naphyrone and cathinone

Naphyrone, also known as NRG-1, is a novel psychoactive substance (NPS), a cathinone with stimulatory properties available on the grey/illicit drug market for almost a decade. It is structurally related to infamously known powerful stimulants with the pyrovalerone structure, such as alpha-pyrrolidinovalerophenone (α-PVP) or methylenedioxypyrovalerone (MDPV) that are labeled as a cheap replacement for cocaine and other stimulants. Despite the known addictive potential of α-PVP and MDPV, there are no studies directly evaluating naphyrone's addictive potential e.g., in conditioned place preference (CPP) test or using self-administration. Therefore, our study was designed to evaluate the addictive potential in a CPP test in male Wistar rats and compare its effect to another powerful stimulant with a high addictive potential - methamphetamine. Naphyrone increased time spent in the drug-paired compartment with 5 and 20 mg/kg s.c. being significant and 10 mg/kg s.c. reaching the threshold (p = 0.07); the effect was comparable to that of methamphetamine 1.5 mg/kg s.c. The lowest dose, naphyrone 1 mg/kg s.c., had no effect on CPP. Interestingly, no dose response effect was detected. Based on these data, we are able to conclude that naphyrone has an addictive potential and may possess a significant risk to users.

Topics: Alkaloids; Animals; Behavior, Animal; Central Nervous System Stimulants; Conditioning, Classical; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Methamphetamine; Pentanones; Pyrrolidines; Rats; Rats, Wistar; Substance-Related Disorders

Synthetic cathinones are a new class of psychostimulant substances. Rarely, they can cause liver injury but associated mechanisms are not completely elucidated. In order to increase our knowledge about mechanisms of hepatotoxicity, we investigated the effect of five frequently used cathinones on two human cell lines. Bupropion was included as structurally related drug used therapeutically. In HepG2 cells, bupropion, MDPV, mephedrone and naphyrone depleted the cellular ATP content at lower concentrations (0.2-1mM) than cytotoxicity occurred (0.5-2mM), suggesting mitochondrial toxicity. In comparison, methedrone and methylone depleted the cellular ATP pool and induced cytotoxicity at similar concentrations (≥2mM). In HepaRG cells, cytotoxicity and ATP depletion could also be demonstrated, but cytochrome P450 induction did not increase the toxicity of the compounds investigated. The mitochondrial membrane potential was decreased in HepG2 cells by bupropion, MDPV and naphyrone, confirming mitochondrial toxicity. Bupropion, but not the other compounds, uncoupled oxidative phosphorylation. Bupropion, MDPV, mephedrone and naphyrone inhibited complex I and II of the electron transport chain, naphyrone also complex III. All four mitochondrial toxicants were associated with increased mitochondrial ROS and increased lactate production, which was accompanied by a decrease in the cellular total GSH pool for naphyrone and MDPV. In conclusion, bupropion, MDPV, mephedrone and naphyrone are mitochondrial toxicants impairing the function of the electron transport chain and depleting cellular ATP stores. Since liver injury is rare in users of these drugs, affected persons must have susceptibility factors rendering them more sensitive for these drugs.

Topics: Adenosine Triphosphate; Alkaloids; Benzodioxoles; Bupropion; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Electron Transport Chain Complex Proteins; Hep G2 Cells; Hepatocytes; Humans; Lactic Acid; Membrane Potential, Mitochondrial; Methamphetamine; Mitochondria, Liver; Oxidative Phosphorylation; Oxidative Stress; Oxygen Consumption; Pentanones; Psychotropic Drugs; Pyrrolidines; Reactive Oxygen Species; Synthetic Cathinone

