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The acute psychoactive, autonomic, and endocrine effects of the new psychoactive substance (NPS) 5,6‐methylenedioxy‐2‐aminoindane (MDAI; 3.0 mg/kg, range 180–228 mg) were investigated in six healthy volunteers (four males, two females) in a non‐blinded fashion without placebo. Subjective, cardiovascular, and endocrine responses were compared with two different doses of 3,4‐methylenedioxymethamphetamine (MDMA) (75 mg and 125 mg) described in previously published placebo‐controlled studies, which used identical outcome measures including Visual Analogue Scales (VAS), the Adjective Mood Rating Scale (AMRS), and the 5 Dimensions of Altered States of Consciousness (5D‐ASC) scale. MDAI was well tolerated and produced subjective effects comparable with those of 125 mg MDMA. MDAI increased blood pressure similar to 125 mg MDMA but did not increase heart rate or body temperature. MDAI increased cortisol and prolactin levels and could be detected in serum about 20 min post ingestion and remained detectable at least for 4 days. In urine, MDAI was detectable over a period of at least 6 days. Further clinical investigations are warranted to assess whether MDAI could serve as drug with medicinal properties. [ABSTRACT FROM AUTHOR]

3,4‐Methylenedioxymethamphetamine (MDMA, 'ecstasy') is re‐emerging in clinical settings as a candidate for the treatment of specific neuropsychiatric disorders (e.g. post‐traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter‐mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose‐, individual‐, and context‐dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off‐target profile. In vitro methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence‐based assays, pooled human liver microsome/S9 fraction incubations, metabolic stability studies, isozyme mapping, and liquid chromatography coupled to high‐resolution mass spectrometry. In silico methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) but decreased agonist activity at 5‐HT2A/2B/2C receptors. Regarding their hepatic metabolism, they differed from MDMA, with N‐demethylation being the only metabolic route shared, and without forming phase II metabolites. In addition, TDMA showed an enhanced intrinsic clearance in comparison to its congeners. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane monoamine transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5‐HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re‐emerging MDMA warrants further studies. [ABSTRACT FROM AUTHOR]

Ketamine derivatives such as deschloroketamine and deschloro-N-ethyl-ketamine show dissociative and psychoactive properties and their abuse as new psychoactive substances (NPSs) has been reported. Though some information is available on the biotransformation of dissociative NPSs, data on deschloro-N-cyclopropyl-ketamine deschloro-N-isopropyl-ketamine and deschloro-N-propyl-ketamine concerning their biotransformation and, thus, urinary detectability are not available. The aims of the presented work were to study the in vivo phase I and II metabolism; in vitro phase I metabolism, using pooled human liver microsomes (pHLMs); and detectability, within a standard urine screening approach (SUSA), of five deschloroketamine derivatives. Metabolism studies were conducted by collecting urine samples from male Wistar rats over a period of 24 h after their administration at 2 mg/kg body weight. The samples were analyzed using liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) and gas chromatography–mass spectrometry (GC-MS). The compounds were mainly metabolized by N-dealkylation, hydroxylation, multiple oxidations, and combinations of these metabolic reactions, as well as glucuronidation and N-acetylation. In total, 29 phase I and 10 phase II metabolites were detected. For the LC-HRMS/MS SUSA, compound-specific metabolites were identified, and suitable screening targets could be recommended and confirmed in pHLMs for all derivatives except for deschloro-N-cyclopropyl-ketamine. Using the GC-MS-based SUSA approach, only non-specific acetylated N-dealkylation metabolites could be detected. [ABSTRACT FROM AUTHOR]

Preclinical investigations have shown that N‐ethyl‐N‐isopropyllysergamide (EIPLA) exhibits lysergic acid diethylamide (LSD)‐like properties, which suggests that it might show psychoactive effects in humans. EIPLA is also an isomer of N6‐ethylnorlysergic acid N,N‐diethylamide (ETH‐LAD), a lysergamide known to produce psychedelic effects in humans that emerged as a research chemical. EIPLA was subjected to analysis by various forms of mass spectrometry, chromatography (GC, LC), nuclear magnetic resonance (NMR) spectroscopy, and GC condensed‐phase infrared spectroscopy. The most straightforward differentiation between EIPLA and ETH‐LAD included the evaluation of mass spectral features that reflected the structural differences (EIPLA: N6‐methyl and N‐ethyl‐N‐isopropylamide group; ETH‐LAD: N6‐ethyl and N,N‐diethylamide group). Proton NMR analysis of blotter extracts suggested that EIPLA was detected as the base instead of a salt, and two blotter extracts suspected to contain EIPLA revealed the detection of 96.9 ± 0.5 μg (RSD: 0.6%) and 85.8 ± 2.8 μg base equivalents based on LC–MS analysis. The in vivo activity of EIPLA was evaluated using the mouse head‐twitch response (HTR) assay. Similar to LSD and other serotonergic psychedelics, EIPLA induced the HTR (ED50 = 234.6 nmol/kg), which was about half the potency of LSD (ED50 = 132.8 nmol/kg). These findings are consistent with the results of previous studies demonstrating that EIPLA can mimic the effects of known psychedelic drugs in rodent behavioral models. The dissemination of analytical data for EIPLA was deemed justifiable to aid future forensic and clinical investigations. [ABSTRACT FROM AUTHOR]

The development of novel lysergamides continues to occur, based on both the needs of psychedelic medicine and commercial interest in new recreational substances. The present study continues the authors' research on novel lysergamides and describes the analytical profile of 1‐cyclopropanoyl‐AL‐LAD (IUPAC name: 1‐(cyclopropanecarbonyl)‐N,N‐diethyl‐6‐(prop‐2‐en‐1‐yl)‐9,10‐didehydroergoline‐8β‐carboxamide; 1cP‐AL‐LAD), using various chromatographic, mass spectrometric, and spectroscopic methods. Analysis of a powdered sample of 1cP‐AL‐LAD, obtained from an online vendor, by high performance liquid chromatography‐electrospray ionization‐quadrupole time‐of‐flight mass spectrometry in full scan/AutoMS/MS mode revealed the detection of 17 impurities based on high‐resolution tandem mass spectral data; tentative determination of their identity was based on mass spectral grounds alone, though detection of AL‐LAD and 1P‐AL‐LAD was confirmed using available reference standards. Other tentative compound identifications included 1‐acetyl‐AL‐LAD and several other substances potentially reflecting oxidation of the N6‐allyl group as well as other positions on the ergoline ring system. These data may assist those interested in the chemistry of lysergamides. Finally, 1cP‐AL‐LAD was also detected in samples of "blotters" sold online for recreational use. [ABSTRACT FROM AUTHOR]

The synthetic cannabinoid receptor agonists (SCRAs) (quinolin‐8‐yl 4‐methyl‐3‐(morpholine‐4‐sulfonyl)benzoate [QMMSB]) and (quinolin‐8‐yl 4‐methyl‐3‐((propan‐2‐yl)sulfamoyl)benzoate [QMiPSB], also known as SGT‐46) are based on the structure of quinolin‐8‐yl 4‐methyl‐3‐(piperidine‐1‐sulfonyl)benzoate (QMPSB) that has been identified on seized plant material in 2011. In clinical toxicology, knowledge of the metabolic fate is important for their identification in biosamples. Therefore, the aim of this study was the identification of in vitro Phase I and II metabolites of QMMSB and QMiPSB in pooled human liver S9 fraction (pHLS9) incubations for use as screening targets. In addition, the involvement of human monooxygenases and human carboxylesterases (hCES) was examined. Analyses were performed by liquid chromatography coupled with high‐resolution tandem mass spectrometry. Ester hydrolysis was found to be an important step in the Phase I metabolism of both SCRAs, with the carboxylic acid product being found only in negative ionization mode. Monohydroxy and N‐dealkyl metabolites of the ester hydrolysis products were detected as well as glucuronides. CYP2C8, CYP2C9, CYP3A4, and CYP3A5 were involved in hydroxylation. Whereas enzymatic ester hydrolysis of QMiPSB was mainly catalyzed by hCES1 isoforms, nonenzymatic ester hydrolysis was also observed. The results suggest that ester hydrolysis products of QMMSB and QMiPSB and their glucuronides are suitable targets for toxicological screenings. The additional use of the negative ionization mode is recommended to increase detectability of analytes. Different cytochrome P450 (CYP) isozymes were involved in the metabolism; thus, the probability of drug–drug interactions due to CYP inhibition can be assessed as low. [ABSTRACT FROM AUTHOR]

