MAPB) and 3,4‐methylenedioxy‐N‐methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N‐acetyl‐l ‐cysteine (NAC) on 5‐MAPB‐ and MDMA‐induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration‐dependent (0–4 mm ) and time‐dependent (0–3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH. The toxic effects of 5‐MAPB were greater than those of MDMA. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or NAC at a concentration of 2.5 mm prevented 5‐MAPB?/MDMA‐induced cytotoxicity. In addition, the exposure of hepatocytes to 5‐MAPB/MDMA caused the loss of mitochondrial membrane potential, although the preventive effect of fructose was weaker than that of NAC. These results suggest that: (1) 5‐MAPB?/MDMA‐induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were ameliorated, at least in part, by the addition of fructose; and (3) GSH loss via oxidative stress was prevented by NAC. Taken collectively, these results indicate that the onset of toxic effects caused by 5‐MAPB/MDMA may be partially attributable to cellular energy stress as well as oxidative stress.     

Development and validation of an LC‐MS/MS method after chiral derivatization for the simultaneous stereoselective determination of methylenedioxy‐methamphetamine (MDMA) and its phase I and II metabolites in human blood plasma

3,4‐Methylenedioxymethamphetamine (MDMA, ecstasy) is a racemic drug of abuse and its two enantiomers are known to differ in their dose‐response curves. The S‐enantiomer was shown to be eliminated at a higher rate than the R‐enantiomer. The most likely explanation for this is a stereoselective metabolism also claimed in in vitro studies. Urinary excretion studies showed that the main metabolites in humans are 4‐hydroxy 3‐methoxymethamphetamine (HMMA) 4‐sulfate, HMMA 4‐glucuronide and 3,4‐dihydroxymethamphetamine (DHMA) 3‐sulfate. For stereoselective pharmacokinetic analysis of phase I and phase II metabolites in human blood plasma useful analytical methods are needed. Therefore the aim of the presented study was the development and validation of a stereoselective liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method for the simultaneous quantification of MDMA, 3,4‐methylenedioxyamphetamine, DHMA, DHMA 3‐sulfate, HMMA, HMMA 4‐glucuronide, HMMA 4‐sulfate, and 4‐hydroxy 3‐methoxyamphetamine in blood plasma for evaluation of the stereoselective pharmacokinetics in humans. Blood plasma samples were prepared by simple protein precipitation and afterwards all analytes were derivatized using N‐(2,4‐dinitro‐5‐fluorophenyl) L‐valinamide resulting in the formation of diastereomers which were easily separable on standard reverse phase stationary phases. This simple and fast method was validated according to international guidelines including specificity, recovery, matrix effects, accuracy and precision, stabilities, and limits of quantification. The method proved to be selective, sensitive, accurate and precise for all tested analytes except for DHMA. Copyright © 2014 John Wiley & Sons, Ltd.     

Metabolism of the tryptamine‐derived new psychoactive substances 5‐MeO‐2‐Me‐DALT, 5‐MeO‐2‐Me‐ALCHT,and 5‐MeO‐2‐Me‐DIPT and their detectability in urine studied by GC–MS,LC–MSn,and LC‐HR‐MS/MS