Workplace drug testing in Australia is usually adherent to one of two standards, AS/NZS 4308:2008 for urine or AS 4760:2006 for oral fluid. These standards prescribe the drugs tested, devices used and testing methodology followed by the testing agency. However, they are not comprehensive and for many years workers have been able to consume novel psychoactive substances to avoid detection and without consequences. Here, we present a validated method for the detection of 32 Synthetic Stimulant and Hallucogenic drugs, commonly sold as bath salts, in oral fluid. These drugs are cathinone, ephedrone, methylone, flephedrone, MDA, PMA, methedrone, TMA, MDMA, butylone, mephedrone, MDEA, MEC, pentedrone, MBDB, MTA, Alpha-PVP, MPBP, 2C-B, MDPV, DOB, 2C-T-2, TFMPP, DOET, 2C-T-7, naphyrone, MDAI, FMA, DMA, 25C-NBOMe, 25B-NBOMe and 25T4-NBOMe. Sample preparation was undertaken using a simple protein precipitation in acetonitrile. Chromatographic separation was achieved in 7.5 min on a Kinetex F5 column (50 mm × 3 mm × 2.6 μm) using 0.1% formic acid in water and acetonitrile as the mobile phases. The method was validated with limit of detection (1 ng/mL), limit of quantitation (2.5 ng/mL), selectivity, linearity (2.5-500 ng/mL), accuracy (85.3-108.4% of the target concentration) and precision (1.9-14%). This method was applied to 12 samples previously submitted for routine testing and two were found to contain 2-CB and DOB (5 and 4 ng/mL) and, MPBP and TFMPP (both at 4 ng/mL). This method provides for the rapid detection of a large number of compounds in oral fluid which is readily applicable to routine testing laboratories.

Topics: Alkaloids; Anisoles; Australia; Benzylamines; Dimethoxyphenylethylamine; Humans; Illicit Drugs; Methamphetamine; Pentanones; Phenethylamines; Propiophenones; Psychotropic Drugs; Pyrrolidines; Saliva; Substance Abuse Detection

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.

Topics: Alkaloids; Chromatography, Liquid; Gas Chromatography-Mass Spectrometry; Illicit Drugs; Magnetic Resonance Spectroscopy; Mass Spectrometry; Methamphetamine; Methylamines; Pentanones; Powders; Propane; Pyrrolidines

A large number of cathinone derivatives have shown a wide range of bioactive properties, attracting great interest from communities associated with pharmaceutical research. Some of these derivatives have gained popularity as so-called recreational 'legal highs' due to their availability on the Internet and high street shops. A previous study described the qualitative analysis of 24 'legal high' Energy-1 (NRG-1) and NRG-2 products obtained from 18 websites following the ban on mephedrone and derivatives in April 2010. The majority of these products contained a mixture of cathinones just carrying a new label. Here, three additional cathinone products have been detected; two from an NRG-1 sample and one from an NRG-3 sample. This report describes their identification. NRG-1 sample 1 consisted of a mixture of 4 cathinones namely 4-fluoromethcathinone (1), 1-(3,4-methylenedioxyphenyl)-2-(methylamino)pentan-1-one (pentylone, 2), 3,4-methylenedioxy-α-pyrrolidinobutyrophenone (MDPBP, 3) and 3,4-methylenedioxypyrovalerone (MDPV, 4). The sample labelled as NRG-3 (mislabelled with the chemical structure of mephedrone) consisted of a mixture of 4-methyl-α-pyrrolidinopropiophenone (MPPP, 5) and (2), whereas the remaining NRG-1 sample 2 (also mislabelled with the chemical structure of mephedrone) consisted of a mixture of (2) and (3). Qualitative analyses were carried out by GC-(EI/CI)-MS, NMR spectroscopy and confirmation by preparation of standards. The preparation of brominated precursors carrying the 3,4-methylenedioxyphenyl nucleus revealed extensive α,α-dibromination: the mass spectral and NMR data of these intermediates are also presented and discussed.

Topics: Alkaloids; Gas Chromatography-Mass Spectrometry; Illicit Drugs; Internet; Magnetic Resonance Spectroscopy; Pentanones; Pyrrolidines; United Kingdom