Rationale: 4-Thio-substituted phenylalkylamines such as 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) produce psychedelic effects in humans and have been distributed as recreational drugs. Objectives: The present studies were conducted to examine the structure–activity relationships (SAR) of a series of 4-thio-substituted phenylalkylamines using the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by psychedelic drugs in mice. The HTR is commonly used as a behavioral proxy in rodents for human psychedelic effects and can be used to discriminate hallucinogenic and non-hallucinogenic 5-HT2A agonists. Methods: HTR dose–response studies with twelve different 4-thio-substituted phenylalkylamines were conducted in male C57BL/6 J mice. To detect the HTR, head movement was recorded electronically using a magnetometer coil and then head twitches were identified in the recordings using a validated method based on artificial intelligence. Results: 2C-T, the parent compound of this series, had relatively low potency in the HTR paradigm, but adding an α-methyl group increased potency fivefold. Potency was also increased when the 4-methylthio group was extended by one to three methylene units. Fluorination of the 4-position alkylthio chain, however, was detrimental for activity, as was the presence of a 4-allylthio substituent versus a propylthio group. 2C-T analogs containing a 4-benzylthio group showed little or no effect in the HTR paradigm, which is consistent with evidence that bulky 4-substituents can dampen agonist efficacy at the 5-HT2A receptor. Binding and functional studies confirmed that the compounds have nanomolar affinity for 5-HT2 receptor subtypes and act as partial agonists at 5-HT2A. Conclusions: In general, there were close parallels between the HTR data and the known SAR governing activity of phenylalkylamines at the 5-HT2A receptor. These findings further support the classification of 2C-T compounds as psychedelic drugs. [ABSTRACT FROM AUTHOR]

Quinolin-8-yl 3-(4,4-difluoropiperidine-1-sulfonyl)-4-methylbenzoate (2F-QMPSB) and 3-(4,4-difluoropiperidine-1-sulfonyl)-4-methyl- N -(2-phenylpropan-2-yl)benzamide (SGT-233) belong to a new group of synthetic cannabinoid receptor agonists containing a sulfamoyl benzoate or sulfamoyl benzamide core structure. 2F-QMPSB was identified in herbal material seized in Europe in 2018. The aims of this study were the identification of in vitro Phase I and II metabolites of 2F-QMPSB and SGT-233 to find analytical targets for toxicological screenings. Furthermore, the contribution of different monooxygenases and human carboxylesterases to Phase I metabolism was investigated. Liquid chromatography coupled to high-resolution tandem mass spectrometry was used for analysis. Ester hydrolysis was found to be an important step in the metabolism of 2F-QMPSB, which was catalyzed mainly by human carboxylesterases (hCES)1 isoforms. Additionally, nonenzymatic ester hydrolysis was observed in case of 2F-QMPSB. Notably, the carboxylic acid product derived from ester hydrolysis and metabolites thereof were only detectable in negative ionization mode. In case of SGT-233, mono- and dihydroxy metabolites were identified, as well as glucuronides. The cytochrome P450 (CYP) isozymes CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 were found to be involved in the hydroxylation of both compounds. The results of these in vitro experiments suggest that the ester hydrolysis products of 2F-QMPSB and their glucuronides are suitable targets for toxicological screenings. In the case of SGT-233, the mono- and dihydroxy metabolites were identified as suitable screening targets. The involvement of various CYP isoforms in the metabolism of both substances reduces the likelihood of drug–drug interactions due to CYP inhibition. [ABSTRACT FROM AUTHOR]

Lysergic acid diethylamide (LSD) is known to induce powerful psychoactive effects in humans, which cemented its status as an important tool for clinical research. A range of analogues and derivatives has been investigated over the years, including those classified as new psychoactive substances. This study presents the characterization of the novel lysergamide N,N‐diethyl‐1‐propanoyl‐6‐(prop‐2‐en‐1‐yl)‐9,10‐didehydroergoline‐8β‐carboxamide (1P‐AL‐LAD) using various mass spectrometric, gas‐ and liquid chromatographic and spectroscopic methods. In vitro metabolism studies using pooled human liver microsomes (pHLM) confirmed that 1P‐AL‐LAD converted to AL‐LAD as the most abundant metabolite consistent with the hypothesis that 1P‐AL‐LAD may act as a prodrug. Fourteen metabolites were detected in total; metabolic reactions included hydroxylation of the core lysergamide ring structure or the N6‐allyl group, formation of dihydrodiol metabolites, N‐dealkylation, N1‐deacylation, dehydrogenation, and combinations thereof. The in vivo behavioral activity of 1P‐AL‐LAD was evaluated using the mouse head twitch response (HTR), a 5‐HT2A‐mediated head movement that serves as a behavioral proxy in rodents for human hallucinogenic effects. 1P‐AL‐LAD induced a dose‐dependent increase in HTR counts with an inverted U‐shaped dose–response function, similar to lysergic acid diethylamide (LSD), psilocybin, and other psychedelics. Following intraperitoneal injection, the median effective dose (ED50) for 1P‐AL‐LAD was 491 nmol/kg, making it almost three times less potent than AL‐LAD (174.9 nmol/kg). Previous studies have shown that N1‐substitution disrupts the ability of lysergamides to activate the 5‐HT2A receptor; based on the in vitro metabolism data, 1P‐AL‐LAD may induce the HTR because it acts as a prodrug and is metabolized to AL‐LAD after administration to mice. [ABSTRACT FROM AUTHOR]

The psychopharmacological properties of the psychedelic drug lysergic acid diethylamide (LSD) have attracted the interest of several generations of scientists. While further explorations involving novel LSD‐type compounds are needed to assess their potential as medicinal drugs, the emergence of novel derivatives as recreational drugs has also been observed. 1‐Valeroyl‐LSD (also known as 1‐valeryl‐LSD, 1‐pentanoyl‐LSD, 1V‐LSD, or "Valerie") is a new N1‐acylated LSD derivative that recently appeared on the online market, and it could be viewed as a higher homolog of ALD‐52, 1P‐LSD, and 1B‐LSD. The present study included the analytical characterization and involved various methods of mass spectrometry (MS), gas and liquid chromatography (GC and LC), nuclear magnetic resonance (NMR) spectroscopy, GC–solid‐state infrared (GC‐sIR) analysis, and Raman spectroscopy. The in vivo activity of 1V‐LSD was assessed using the mouse head‐twitch response (HTR), a 5‐HT2A‐mediated head movement that serves as a behavioral proxy in rodents for human hallucinogenic effects. Similar to LSD and other psychedelic drugs, the HTR induced by 1V‐LSD was dose dependent, and the median effective dose for 1V‐LSD was 373 nmol/kg, which was about a third of the potency of LSD (ED50 = 132.8 nmol/kg). Lysergamides containing the N1‐substituent typically act as weak partial agonists at the 5‐HT2A receptor and are believed to serve as prodrugs for LSD. 1V‐LSD is also likely to be hydrolyzed to LSD and serve as a prodrug, but studies to assess the biotransformation and receptor pharmacology of 1V‐LSD should be performed to fully elucidate its mechanism of action. [ABSTRACT FROM AUTHOR]

Lysergic acid diethylamide (LSD) is a potent psychoactive substance that has attracted great interest in clinical research. As the pharmacological exploration of LSD analogs continues to grow, some of those analogs have appeared on the street market. Given that LSD analogs are uncontrolled in many jurisdictions, it is important that these analogs be differentiated from LSD. This report presents the analysis of blotters found to contain the N‐methyl‐N‐isopropyl isomer of LSD (MIPLA), and techniques to differentiate it from LSD and the N‐methyl‐N‐propyl isomer (LAMPA) under routine conditions. Gas chromatography (GC)‐solid phase infrared spectroscopy was particularly helpful. GC‐electron ionization‐tandem mass spectrometry of the m/z 72 iminium ion also provided sufficient information to distinguish the three isomers on mass spectral grounds alone, where chromatographic separation proved challenging. Derivatization with 2,2,2‐trifluoro‐N,N‐bis (trimethylsilyl)acetamide (BSTFA) also led to improved GC separation. Liquid chromatography single quadrupole mass spectrometry (LC‐Q‐MS) and in‐source collision‐induced dissociation allowed for the differentiation between MIPLA and LAMPA based on distinct m/z 239 ion ratios when co‐eluting. An alternative LC‐MS/MS method improved the separation between all three lysergamides, but LSD was found to co‐elute with iso‐LSD. However, a comparison of ion ratios recorded for transitions at m/z 324.2 > 223.2 and m/z 324.2 > 208.2 facilitated their differentiation. The analysis of two blotters by LC‐Q‐MS revealed the presence of 180 and 186 μg MIPLA per blotter. These procedures may be used to avoid inadvertent misidentification of MIPLA or LAMPA as LSD. [ABSTRACT FROM AUTHOR]

A diverse assortment of molecules designed to explore the cannabinoid receptor system and considered new psychoactive substances (NPS) have become known as synthetic cannabinoid receptor agonists (SCRAs). One group of SCRAs that has received little attention involves those exhibiting sulfamoyl benzoate, sulfamoyl benzamide, and N‐benzoylpiperidine based structures. In this study, quinolin‐8‐yl 4‐methyl‐3‐(piperidine‐1‐sulfonyl)benzoate (QMPSB), quinolin‐8‐yl 4‐methyl‐3‐(morpholine‐4‐sulfonyl)benzoate (QMMSB), quinolin‐8‐yl 4‐methyl‐3‐(piperidine‐1‐carbonyl)benzoate (QMPCB, SGT‐11), quinolin‐8‐yl 3‐(4,4‐difluoropiperidine‐1‐sulfonyl)‐4‐methylbenzoate (2F‐QMPSB, QMDFPSB, SGT‐13), quinolin‐8‐yl 4‐methyl‐3‐[(propan‐2‐yl)sulfamoyl]benzoate (QMiPSB, SGT‐46), and 3‐(4,4‐difluoropiperidine‐1‐sulfonyl)‐4‐methyl‐N‐(2‐phenylpropan‐2‐yl)benzamide (SGT‐233) were extensively characterized (including data on impurities). The analytical profiles may be useful to researchers and scientists who deal with the emergence of NPS during forensic and clinical investigations. The detection of QMPSB was first published in 2016 but it is worth noting that Stargate International, a company originally formed to develop harm reduction solutions, were involved in the investigation and development of these six compounds for potential release between 2011 and early 2014. Whilst information on the prevalence of use of these particular compounds at the present time is limited, one of the key outcomes of the research performed by Stargate International reviewed here was to set the stage for the quinolin‐8‐yl ester head group that ultimately led to hybridization with an N‐alkyl‐1H‐indole core to give SGT‐21 and SGT‐32, which became later known as PB‐22 (QMPSB/JWH‐018 hybrid) and BB‐22, respectively, thus, opening the door to a range of SCRAs carrying the quinolin‐8‐yl head group from about 2012 onwards. [ABSTRACT FROM AUTHOR]

Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called "benzofury" compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models. Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats. Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection. Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain. [ABSTRACT FROM AUTHOR]

Recent investigations have shown that N‐ethyl‐N‐cyclopropyl lysergamide (ECPLA) produces LSD‐like behavioral effects in mice, which suggests that it may act as a hallucinogen in humans. Although the use of ECPLA as a recreational drug has been limited, key analytical data that can be used to detect ECPLA are required for future forensic and clinical investigations. ECPLA is an isomer of (2′S,4′S)‐lysergic acid 2,4‐dimethylazetidide (LSZ), a lysergamide that emerged as a recreational drug in 2013. Several analytical approaches were examined, including single‐ and tandem mass spectrometry platforms at low and high resolution, gas‐ and liquid chromatography (GC, LC), nuclear magnetic resonance spectroscopy (NMR), and GC condensed‐phase infrared spectroscopy (GC‐sIR). ECPLA and LSZ could be differentiated by NMR, GC‐sIR, GC, and LC‐based methods. The electron ionization mass spectra of ECPLA and LSZ contained ion clusters typically observed with related lysergamides such as m/z 150–155, m/z 177–182, m/z 191–197, m/z 205–208, and m/z 219–224. One of the significant differences in abundance related to these clusters included ions at m/z 196 and m/z 207/208. The base peaks were detected at m/z 221 in both cases followed by the retro‐Diels‐Alder fragment at m/z 292. Minor but noticeable differences between the two isomers could also be seen in the relative abundance of m/z 98 and m/z 41. Electrospray ionization mass spectra included lysergamide‐related ions at m/z 281, 251, 223, 208, 197, 180, and 140. LSZ (but not ECPLA) showed product ions at m/z 267 and m/z 98 under the conditions used. [ABSTRACT FROM AUTHOR]

1‐Propanoyl‐lysergic acid diethylamide (1P‐LSD) appeared as a non‐controlled alternative to LSD a few years ago. Although evidence is beginning to emerge from in vitro and animal studies that 1P‐LSD might serve as a prodrug for LSD, an equivalent evaluation in humans is unavailable. Controlled oral and intravenous self‐administrations of 100 μg 1P‐LSD hemitartrate are reported in two human volunteers followed by analyses of urine and serum samples using a fully validated LC–MS/MS method. Psychometric evaluations included assessment of selected subjective drug effects and administration of the Five‐Dimensions of Altered States of Consciousness rating scale (5D‐ASC). In serum and urine, oral administrations of 1P‐LSD only led to the detection of LSD reflecting biphasic elimination with a terminal elimination half‐life of approx. t1/2 = 6.4 h. 1P‐LSD could be detected for only up to 4.16 h in serum and 2.7 h in urine following intravenous administration, whereas LSD was detected in all serum samples (last sampling after approx. 24 h) and up to 80 h in urine. LSD showed first order elimination kinetics with an approx. t1/2 = 5.7 h, whereas 1P‐LSD showed a rapid decrease in concentration within the first hour followed by a slower decrease, most probably due to hydrolysis. The bioavailability of LSD after oral ingestion of 1P‐LSD was close to 100%. The psychosensory effects of 1P‐LSD and their time course were comparable to those seen after uptake of LSD in other studies which further supports the prodrug hypothesis. The 5D‐ASC scores were higher after oral compared with intravenous administration of 1P‐LSD. [ABSTRACT FROM AUTHOR]

Two groups of amphetamine‐like drugs with psychostimulant properties that were first developed during the course of scientific studies and later emerged as new psychoactive substances (NPS) are based on the (2‐aminopropyl)indole (API) and (2‐aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur‐based analogs with a benzo[b]thiophene structure (resulting in (2‐aminopropyl)benzo[b]thiophene (APBT) derivatives) have received little attention. In the present investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure–activity relationships relative to API‐ and APB‐based drugs. One lesson learned from the NPS phenomenon is that one cannot exclude the appearance of such substances on the market. Therefore, an in‐depth analytical characterization was performed, including various single‐ and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC‐sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non‐routine conditions. Discriminating analytical features can also be derived from NMR, GC‐EI/CI‐ single‐ and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC‐sIR). Availability of detailed analytical data obtained from these novel APBT‐type stimulants may be useful to researchers and scientists in cases where forensic and clinical investigations are warranted. [ABSTRACT FROM AUTHOR]

Lysergic acid diethylamide (LSD) is a prototypical serotonergic psychedelic drug and the subject of many clinical investigations. In recent years, a range of lysergamides has emerged with the production of some being inspired by the existing scientific literature. Others, for example various 1‐acyl substituted lysergamides, did not exist before their appearance as research chemicals. 1‐Cylopropanoyl‐LSD (1CP‐LSD) has recently emerged as a new addition to the group of lysergamide‐based designer drugs and is believed to be psychoactive in humans. In this investigation, 1CP‐LSD was subjected to detailed analytical characterizations including various mass spectrometry (MS) platforms, gas and liquid chromatography, nuclear magnetic resonance spectroscopy, solid phase and GC condensed phase infrared spectroscopy. Analysis by GC–MS also revealed the detection of artificially induced degradation products. Incubation of 1CP‐LSD with human serum led to the formation of LSD, indicating that it may act as a prodrug for LSD in vivo, similar to other 1‐acyl substituted lysergamides. The analysis of blotters and pellets is also included. 1CP‐LSD also induces the head‐twitch response (HTR) in C57BL/6 J mice, indicating that it produces an LSD‐like behavioural profile. 1CP‐LSD induced the HTR with an ED50 = 430.0 nmol/kg which was comparable to 1P‐LSD (ED50 = 349.6 nmol/kg) investigated previously. Clinical studies are required to determine the potency and profile of the effects produced by 1CP‐LSD in humans. [ABSTRACT FROM AUTHOR]

The concept of a substance acting as a prodrug for an intended drug is not new and has been known and utilized with particular benefits within medicine for efficacy and patient safety. Prodrugs of psychoactive substances are also not particularly new but this has also extended to considerations of prodrugs of new psychoactive substances (NPS). The continuing evolution of NPS has been a constant forensic challenge. In some countries, this constant evolution has led to the introduction of various alternative methods of drug control. Whether for this reason or in the pursuit of user experimentation, prodrugs of NPS have been discussed, developed, and exploited, posing some distinct forensic challenges. This is especially the case within toxicological analysis of biological fluids and for some substances, also forensic chemical analysis, through inherent instability of the prodrug or metabolism in the body. Particular examples of NPS prodrugs include 1‐propanoyl‐LSD, 1‐butanoyl‐LSD, 1‐acetyl‐LSD, and 2C‐B‐AN. This is in addition to associated substances and medicines that may be used for an intended pharmacological effect. Various prodrugs for stimulant and hallucinogenic substances in particular have appeared in the literature and have been discussed within drug user forums and made available for purchase online. Presently, drug monitoring data from national and international systems indicate that prodrugs are not widely available or problematic. Nevertheless, it is important that there is sufficient awareness of the prodrug concept and potential impact and associated forensic implications, not just for chemical analysis but also for toxicological considerations when a substance has been used. [ABSTRACT FROM AUTHOR]

Purpose: Toxicokinetic studies are essential in clinical and forensic toxicology to understand drug–drug interactions, influence of individual polymorphisms, and elimination routes, as well as to evaluate targets for toxicological screening procedures. N-(2-Methoxybenzyl)-substituted phenethylamines (NBOMe analogues) intake has been associated with severe adverse reactions including deaths. 1-(1-Benzofuran-5-yl)-N-[(2-methoxyphenyl)methyl]propan-2-amine (5-APB-NBOMe), 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)-N-[(5-chloro-2-ethoxyphenyl)methyl]ethan-1-amine (2C-B-FLY-NB2EtO5Cl), and 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)-N-[(2-methoxyphenyl)methyl]ethan-1-amine (2C-B-FLY-NBOMe) are three emerging NBOMe analogues, which have encountered on the drugs of abuse market. So far, their toxicokinetic data are completely unexplored. Methods: The study included mass spectrometry-based identification of phase I and II metabolites following exposure to the terminally differentiated human hepatocellular carcinoma cells (HepaRG). The determination of enzymes involved in the major phase I/II metabolic steps and determination of plasma protein binding (PPB) were done. Finally, the evaluation of the toxicological detectability by different hyphenated mass spectrometry techniques in standard urine screening approaches (SUSAs) was investigated. Results: The compounds were extensively metabolized in HepaRG cells mainly via O-dealkylation, hydroxylation, glucuronidation, and combinations thereof. CYP1A2, 2D6, 2C8, 2C19, and 3A4, were involved in the initial reactions of all investigated compounds. Glucuronidation of the phase I metabolites—when observed—was mainly catalyzed by UGT1A9. The PPB of all compounds was determined to be > 85%. Only the high-resolution mass spectrometry-based SUSA allowed detection of all compounds in rat urine, but only via metabolites. Conclusions: The toxicokinetic data provided by this study will help forensic and clinical toxicologists to reliably identify these substances in case of abuse and/or intoxication and will allow them a thorough risk assessment. [ABSTRACT FROM AUTHOR]

Psychoactive substances of the 2C‐series are phenethylamine‐based designer drugs that can induce psychostimulant and hallucinogenic effects. The so‐called 2C‐FLY series contains rigidified methoxy groups integrated in a 2,3,6,7‐tetrahydrobenzo[1,2‐b:4,5‐b']difuran core. The aim of the presented work was to investigate the in vivo and in vitro metabolic fate including isoenzyme activities and toxicological detectability of the three new psychoactive substances (NPS) 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY to allow clinical and forensic toxicologists the identification of these novel compounds. Rat urine, after oral administration, and pooled human liver S9 fraction (pS9) incubations were analyzed by liquid chromatography−high‐resolution tandem mass spectrometry (LC−HRMS/MS). By performing activity screenings, the human isoenzymes involved were identified and toxicological detectability in rat urine investigated using standard urine screening approaches (SUSAs) based on gas chromatography (GC)−MS, LC−MSn, and LC−HRMS/MS. In total, 32 metabolites were tentatively identified. Main metabolic steps consisted of hydroxylation and N‐acetylation. Phase I metabolic reactions were catalyzed by CYP2D6, 3A4, and FMO3 and N‐acetylation by NAT1 and NAT2. Methoxyamine was used as a trapping agent for detection of the deaminated metabolite formed by MAO‐A and B. Interindividual differences in the metabolism of the 2C‐FLY drugs could be caused by polymorphisms of enzymes involved or drug–drug interactions. All three SUSAs were shown to be suitable to detect an intake of these NPS but common metabolites of 2C‐E‐FLY and 2C‐EF‐FLY have to be considered during interpretation of analytical findings. [ABSTRACT FROM AUTHOR]

The psychedelic properties of lysergic acid diethylamide (LSD) have captured the imagination of researchers for many years and its rediscovery as an important research tool is evidenced by its clinical use within neuroscientific and therapeutic settings. At the same time, a number of novel LSD analogs have recently emerged as recreational drugs, which makes it necessary to study their analytical and pharmacological properties. One recent addition to this series of LSD analogs is 1‐butanoyl‐LSD (1B‐LSD), a constitutional isomer of 1‐propanoyl‐6‐ethyl‐6‐nor‐lysergic acid diethylamide (1P‐ETH‐LAD), another LSD analog that was described previously. This study presents a comprehensive analytical characterization of 1B‐LSD employing nuclear magnetic resonance spectroscopy (NMR), low‐ and high‐resolution mass spectrometry platforms, gas‐ and liquid chromatography (GC and LC), and GC‐condensed phase and attenuated total reflection infrared spectroscopy analyses. Analytical differentiation of 1B‐LSD from 1P‐ETH‐LAD was straightforward. LSD and other serotonergic hallucinogens induce the head‐twitch response (HTR) in rats and mice, which is believed to be mediated largely by 5‐HT2A receptor activation. HTR studies were conducted in C57BL/6J mice to assess whether 1B‐LSD has LSD‐like behavioral effects. 1B‐LSD produced a dose‐dependent increase in HTR counts, acting with ~14% (ED50 = 976.7 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). This finding suggests that the behavioral effects of 1B‐LSD are reminiscent of LSD and other serotonergic hallucinogens. The possibility exists that 1B‐LSD serves as a pro‐drug for LSD. Further investigations are warranted to confirm whether 1B‐LSD produces LSD‐like psychoactive effects in humans. [ABSTRACT FROM AUTHOR]

A number of substances based on the 1,2‐diarylethylamine template have been investigated for various potential clinical applications whereas others have been encountered as research chemicals sold for non‐medical use. Some of these substances have transpired to function as NMDA receptor antagonists that elicit dissociative effects in people who use these substances recreationally. 1‐[1‐(2‐Fluorophenyl)‐2‐phenylethyl]pyrrolidine (fluorolintane, 2‐F‐DPPy) has recently appeared as a research chemical, which users report has dissociative effects. One common difficulty encountered by stakeholders confronting the appearance of new psychoactive substances is the presence of positional isomers. In the case of fluorolintane, the presence of the fluorine substituent on either the phenyl and benzyl moieties of the 1,2‐diarylethylamine structure results in a total number of six possible racemic isomers, namely 2‐F‐, 3‐F‐, and 4‐F‐DPPy (phenyl ring substituents) and 2"‐F‐, 3"‐F‐, and 4"‐F‐DPPy (benzyl ring substituents). The present study reports the chemical syntheses and comprehensive analytical characterizations of the two sets of three positional isomers. These studies included various low‐ and high‐resolution mass spectrometry platforms, gas‐ and liquid chromatography (GC and LC), nuclear magnetic resonance (NMR) spectroscopy and GC‐condensed phase and attenuated total reflection infrared spectroscopy analyses. The differentiation between each set of three isomers was possible under a variety of experimental conditions including GC chemical ionization triple quadrupole tandem mass spectrometric analysis of the [M + H – HF]+ species. The latter MS method was particularly helpful as it revealed distinct formations of product ions for each of the six investigated substances. [ABSTRACT FROM AUTHOR]

The market of new psychoactive substances (NPS) is characterized by a high turnover and thus provides several challenges for analytical toxicology. The analysis of urine samples often requires detailed knowledge about metabolism given that parent compounds either may be present only in small amounts or may not even be excreted. Hence, knowledge of the metabolism of NPS is a prerequisite for the development of reliable analytical methods. The main aim of this work was to elucidate for the first time the pooled human liver S9 fraction metabolism of the nine d-lysergic acid diethylamide (LSD) derivatives 1-acetyl-LSD (ALD-52), 1-propionyl-LSD (1P-LSD), 1-butyryl-LSD (1B-LSD), N6-ethyl-nor-LSD (ETH-LAD), 1-propionyl-N6-ethyl-nor-LSD (1P-ETH-LAD), N6-allyl-nor-LSD (AL-LAD), N-ethyl-N-cyclopropyl lysergamide (ECPLA), (2′S,4′S)-lysergic acid 2,4-dimethylazetidide (LSZ), and lysergic acid morpholide (LSM-775) by means of liquid chromatography coupled to high-resolution tandem mass spectrometry. Identification of the monooxygenase enzymes involved in the initial metabolic steps was performed using recombinant human enzymes and their contribution confirmed by inhibition experiments. Overall, N-dealkylation and hydroxylation, as well as combinations of these steps predominantly catalyzed by CYP1A2 and CYP3A4, were found. For ALD-52, 1P-LSD, and 1B-LSD, deacylation to LSD was observed. The obtained mass spectral data of all metabolites are essential for reliable analytical detection particularly in urinalysis and for differentiation of the LSD-like compounds as biotransformations also led to structurally identical metabolites. However, in urine of rats after the administration of expected recreational doses and using standard urine screening approaches, parent drugs or metabolites could not be detected. [ABSTRACT FROM AUTHOR]

Background: In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models.Methods: In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxyphenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxyamphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-propoxyamphetamine).Results: TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2.Conclusions: The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens. [ABSTRACT FROM AUTHOR]

Rationale: Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute. Methods: Here, we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites. Results: 2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with tenfold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having sixfold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for α2-adrenoceptor subtypes. 2-AI had particularly high affinity for α2C receptors (Ki = 41 nM) and slightly lower affinity for the α2A (Ki = 134 nM) and α2B (Ki = 211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B receptor. Conclusions: 2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability. [ABSTRACT FROM AUTHOR]

Psychoactive substances of the 2C‐series (2Cs) are phenethylamine‐derived designer drugs that can induce psychostimulant and hallucinogenic effects. Chemically, the classic 2Cs contain two methoxy groups in positions 2 and 5 of the phenyl ring, whereas substances of the so‐called FLY series contain rigidified methoxy groups integrated in a 2,3,6,7‐tetrahydrobenzo[1,2‐b:4,5‐b']difuran core. One of the pharmacological features that has not been investigated in detail is the inhibition of monoamine oxidase (MAO). Inhibition of this enzyme can cause elevated monoamine levels that have been associated with adverse events such as agitation, nausea, vomiting, tachycardia, hypertension, or seizures. The aim of this study was to extend the knowledge surrounding the potential of MAO inhibition for 17 test drugs, which consisted of 12 2Cs (2C‐B, 2C‐D, 2C‐E, 2C‐H, 2C‐I, 2C‐N, 2C‐P, 2C‐T‐2, 2C‐T‐7, 2C‐T‐21, bk‐2C‐B, and bk‐2C‐I) and five FLY analogs (2C‐B‐FLY, 2C‐E‐FLY, 2C‐EF‐FLY, 2C‐I‐FLY, and 2C‐T‐7‐FLY). The extent of MAO inhibition was assessed using an established in vitro procedure based on heterologously expressed enzymes and analysis by hydrophilic interaction liquid chromatography–high resolution tandem mass spectrometry. Thirteen test drugs showed inhibition potential for MAO‐A and 11 showed inhibition of MAO‐B. In cases where MAO‐A IC50 values were determined, values ranged from 10 to 125 μM (7 drugs) and from 1.7 to 180 μM for MAO‐B (9 drugs). In the absence of detailed clinical information on most test drugs, it is concluded that a pharmacological contribution of MAO inhibition cannot be excluded and that further studies are warranted. FLYs were identified as MAO‐A inhibitors, classic 2Cs with or without beta‐keto functionality exhibited MAO‐B inhibition potential. 2C‐T‐7‐FLY and 2C‐H were identified as the most potent MAO‐A or B inhibitors with IC50 values of 10 and 1.7 μM, respectively. [ABSTRACT FROM AUTHOR]

Rationale: The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.Objective: In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens.Methods: Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes.Results: ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA.Conclusions: These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens. [ABSTRACT FROM AUTHOR]

Abstract: The availability of new psychoactive substances (NPS) on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM), and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization, and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic, and mass spectrometric platforms. Pharmacological studies were conducted to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to 3,4‐methylenedioxymethamphetamine (MDMA). The combination of test purchases, analytical characterization, targeted organic synthesis, and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace. [ABSTRACT FROM AUTHOR]

Abstract: Nitrazolam and clonazolam are 2 designer benzodiazepines available from Internet retailers. There is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material. Variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered form. The unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in‐house approaches to the preparation of new psychoactive substances (NPS) that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analog nitrazolam were developed utilizing polymer‐supported reagents starting from 2‐amino‐2'‐chloro‐5‐nitrobenzophenone (clonazolam) and 2‐amino‐5‐nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4‐triazole ring moiety was performed within a gas chromatography–mass spectrometry (GC–MS) injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by‐product profiles for both the micro and the preparative scale syntheses are also presented. [ABSTRACT FROM AUTHOR]

Lysergic acid diethylamide (LSD) is perhaps one of the best-known psychoactive substances and many structural modifications of this prototypical lysergamide have been investigated. Several lysergamides were recently encountered as 'research chemicals' or new psychoactive substances (NPS). Although lysergic acid morpholide (LSM-775) appeared on the NPS market in 2013, there is disagreement in the literature regarding the potency and psychoactive properties of LSM-775 in humans. The present investigation attempts to address the gap of information that exists regarding the analytical profile and pharmacological effects of LSM-775. A powdered sample of LSM-775 was characterized by X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC-MS), high mass accuracy electrospray MS/ MS, high performance liquid chromatography (HPLC) diode array detection, HPLC quadrupole MS, and GC solid-state infrared analysis. Screening for receptor affinity and functional efficacy revealed that LSM-775 acts as a nonselective agonist at 5-HT1A and 5-HT2A receptors. Head twitch studies were conducted in C57BL/6J mice to determine whether LSM-775 activates 5-HT2A receptors and produces hallucinogen-like effects in vivo. LSM-775 did not induce the head twitch response unless 5-HT1A receptors were blocked by pretreatment with the antagonist WAY-100,635 (1 mg/kg, subcutaneous). These findings suggest that 5-HT1A activation by LSM-775 masks its ability to induce the head twitch response, which is potentially consistent with reports in the literature indicating that LSM-775 is only capable of producing weak LSD-like effects in humans. [ABSTRACT FROM AUTHOR]

New psychoactive substances (NPS) are commonly referred to as 'research chemicals', 'designer drugs' or 'legal highs'. One NPS class is represented by dissociative anesthetics, which include analogues of the arylcyclohexylamine phencyclidine (PCP), ketamine and diphenidine. A recent addition to the NPS market was 4-[1-(3-methoxyphenyl)cyclohexyl] morpholine (3-MeO-PCMo), a morpholine analogue of 3-MeO-PCP. Although suspected to have dissociative effects in users, information about its pharmacological profile is not available. From clinical and forensic perspectives, detailed analytical data are needed for identification, especially when facing the presence of positional isomers, as these are frequently unavailable commercially. This study presents the analytical and pharmacological characterization of 3-MeO-PCMo along with five additional analogues, namely the 2- and 4-MeO-PCMo isomers, 3,4-methylenedioxy-PCMo (3,4-MD-PCMo), 3-Me-PCMo and PCMo. All six arylcyclohexylmorpholines were synthesized and characterized using chromatographic, mass spectrometric and spectroscopic techniques. The three positional isomers could be differentiated and the identity of 3-MeO-PCMo obtained from an internet vendor was verified. All six compounds were also evaluated for affinity at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), an important target for dissociative anesthetics such as PCP and ketamine. In vitro binding studies using (+)-[3-3H]-MK-801 in rat forebrain preparations revealed moderate affinity for NMDAR in the rank order of 3-Me >3-MeO > PCMo >3,4-MD > 2-MeO > 4-MeO-PCMo. 3-MeO-PCMo was found to have moderate affinity for NMDAR comparable to that of ketamine, and had an approximate 12-fold lower affinity than PCP. These results support the anecdotal reports of dissociative effects from 3-MeO-PCMo in humans. [ABSTRACT FROM AUTHOR]

2‐Amino‐1‐(4‐bromo‐2,5‐dimethoxyphenyl)ethanone hydrochloride (bk‐2C‐B) has recently emerged as a new psychoactive substance (NPS). It is most commonly consumed orally, although there are indications that it might also be ingested by inhalation or ‘smoking’. Information about the stability of bk‐2C‐B when exposed to heat is unavailable and the potential for pyrolytic degradation and formation of unknown substances available for inhalation prompted an investigation using a simulated ‘meth pipe’ scenario. Twelve products following pyrolysis of bk‐2C‐B were detected and verified by organic synthesis of the corresponding standards. In addition, 2‐amino‐1‐(4‐iodo‐2,5‐dimethoxyphenyl)ethanone hydrochloride (bk‐2C‐I) was characterized for the first time and subjected to pyrolysis as well. Similar products were formed, which indicated that the replacement of the bromo with the iodo substituent did not affect the pyrolysis pattern under the conditions used. Two additional products were detected in the bk‐2C‐I pyrolates, namely 1‐(2,5‐dimethoxyphenyl)‐ethanone and 1‐iodo‐4‐ethenyl‐5‐methoxyphenol. The potential ingestion of pyrolysis products with unknown toxicity adds an element of concern. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The psychoactive properties of lysergic acid diethylamide (LSD) have fascinated scientists across disciplines and the exploration of other analogues and derivatives has been motivated by deepening the understanding of ligand-receptor interactions at the molecular level as well as by the search for new therapeutics. Several LSD congeners have appeared on the new psychoactive substances (NPS) market in the form of blotters or powders. Examples include 1-propionyl-LSD (1P-LSD), AL-LAD, and LSZ. The absence of analytical data for novel compounds is a frequent challenge encountered in clinical and toxicological investigations. Two newly emerging lysergamides, namely N6-ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1P-ETH-LAD, were characterized by gas chromatography-mass spectrometry (GC-MS), low and high mass accuracy electrospray MS(/MS), GC solid-state infrared analysis, high performance liquid chromatography diode array detection as well as nuclear magnetic resonance spectroscopy. Limited analytical data for ETH-LAD were previously available, whereas information about 1P-ETH-LAD has not previously been encountered in the scientific literature. This study extends the characterization of lysergamides distributed on the NPS market, which will help to make analytical data available to clinicians, toxicologists, and other stakeholders who are likely to encounter these substances. The analysis of a test incubation of 1P-ETH-LAD with human serum at 37°C by LC single quadrupole MS at various time points (0-6 h, once per hour and one measurement after 24 h) revealed the formation of ETH-LAD, suggesting that 1P-ETH-LAD might serve as a pro-drug. 1P-ETH-LAD was still detectable in serum after 24 h. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This perspective examines amphetamine importations into Ireland. Some novel by‐products were detected and linked to a change in the method of production of P2P from APAAN. These by‐products remained present during subsequent Leuckart reaction conditions. Novel by‐products from substituted cathinone synthesis reactions were also isolated and characterized. [ABSTRACT FROM AUTHOR]

2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil) is commonly prescribed for the treatment of narcolepsy. Increasing popularity and off-label use as a cognitive enhancer has resulted in a reputation as an intelligence boosting 'wonder drug'. Common alternatives available from online shops and other retail outlets include 2-[(diphenylmethyl)sulfinyl]- N-hydroxyacetamide (adrafinil), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}acetamide (CRL-40,940), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}- N-hydroxyacetamide (CRL-40,941), and N-methyl-4,4-difluoro-modafinil (modafiendz), respectively. Gas chromatography-mass spectrometry (GC-MS) is a common tool used in forensic and clinical analysis but there is a potential for inducing analysis-related ambiguities. This study reports on the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940, and CRL-40,941 due to exposure to the heated GC injection port dissolved in a variety of solvents. Key degradation products common to modafinil, modafinic acid, and adrafinil analysis included diphenylmethanol and 1,1,2,2-tetraphenylethane (TPE), the latter of which was verified by its synthesis and characterization by x-ray crystallography. The investigated compounds were also characterized by 1H and 13C NMR. Diphenylmethane and thiobenzophenone were also identified in some instances. TPE formation was suggested to involve the generation of a benzhydrylium ion and its reaction with the sulfoxide oxygen of the parent compound to give an oxysulfonium intermediate. Correspondingly, the fluorinated TPE analogue was formed during heat-induced degradation of modafiendz, CRL-40,940 and CRL-40,941, respectively. When a mixture of modafinil (non-fluorinated) and modafiendz (fluorinated) were subjected to GC analysis, 4,4'-(2,2-diphenylethane-1,1-diyl)bis(fluorobenzene) was detected as a third cross reaction product in addition to the two expected TPE analogues. These observations served as a reminder that the seemingly straightforward implementation of GC-MS analysis can lead to challenges during routine analysis. [ABSTRACT FROM AUTHOR]

Six collected phenidates, i.e., 4-methylmethylphenidate, 3,4-dichloromethylphenidate, ethylphenidate, 3,4-dichloroethylphenidate, ethylnaphthidate, and N-benzyl-ethylphenidate were fully characterized by means of X-ray, nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), electrospray ionization-tandem mass spectrometry (ESI-MS/MS), attenuated total reflectance Fourier transform infrared (ATR-FTIR) and GC solid-state IR analysis. Crystallography revealed the exclusive presence of the threo-configuration. Steric crowding induced by N-benzyl substitution at the piperidine moiety prompted an adoption of an unexpected axial positioning of substituents on the piperidine moiety in the crystal state as opposed to the exclusive equatorial positioning encountered in N-unsubstituted phenidate analogues. Gas phase computations of the relative lowest energy conformers confirm that the axial positioning appears to be favoured over the equatorial positioning; in solution, however, equatorial positioning is predominant according to nuclear Overhauser effect experiments. All samples, mainly originating from China, had a good to very good degree of purity indicative of their professional chemical synthesis. Routine analysis of these drugs by GC-MS revealed thermal decomposition of phenidate analogues in the injection port and/or on column to 2-aryl-ethyl-acetates and 2,3,4,5-tetrahydropyridines. The decomposition pathway was suggested to proceed via a 6-membered transition state which was supported by density functional theory (DFT) computations. Fragmentation pathways of decomposition products as well as the corresponding electron ionization (EI) mass spectra are provided. The thermal instability might thus render smoking or 'vaping' of these drugs a less effective route of administration. The analytical fingerprints of six structurally diverse phenidate analogues provide a helpful reference to forensic chemists in charge of identifying new psychoactive substances. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

3-Methoxy-2-(methylamino)-1-(4-methylphenyl)propan-1-one (mexedrone) appeared in 2015 and was advertised by UK Internet retailers as a non-controlled mephedrone derivative (2-(methylamino)-1-(4-methylphenyl)propan-1-one), which was of particular interest to countries who operate generic drugs legislation. This study describes the synthesis and analytical characterization of mexedrone and the differentiation from its isomer, N-methoxymephedrone, which was predicted to be a suitable candidate before the identity of mexedrone was revealed. A full analytical characterization is described using various chromatographic, spectroscopic and mass spectrometric platforms and X-ray crystal structure analysis. The analytical data obtained for a vendor sample were consistent with the synthesized mexedrone reference standard and analytical differentiation between the mexedrone and N-methoxymephedrone positional isomers was achieved. Furthermore, α-chloromethylmephedrone was identified as a by-product during mexedrone synthesis. All three substances were also studied for their uptake and releasing properties at dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) using in vitro monoamine transporter assays in rat brain synaptosomes and compared to mephedrone. Mexedrone was a weak non-selective uptake blocker with IC50 values in the low μM range. It was also devoid of releasing activity at DAT and NET but displayed weak releasing activity at SERT (EC50 = 2.5 μM). The isomer N-methoxymephedrone was found to be a weak uptake blocker at DAT, NET and SERT, as well as a fully efficacious substrate-type releasing agent across all three transporters with EC50 values in the low micromolar range. The synthesis by-product α-chloromethylmephedrone was inactive in all assays. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

1-Phenyl-2-propanone (P2P) is an internationally monitored precursor that has become increasingly difficult for illicit amphetamine producers to source, which means that alternative routes to its preparation have become increasingly important. One such approach includes the hydrolysis of alpha-phenylacetoacetonitrile (APAAN) with sulfuric acid. Previously, we reported the identification of 4,6-dimethyl-3,5-diphenylpryid-2-one following implementation of hydrolysis conditions and it was proposed that this compound might serve as one route specific by-product in the APAAN to P2P conversion. This study continued to explore the presence of impurities formed during this conversion and expanded also into a second route of P2P synthesis starting from alpha-methylstyrene (AMS). All P2P products underwent the Leuckart procedure to probe the presence of P2P-related impurities that might have carried through to the final product. Two by-products associated with the APAAN hydrolysis route to P2P were identified as 2,3-diacetyl-2,3-diphenylsuccinonitrile ( 1) and 2-methyl-1-phenyl-1,3-dicarbonitrile-1 H-indene ( 2), respectively. Two by-products associated with the AMS route to P2P and subsequent Leuckart reaction were 1,1,3-trimethyl-3-phenyl-2,3-dihydro-1 H-indene ( 3) and 1-phenyl- N-(phenylethyl)propan-2-amine ( 4), respectively. The two indenes ( 2 and 3) identified in synthesized amphetamine originating from P2P suggested that it might be possible to differentiate between the two synthetic routes regarding the use of APAAN and AMS. Furthermore, the association of these compounds with amphetamine production appears to have been reported for the first time. The presence of compounds 1 - 4 in seized amphetamine samples and waste products could facilitate the suggestion whether APAAN or AMS were employed in the synthesis route to the P2P. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The knowledge captured in patent and scientific research literature stimulates new ideas and fosters new drug development efforts. Manufacturers and entrepreneurs dedicated to the sale of 'research chemicals' and/or new psychoactive substances (NPS) also make use of access to information to identify, prepare, and launch a range of new substances. One of the most recent compounds to appear on the NPS market is the phenmetrazine analog 3-fluorophenmetrazine (3-FPM) which represents one of many phenylmorpholines designed to explore treatment options in areas such as obesity and drug dependence. The anorectic drug analogs phenmetrazine and phendimetrazine, used as prescription medicines before they were withdrawn, feature amphetamine-like properties associated with monoamine release. Available data on 3-FPM suggest that the effects might show mechanistic overlaps. This study describes the synthesis and extensive analytical characterization of 3-FPM and its differentiation from synthesized ortho- and para- substituted isomers, 2-FPM and 4-FPM, respectively. This study was triggered by the purchase of five powdered samples advertised as 3-FPM by five different Internet vendors based in the United Kingdom. The analytical data obtained for the vendor samples were consistent with the synthesized 3-FPM standard and differentiation between all three isomers was possible. The presence of positional isomers and the absence of suitable reference material can cause difficulties in the day-to-day operation of forensic work and given the rate at which many of the newly emerging NPS appear on the market, a comprehensive approach is needed when attempting to decipher the identity of NPS arriving onto the drug market. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Misuse of (±)- threo-methylphenidate (methyl-2-phenyl-2-(piperidin-2-yl)acetate; Ritalin®; MPH) has long been acknowledged, but the appearance of MPH analogs in the form of 'research chemicals' has only emerged in more recent years. 4-Fluoromethylphenidate (4F-MPH) is one of these recent examples. This study presents the identification and analytical characterization of two powdered 4F-MPH products that were obtained from an online vendor in 2015. Interestingly, the products appeared to have originated from two distinct batches given that one product consisted of (±)- threo-4F-MPH isomers whereas the second sample consisted of a mixture of (±)- threo and (±)- erythro 4F-MPH. Monoamine transporter studies using rat brain synaptosomes revealed that the biological activity of the 4F-MPH mixture resided with the (±)- threo and not the (±)- erythro isomers based on higher potencies determined for blockage of dopamine uptake (IC50 4F-MPHmixture = 66 nM vs. IC50 (±)- threo = 61 nM vs. IC50 (±)- erythro = 8,528 nM) and norepinephrine uptake (IC50 4F-MPHmixture = 45 nM vs. (±)- threo = 31 nM vs. IC50 (±)- erythro = 3,779 nM). In comparison, MPH was three times less potent than (±)- threo-4F-MPH at the dopamine transporter (IC50 = 131 nM) and around 2.5 times less potent at the norepinephrine transporter (IC50 = 83 nM). Both substances were catecholamine selective with IC50 values of 8,805 nM and >10,000 nM for (±)- threo-4F-MPH and MPH at the serotonin transporter. These findings suggest that the psychostimulant properties of (±)- threo-4F-MPH might be more potent in humans than MPH. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Recently, the pyrazole-containing synthetic cannabinoid N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1 H-pyrazole-5-carboxamide (3,5-AB-CHMFUPPYCA) has been identified as a 'research chemical' both in powdered form and as an adulterant present in herbal preparations. Urine is the most common matrix used for abstinence control and the extensive metabolism of synthetic cannabinoids requires implementation of targeted analysis. The present study describes the investigation of the in vitro phase I metabolism of 3,5-AB-CHMFUPPYCA and its regioisomer 5,3-AB-CHMFUPPYCA using pooled human liver microsomes. Metabolic patterns of both AB-CHMFUPPYCA isomers were qualitatively similar and dominated by oxidation of the cyclohexylmethyl side chain. Biotransformation to monohydroxylated metabolites of high abundance confirmed that these species might serve as suitable targets for urine analysis. Furthermore, since synthetic cannabinoids are commonly administered by smoking and because some metabolites can also be formed as thermolytic artefacts, the stability of both isomers was assessed under smoking conditions. Under these conditions, pyrolytic cleavage of the amide bond occurred that led to approximately 3 % conversion to heat-induced degradation products that were also detected during metabolism. These artefactual 'metabolites' could potentially bias in vivo metabolic profiles after smoking and might have to be considered for interpretation of metabolite findings during hair analysis. This might be relevant to the analysis of hair samples where detection of metabolites is generally accepted as a strong indication of drug use rather than a potential external contamination. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Lysergic acid N, N-diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances known and numerous analogs have been explored to varying extents in previous decades. In 2013, N6-allyl-6-norlysergic acid diethylamide (AL-LAD) and (2' S,4' S)-lysergic acid 2,4-dimethylazetidide (LSZ) appeared on the 'research chemicals'/new psychoactive substances (NPS) market in both powdered and blotter form. This study reports the analytical characterization of powdered AL-LAD and LSZ tartrate samples and their semi-quantitative determination on blotter paper. Included in this study was the use of nuclear magnetic resonance (NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS), low and high mass accuracy electrospray MS(/MS), high performance liquid chromatography diode array detection and GC solid-state infrared analysis. One feature shared by serotonergic psychedelics, such as LSD, is the ability to mediate behavioural responses via activation of 5-HT2A receptors. Both AL-LAD and LSZ displayed LSD-like responses in male C57BL/6 J mice when employing the head-twitch response (HTR) assay. AL-LAD and LSZ produced nearly identical inverted-U-shaped dose-dependent effects, with the maximal responses occurring at 200 µg/kg. Analysis of the dose responses by nonlinear regression confirmed that LSZ (ED50 = 114.2 nmol/kg) was equipotent to LSD (ED50 = 132.8 nmol/kg) in mice, whereas AL-LAD was slightly less potent (ED50 = 174.9 nmol/kg). The extent to which a comparison in potency can be translated directly to humans requires further investigation. Chemical and pharmacological data obtained from NPS may assist research communities that are interested in various aspects related to substance use and forensic identification. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Many N, N-dialkylated tryptamines show psychoactive properties in humans and the number of derivatives involved in multidisciplinary areas of research has grown over the last few decades. Whereas some derivatives form the basis of a range of medicinal products, others are predominantly encountered as recreational drugs, and in some cases, the areas of therapeutic and recreational use can overlap. In recent years, 5-methoxy- N, N-diallyltryptamine (5-MeO-DALT) has appeared as a new psychoactive substance (NPS) and 'research chemical' whereas 4-acetoxy-DALT and the ring-unsubstituted DALT have only been detected very recently. Strategies pursued in the authors' laboratories included the preparation and biological evaluation of previously unreported N, N-diallyltryptamines (DALTs). This report describes the analytical characterization of 17 DALTs. Fifteen DALTs were prepared by a microwave-accelerated Speeter and Anthony procedure following established procedures developed previously in the authors' laboratories. In addition to DALT, the substances included in this study were 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 4,5-ethylenedioxy-, 5-methyl-, 5-methoxy-, 5-methoxy-2-methyl-, 5-ethoxy-, 5-fluoro-, 5-fluoro-2-methyl-, 5-chloro-, 5-bromo-, 5,6-methylenedioxy-, 6-fluoro-, 7-methyl, and 7-ethyl-DALT, respectively. The DALTs were characterized by nuclear magnetic resonance spectroscopy (NMR), gas chromatography (GC) quadrupole and ion trap (EI/CI) mass spectrometry (MS), low and high mass accuracy MS/MS, photodiode array detection, and GC solid-state infrared analysis, respectively. A comprehensive collection of spectral data was obtained that are provided to research communities who face the challenge of encountering newly emerging substances where analytical data are not available. These data are also relevant to researchers who might wish to explore the clinical and non-clinical uses of these substances. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This study presents the identification of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1 H-pyrazole-5-carboxamide that was termed 3,5-AB-CHMFUPPYCA. This compound was obtained from a UK-based Internet vendor, who erroneously advertised this 'research chemical' as AZ-037 and which would have been associated with ( S)- N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-5-(4-fluorophenyl)-1 H-pyrazole-3-carboxamide. The presence of the pyrazole core indicates a bioisosteric replacement of an indazole ring that is frequently associated with synthetic cannabinoids of the PINACA, FUBINACA, and CHMINACA series. The pyrazole ring system present in 3,5-AB-CHMFUPPYCA gives rise to the regioisomer N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-5-(4-fluorophenyl)-1 H-pyrazole-3-carboxamide (named 5,3-AB-CHMFUPPYCA) and both isomers were synthesized using two specific routes which supported the correct identification of the 'research chemical' as 3,5-AB-CHMFUPPYCA. Both isomers could be conveniently differentiated. Interestingly, a route specific chlorine-containing by-product also was observed during the synthesis of 3,5-AB-CHMFUPPYCA and identified as N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-chloro-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1 H-pyrazole-5-carboxamide. An extensive analytical characterization included chromatographic, spectroscopic, mass spectrometric platforms as well as crystal structure analysis. The syntheses and analytical characterizations of both AB-CHMFUPPYCA isomers are reported for the first time and serves as a reminder that the possibility of mislabeling of 'research chemicals' cannot be excluded. The pharmacological activities of both AB-CHMFUPPYCA isomers remain to be explored. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

1-Propionyl- d-lysergic acid diethylamide hemitartrate (1P-LSD) has become available as a 'research chemical' in the form of blotters and powdered material. This non-controlled derivative of d-lysergic acid diethylamide (LSD) has previously not been described in the published literature despite being closely related to 1-acetyl-LSD (ALD-52), which was developed in the 1950s. This study describes the characterization of 1P-LSD in comparison with LSD using various chromatographic and mass spectrometric methods, infrared and nuclear magnetic resonance spectroscopy. An important feature common to LSD and other serotonergic hallucinogens is that they produce 5-HT2A-receptor activation and induce the head-twitch response (HTR) in rats and mice. In order to assess whether 1P-LSD displays LSD-like properties and activates the 5-HT2A receptor, male C57BL/6 J mice were injected with vehicle (saline) or 1P-LSD (0.025-0.8 mg/kg, IP) and HTR assessed for 30 min using magnetometer coil recordings. It was found that 1P-LSD produced a dose-dependent increase in HTR counts, and that it had ~38% (ED50 = 349.6 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). Furthermore, HTR was abolished when 1P-LSD administration followed pretreatment with the selective 5-HT2A receptor antagonist M100907 (0.1 mg/kg, SC), which was consistent with the concept that the behavioural response was mediated by activation of the 5-HT2A receptor. These results indicate that 1P-LSD produces LSD-like effects in mice, consistent with its classification as a serotonergic hallucinogen. Nevertheless, the extent to which 1P-LSD might show psychoactive effects in humans similar to LSD remains to be investigated. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]