Many N,N‐dialkylated tryptamines show psychoactive properties and were encountered as new psychoactive substances. The aims of the presented work were to study the phase I and II metabolism and the detectability in standard urine screening approaches (SUSA) of 5‐methoxy‐2‐methyl‐N,N‐diallyltryptamine (5‐MeO‐2‐Me‐DALT), 5‐methoxy‐2‐methyl‐N‐allyl‐N‐cyclohexyltryptamine (5‐MeO‐2‐Me‐ALCHT), and 5‐methoxy‐2‐methyl‐N,N‐diisopropyltryptamine (5‐MeO‐2‐Me‐DIPT) using gas chromatography–mass spectrometry (GC–MS), liquid chromatography coupled with multistage accurate mass spectrometry (LC–MSⁿ), and liquid chromatography‐high‐resolution tandem mass spectrometry (LC‐HR‐MS/MS). For metabolism studies, urine was collected over a 24 h period after administration of the compounds to male Wistar rats at 20 mg/kg body weight (BW). Phase I and II metabolites were identified after urine precipitation with acetonitrile by LC‐HR‐MS/MS. 5‐MeO‐2‐Me‐DALT (24 phase I and 12 phase II metabolites), 5‐MeO‐2‐Me‐ALCHT (24 phase I and 14 phase II metabolites), and 5‐MeO‐2‐Me‐DIPT (20 phase I and 11 phase II metabolites) were mainly metabolized by O‐demethylation, hydroxylation, N‐dealkylation, and combinations of them as well as by glucuronidation and sulfation of phase I metabolites. Incubations with mixtures of pooled human liver microsomes and cytosols (pHLM and pHLC) confirmed that the main metabolic reactions in humans and rats might be identical. Furthermore, initial CYP activity screenings revealed that CYP1A2, CYP2C19, CYP2D6, and CYP3A4 were involved in hydroxylation, CYP2C19 and CYP2D6 in O‐demethylation, and CYP2C19, CYP2D6, and CYP3A4 in N‐dealkylation. For SUSAs, GC–MS, LC‐MSⁿ, and LC‐HR‐MS/MS were applied to rat urine samples after 1 or 0.1 mg/kg BW doses, respectively. In contrast to the GC–MS SUSA, both LC–MS SUSAs were able to detect an intake of 5‐MeO‐2‐Me‐ALCHT and 5‐MeO‐2‐Me‐DIPT via their metabolites following 1 mg/kg BW administrations and 5‐MeO‐2‐Me‐DALT following 0.1 mg/kg BW dosage. Copyright © 2017 John Wiley & Sons, Ltd.     

MDA,MDMA, and other “mescaline‐like” substances in the US military's search for a truth drug (1940s to 1960s)

This article describes the context in which 3,4‐methylenedioxyamphetamine (MDA), 3,4‐methylenedioxymethamphetamine (MDMA) and other mescaline‐like compounds were explored as hallucinogens for military and intelligence purposes from the 1940s to the 1960s. Germans first tested mescaline as a “truth drug” in a military context. In the 1940s, the United States military started testing hallucinogenic substances as truth drugs for interrogation and behavior manipulation. After tests carried out using mescaline and other drugs in 1950, some derivatives of mescaline were synthesized by the Army for the exploration of possible “speech‐inducing” effects. After insufficient animal testing, the substances were given to patients at the New York State Psychiatric Institute (NYSPI). 3,4‐Methylenedioxy‐N‐ethylamphetamine (MDE), a compound almost identical to MDMA, was among the compounds delivered for testing at the NYSPI. During tests with other derivatives (3,4‐dimethoxyphenethylamine (DMA), 3,4‐methylenedioxyphenethylamine (MDPEA), MDA) in 1952–53, an unwitting patient died in these tests, which was kept secret from the public. Research was interrupted and toxicological animal testing procedures were initiated. The secret animal studies run in 1953/1954 revealed that some of the “mescaline derivatives” tested (e.g. MDA, MDE, DMA, 3,4,5‐trimethoxyamphetamine (TMA), MDMA) were considered for further testing in humans. In 1955, the military changed focus to lysergic acid diethylamide (LSD), but some interest in mescaline‐like compounds remained for their ability to change mood and habit without interfering with cognition and sensory perception. Based on the known documents, it remains unclear (but probable) whether any of the mescaline derivatives tested were being used operationally.     

Synthesis of deuterium‐labelled standards of (±)‐DOM and (±)‐MMDA

This study describes the synthesis of deuterium‐labelled (±)‐4‐methyl‐2,5‐dimethoxyamphetamine (DOM) and (±)‐1‐(7‐methoxy‐1,3‐benzodioxol‐5‐yl)propan‐2‐amine (MMDA). The isotopically labelled compounds are potentially used as internal standards in gas chromatography–mass spectrometry (GC–MS) assays. Copyright © 2007 John Wiley & Sons, Ltd.     

