Phenylethylamine Derivatives Research Articles

Ruthenium(II)-Catalyzed Remote C-H Alkylation of Arenes Using Diverse N-Directing Groups through Aziridine Ring Opening.

An efficient approach for the remote C-H alkylation of arenes, employing a variety of N-directing groups is described. This method facilitates the straightforward synthesis of valuable phenylethylamine derivatives by exclusively cleaving the benzylic C-N bond in aziridines. Furthermore, these products can easily remove the protecting groups, resulting in a variety of meta-substituted compounds, such as amines and ketones, which hold significance in synthetic chemistry.

Goji berry-derived phenylpropionyl phenylethylamine derivatives protect against ethanol-induced hepatic damage

Goji berry-derived phenylpropionyl phenylethylamine derivatives protect against ethanol-induced hepatic damage

Unveiling the antioxidant potential of newly designed phenylethylamine derivatives through computational chemistry: Significance of acid dissociation constants

We have calculated the pKa and the primary antioxidant capacity of the six possible designed isomers of phenylethylamine substituted with a catechol and a carboxylic group. The reaction of these phenylethylamine designed derivatives (Phdd) with a hydroperoxyl radical (•OOH) was studied in both lipid and aqueous environments. The Gaussian 09 computer program was used within the Density Functional Theory, with the M05-2X functional, the 6–311 + G(d,p) basis set, and the SMD continuous solvent model, to perform the necessary thermodynamic and kinetic calculations. The entire study includes the determination of the Phdd pKa values, their •OOH reaction mechanisms, as well as the relative importance of the protonated and deprotonated forms of Phdd at physiological pH in aqueous solution. Compounds Ph178, Ph179 and Ph182 are found to be excellent primary antioxidants against •OOH in water at physiological pH. In lipid medium Ph178 and Ph182, could inhibit the damage caused by the hydroperoxyl radical.

Kinetic Resolution of β-Alkyl Phenylethylamine Derivatives through Palladium-Catalyzed, Nosylamide-Directed C−H Olefination

Palladium-catalyzed C-H activation reactions have attracted the attention of organic researchers due to their unique high selectivity, broad functional group tolerance, and high efficiency, and they are widely used in natural products and asymmetric synthesis. