In Vivo and In Vitro Metabolic Fate and Urinary Detectability of Five Deschloroketamine Derivatives Studied by Means of Hyphenated Mass Spectrometry.

Ketamine derivatives such as deschloroketamine and deschloro--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--cyclopropyl-ketamine deschloro--isopropyl-ketamine and deschloro--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.

Identification of 5-HT receptor signaling pathways associated with psychedelic potential.

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands.

Identification of 5-HT Receptor Signaling Pathways Responsible for Psychedelic Potential.

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT-Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands.

The Pharmacokinetics of Ketamine in the Breast Milk of Lactating Women: Quantification of Ketamine and Metabolites.

Ketamine is a general anesthetic with over 50 years of safe administration that is in increasing use for psychiatric indications. This is evidenced by the recent FDA approval of intranasal esketamine (the S-enantiomer) for the treatment of depression. With respect to ketamine and lactation, incredibly there are no available data on the secretion of ketamine or its metabolites in human breast milk.

Three Birds, One Excipient: Development of an Improved pH, Isotonic, and Buffered Ketamine Formulation for Subcutaneous Injection.

Subcutaneous (SC) ketamine has been found to be effective in pain management, though reports of injection site irritation and sterile abscesses exist with currently available ketamine HCl formulations. Such adverse SC reactions are commonly associated with low pH, high osmolality and/or high injection volumes. An optimal SC formulation of ketamine would thus have a pH and osmolality close to physiological levels, without compromising on concentration and, thus, injection volume.

Return of the lysergamides. Part VI: Analytical and behavioural characterization of 1-cyclopropanoyl-d-lysergic acid diethylamide (1CP-LSD).

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.

Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species.

Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response experiments were conducted with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice, enlarging the available pool of HTR potency data to 41 total compounds.

Pharmacological characterizations of the 'legal high' fluorolintane and isomers.

1,2-Diarylethylamines represent a class of molecules that have shown potential in the treatment of pain, epilepsy, neurodegenerative disease and depression. Examples include lefetamine, remacemide, and lanicemine. Recently, several 1,2-diarylethylamines including the dissociatives diphenidine, methoxphenidine and ephenidine as well as the opioid MT-45, have appeared as 'research chemicals' or 'legal highs'.

Return of the lysergamides. Part V: Analytical and behavioural characterization of 1-butanoyl-d-lysergic acid diethylamide (1B-LSD).

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.

Syntheses and analytical characterizations of the research chemical 1-[1-(2-fluorophenyl)-2-phenylethyl]pyrrolidine (fluorolintane) and five of its isomers.

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.

Correction to: Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

The author of this article wanted to change the Acknowledgments section to: These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously.

Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

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.

1,2-Diarylethylamine- and Ketamine-Based New Psychoactive Substances.

While phencyclidine (PCP) and ketamine remain the most well-studied and widely known dissociative drugs, a number of other agents have appeared since the late 1950s and early 1960s, when the pharmacological potential of this class was first realized. For example, hundreds of compounds have been pursued as part of legitimate research efforts to explore these agents. Some of these found their way out of the research labs and onto illicit markets of the 1960s and following decades as PCP analogs.

Phencyclidine-Based New Psychoactive Substances.

The serendipitous discovery of phencyclidine (PCP) in 1956 sets the stage for significant research efforts that resulted in a plethora of analogs and derivatives designed to explore the biological effects of this class. PCP soon became the prototypical dissociative agent that eventually sneaked through the doors of clinical laboratories and became an established street drug. Estimations suggest that around 14 PCP analogs were identified as "street drugs" in the period between the 1960s and 1990s.

Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775).

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.

Syntheses, analytical and pharmacological characterizations of the 'legal high' 4-[1-(3-methoxyphenyl)cyclohexyl]morpholine (3-MeO-PCMo) and analogues.

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.

Developing selective histone deacetylases (HDACs) inhibitors through ebselen and analogs.

Histone deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors.

Return of the lysergamides. Part III: Analytical characterization of N -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1-propionyl ETH-LAD (1P-ETH-LAD).

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.

Ephenidine: A new psychoactive agent with ketamine-like NMDA receptor antagonist properties.

To avoid legislation based on chemical structure, research chemicals, frequently used for recreational purposes, are continually being synthesized. N-Ethyl-1,2-diphenylethanamine (ephenidine) is a diarylethylamine that has recently become popular with recreational users searching for dissociative hallucinogenic effects. In the present study, the pharmacological basis of its neural actions has been investigated, initially by assessing its profile in central nervous system receptor binding assays and subsequently in targeted electrophysiological studies.

New Psychoactive Substances 3-Methoxyphencyclidine (3-MeO-PCP) and 3-Methoxyrolicyclidine (3-MeO-PCPy): Metabolic Fate Elucidated with Rat Urine and Human Liver Preparations and their Detectability in Urine by GC-MS, "LC-(High Resolution)-MSn" and "LC-(High Resolution)-MS/MS".

Background: 3-Methoxyphencyclidine (3-MeO-PCP) and 3-methoxyrolicyclidine (3-MeOPCPy) are two new psychoactive substances (NPS). The aims of the present study were the elucidation of their metabolic fate in rat and pooled human liver microsomes (pHLM), the identification of the cytochrome P450 (CYP) isoenzymes involved, and the detectability using standard urine screening approaches (SUSA) after intake of common users' doses using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-multi-stage mass spectrometry (LC-MSn), and liquid chromatography-high-resolution tandem mass spectrometry (LC-HR-MS/MS).

Methods: For metabolism studies, rat urine samples were treated by solid phase extraction or simple precipitation with or without previous enzymatic conjugate cleavage.

Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues.

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as 'legal highs' in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs.

Return of the lysergamides. Part II: Analytical and behavioural characterization of N -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ).

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, N -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.

Return of the lysergamides. Part I: Analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD).

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.

Syntheses and analytical characterizations of N-alkyl-arylcyclohexylamines.

The rise in new psychoactive substances that are available as 'research chemicals' (RCs) remains a significant forensic and legislative challenge. A number of arylcyclohexylamines have attracted attention as RCs and continue to be encountered, including 3-MeO-PCP, 3-MeO-PCE and 3-MeO-PCPr. These compounds are commonly perceived as ketamine-like dissociative substances and are believed to act predominantly via antagonism of the N-methyl-D-aspartate (NMDA) receptor.

Test purchase, synthesis, and characterization of 2-methoxydiphenidine (MXP) and differentiation from its meta- and para-substituted isomers.

The structurally diverse nature of the 1,2-diphenylethylamine template provides access to a range of substances for drug discovery work but some have attracted attention as 'research chemicals'. The most recent examples include diphenidine, i.e.