Comparative potencies of 3,4-methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5-HT transport in mammalian cell lines

BACKGROUND AND PURPOSE: Illegal 'ecstasy' tablets frequently contain 3,4-methylenedioxymethamphetamine (MDMA)-like compounds of unknown pharmacological activity. Since monoamine transporters are one of the primary targets of MDMA action in the brain, a number of MDMA analogues have been tested for their ability to inhibit [3H]noradrenaline uptake into rat PC12 cells expressing the noradrenaline transporter (NET) and [3H]5-HT uptake into HEK293 cells stably transfected with the 5-HT transporter (SERT). EXPERIMENTAL APPROACH: Concentration-response curves for the following compounds at both NET and SERT were determined under saturating substrate conditions: 4-hydroxy-3-methoxyamphetamine (HMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 2,5-dimethoxy-4-bromophenylethylamine (2CB), 3,4-dimethoxymethamphetamine (DMMA), 3,4-methylenedioxyphenyl-2-butanamine (BDB), 3,4-methylenedioxyphenyl-N-methyl-2-butanamine (MBDB) and 2,3-methylenedioxymethamphetamine (2,3-MDMA). KEY RESULTS: 2,3-MDMA was significantly less potent than MDMA at SERT, but equipotent with MDMA at NET. 2CB and BDB were both significantly less potent than MDMA at NET, but equipotent with MDMA at SERT. MBDB, DMMA, MDOH and the MDMA metabolites HMA and HMMA, were all significantly less potent than MDMA at both NET and SERT. CONCLUSIONS AND IMPLICATIONS: This study provides an important insight into the structural requirements of MDMA analogue affinity at both NET and SERT. It is anticipated that these results will facilitate understanding of the likely pharmacological actions of structural analogues of MDMA.     

Cytotoxic effects of psychotropic benzofuran derivatives,N‐methyl‐5‐(2‐aminopropyl)benzofuran and its N‐demethylated derivative,on isolated rat hepatocytes

The novel psychoactive compounds derived from amphetamine have been illegally abused as recreational drugs, some of which are known to be hepatotoxic in humans and experimental animals. The cytotoxic effects and mechanisms of 5‐(2‐aminopropyl)benzofuran (5‐APB) and N‐methyl‐5‐(2‐aminopropyl)benzofuran (5‐MAPB), both of which are benzofuran analogues of amphetamine, and 3,4‐methylenedioxy‐N‐methamphetamine (MDMA) were studied in freshly isolated rat hepatocytes. 5‐MAPB caused not only concentration‐dependent (0–4.0 mm ) and time‐dependent (0–3 h) cell death accompanied by the depletion of cellular ATP and reduced glutathione and protein thiol levels, but also accumulation of oxidized glutathione. Of the other analogues examined at a concentration of 4 mm , 5‐MAPB/5‐APB‐induced cytotoxicity with the production of reactive oxygen species and loss of mitochondrial membrane potential was greater than that induced by MDMA. In isolated rat liver mitochondria, the benzofurans resulted in a greater increase in the rate of state 4 oxygen consumption than did MDMA, with a decrease in the rate of state 3 oxygen consumption. Furthermore, the benzofurans caused more of a rapid mitochondrial swelling dependent on the mitochondrial permeability transition than MDMA. 5‐MAPB at a weakly toxic level (1 mm ) was metabolized slowly: levels of 5‐MAPB and 5‐APB were approximately 0.9 mm and 50 μm , respectively, after 3 h incubation. Taken collectively, these results indicate that mitochondria are target organelles for the benzofuran analogues and MDMA, which elicit cytotoxicity through mitochondrial failure, and the onset of cytotoxicity may depend on the initial and/or residual concentrations of 5‐MAPB rather than on those of its metabolite 5‐APB. Copyright © 2016 John Wiley & Sons, Ltd.     

Analytical characterization of three hallucinogenic N‐(2‐methoxy)benzyl derivatives of the 2C‐series of phenethylamine drugs

This publication reports analytical properties of three new hallucinogenic substances identified in blotter papers seized from the drug market, namely 25D‐NBOMe [2‐(2,5‐dimethoxy‐4‐methylphenyl)‐N‐(2‐methoxybenzyl)ethanamine], 25E‐NBOMe [2‐(4‐ethyl‐2,5‐dimethoxyphenyl)‐N‐(2‐methoxybenzyl)ethanamine] and 25G‐NBOMe [2‐(2,5‐dimethoxy‐3,4‐dimethylphenyl)‐N‐(2‐methoxybenzyl)ethanamine]. These substances are N‐(2‐methoxy)benzyl derivatives of the 2C‐series of phenethylamine drugs. The applied procedure covered a variety of analytical methods, including gas chromatography with electron impact mass spectrometry (GC‐EI‐MS; without derivatization and after derivatization with trifluoroacetic anhydride (TFAA)), liquid chromatography‐electrospray ionization‐quadrupole time of flight mass spectrometry (LC‐ESI‐QTOF‐MS), Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR), which made it possible to identify the active components unequivocally. The GC‐MS spectra of analyzed compounds were very similar, with dominant ions observed at m/z = 150, 121, and 91. The remaining ions were analogous to those observed for parent substances, namely 2C‐D, 2C‐E, 2C‐G, but their intensities were low. Derivatization allowed determination of molecular masses of the investigated substances. Their exact masses and chemical formulas were confirmed by LC‐QTOF‐MS experiments and the fragmentation patterns of these compounds following ESI were determined. The tandem mass spectrometry (MS/MS) experiments confirmed that the studied substances were N‐(2‐methoxy)benzyl derivatives of the 2C‐series compounds. Final elucidation of the structures was performed by NMR spectroscopy. The substances were also characterized by FTIR spectroscopy to corroborate the identity of the compounds. Copyright © 2012 John Wiley & Sons, Ltd.     

Chemiluminescence detection of MDMA in street drug samples using tris(2,2′‐bipyridine)ruthenium(III)

Tris(2,2′‐bipyridine)ruthenium(II) chemiluminescence was investigated for the detection of 3,4‐methylenedioxymethamphetamine (MDMA) and several related compounds in street drug samples. Optimization using flow injection analysis showed that the selectivity of the reagent can be targeted towards the detection of secondary amines by altering the pH of the reaction environment. The greater selectivity of this mode of detection, compared to UV‐absorbance, reduces the probability of false positive results from interfering compounds. The detection limit for MDMA under these conditions was 0.48 μM. A HPLC method incorporating post‐column tris(2,2′‐bipyridine)ruthenium(II) chemiluminescence detection was applied to the determination of MDMA in five street drug samples. The results obtained were in good agreement with quantification performed using traditional UV‐absorbance detection, which demonstrates the viability of this method for confirmatory analysis of drug samples. This is the first report of tris(2,2′‐bipyridine)ruthenium(II) chemiluminescence for the detection of MDMA and related amphetamine derivatives. Copyright © 2015 John Wiley & Sons, Ltd.     

Design,Synthesis, and Antitumor Activity of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones

A series of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones ( C1 – C35 ) were designed and synthesized, and the structures of compounds (Z)‐ C27 and (Z)‐ C29 were confirmed by single‐crystal X‐ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF‐7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)‐ C24 exhibited the most consistent potent activities against three neoplastic cells with IC₅₀ values ranging from 3.2 to 7.1 μm . Further researches demonstrated that compounds (E,Z)‐ C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure–activity relationship between the configurations and cytotoxicity of the compounds was also investigated.     

Identification and characterization of 2,5‐dimethoxy‐3,4‐dimethyl‐β‐phenethylamine (2C‐G) – A new designer drug

This study presents and discusses the mass spectrometric, infrared spectroscopic and nuclear magnetic resonance spectroscopic data of 2,5‐dimethoxy‐3,4‐dimethyl‐β‐phenethylamine (2C‐G), a new designer drug. A powder sample containing 2C‐G was seized in Poland in 2011. The paper focuses on a comparison of the analytical features of 2C‐G and other members of the 2C‐series, in order to assess the possibility of unequivocal identification. The occurrence of intense peak at m/z = 178 and different intensities of the ions at m/z = 165 and 180 in the gas chromatography‐electron impact‐mass spectrometry (GC‐EI/MS) spectrum of 2C‐G made it possible to distinguish it from 2C‐E. Differences in relative intensities of the ions at m/z = 192, 179 and 177 were observed for GC‐EI/MS spectra of TFAA derivatives of 2C‐G and 2C‐E. An identical set of ions was recorded for these substances using the liquid chromatography‐electrospray ionization/quadrupole time of flight mass spectrometry (LC‐ESI/QTOFMS) method in both MS and tandem mass spectrometry (MS/MS) mode, but the distinction was possible based on differences in the ion intensities at m/z = 193.1223 and 178.0988. The Fourier transform infrared (FTIR) spectrum of 2C‐G was significantly different from other members of the 2C‐series, with a characteristic doublets at 993–1014 cm^‐1 and 1099–1124 cm^‐1, and the ratio of bands at higher wavenumbers. Final elucidation of the structure of 2C‐G was carried out by ¹H and ¹³C NMR spectroscopy. The study indicated that the marketing of analogues of controlled substances poses a real analytical challenge for forensic laboratories, and the application of sophisticated methods is often required for unequivocal identification of a new substance. Copyright © 2012 John Wiley & Sons, Ltd.     

Screening for illicit drugs in pooled human urine and urinated soil samples and studies on the stability of urinary excretion products of cocaine,MDMA, and MDEA in wastewater by hyphenated mass spectrometry techniques

Monitoring population drug use through wastewater‐based epidemiology (WBE) is a useful method to quantitatively follow trends and estimate total drug consumption in communities. Concentrations of drug biomarkers might be low in wastewater due to dilution; and therefore analysis of pooled urine (PU) is useful to detect consumed drugs and identify targets of illicit drugs use. The aims of the study were (1) to screen PU and urinated soil (US) samples collected at festivals for illicit drug excretion products using hyphenated techniques; (2) to develop and validate a hydrophilic interaction liquid chromatography – mass spectrometry / mass spectrometry (HILIC‐MS/MS) method of quantifying urinary targets of identified drugs in wastewater; and (3) to conduct a 24 h stability study, using PU and US to better reflect the chemical environment for targets in wastewater. Cocaine (COC) and ecstasy‐like compounds were the most frequently detected illicit drugs; an analytical method was developed to quantify their excretion products. Hydroxymethoxymethamphetamine (HMMA), 3,4‐methylenedioxymethamphetamine (MDMA), 3,4‐methylenedioxyamphetamine (MDA), HMMA sulfate (HMMA‐S), benzoylecgonine (BE), and cocaethylene (CE) had 85–102% of initial concentration after 8 h of incubation, whereas COC and ecgonine methyl ester (EME) had 74 and 67% after 8 h, respectively. HMMA showed a net increase during 24 h of incubation (107% ± 27, n = 8), possibly due to the cleavage of HMMA conjugates, and biotransformation of MDMA. The results suggest HMMA as analytical target for MDMA consumption in WBE, due to its stability in wastewater and its excretion as the main phase I metabolite of MDMA. Copyright © 2016 John Wiley & Sons, Ltd.     

Identification of five pyrrolidinyl substituted cathinones and the collision‐induced dissociation of electrospray‐generated pyrrolidinyl substituted cathinones

This article reports on the analytical properties of five pyrrolidinyl substituted cathinones: α ‐pyrrolidinononaphenone (α ‐PNP, 1 ), 4‐chloro‐α ‐pyrrolidinopropiophenone (4‐Cl‐α ‐PPP, 2 ), 4‐chloro‐α ‐pyrrolidinovalerophenone (4‐Cl‐α ‐PVP, 3 ), 5‐dihydrobenzofuranpyrovalerone (5‐DBFPV, 4 ), and 2‐(pyrrolidin‐1‐yl)‐1‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)hexan‐1‐one (β ‐THNPH, 5 ). These identifications were based on liquid chromatography–quadrupole time‐of‐flight‐mass spectrometry (LC–QTOF–MS), gas chromatography–mass spectrometry (GC–MS) and nuclear magnetic resonance spectroscopy (NMR). To our knowledge, no analytical data about α ‐PNP, 4‐Cl‐α ‐PPP, 4‐Cl‐α ‐PVP, and β ‐THNPH have appeared until now, making this the first report on these compounds. Moreover, in order to study the collision‐induced dissociation (CID) characteristic fragmentation routes of pyrrolidinyl substituted cathinones, a total number of 13 pyrrolidinyl substituted cathinones were selected and discussed. The major fragmentation pathways under CID mode are produced, leading to the formation of characteristic ions. Product ions of [M‐C₄H₉N]⁺ and C_nH_2nN⁺ indicate the presence of pyrrolidinyl substitution. Characteristic fragments are also produced via the cleavages of the CH–N(CH₂)₄ bond and the CO‐CHN bond. Copyright © 2016 John Wiley & Sons, Ltd.     

Identification and characterization of chemically masked derivatives of pseudoephedrine,ephedrine, methamphetamine,and MDMA

The emergence of chemically masked illicit drugs represents a challenge to global initiatives that are working to prevent their manufacture and distribution. Targeted analytical techniques currently used by law enforcement to identify unknown materials rely on spectroscopic and spectrophotometric databases that do not currently include some of these compounds, making their identification challenging. This study aimed to update compound spectral libraries to aid in the rapid detection and identification of these masked drugs, as well as to provide insight into their synthetic procedures. Five commonly employed protecting groups, acetyl, p‐tosyl, methoxycarbonyl, Fmoc, and t‐Boc, were appended to pseudoephedrine, ephedrine, methamphetamine, and MDMA. Characterization was carried out using NMR, GC‐MS, FTIR, high‐resolution LC‐MS/MS, and common screening color tests. Some of the methoxycarbonyl and t‐Boc derivatives and all of the Fmoc derivatives showed partial or full thermal degradation or rearrangement during GC‐MS analysis, while LC‐MS/MS analysis did not always show characteristic fragmentation that would allow unambiguous assignment of the structure. Restricted rotation in some of the derivatives meant that NMR assignments could only be made using NMR spectra acquired at elevated temperature. Therefore, GC‐MS and LC‐MS/MS analyses serve complementary roles for these derivatives, with NMR providing confirmation of structure for the pure materials if necessary.     

New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT1A/5‐HT7 Receptor Ligands

A series of new long‐chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5‐HT_1A and 5‐HT₇ receptor ligands. The compounds were prepared by a two‐step procedure using naphthalimide and 2H‐1,3‐benzoxazine‐2,4(3H)‐dione as imides, and 1‐(2‐methoxyphenyl)piperazine (o‐OMe‐PhP) and 1,2,3,4‐tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta‐ and hexamethylene chains as well as partly constrained m‐ and p‐xylyl moieties. In general, the new compounds were more active at the 5‐HT_1A than at the 5‐HT₇ receptor, and the o‐OMe‐PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o‐OMe‐PhP series, except for a small binding reduction for ligands containing the m‐xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure–activity relationship was visible only for the interaction of the compounds with the 5‐HT₇ receptor, which strongly favored flexible analogs.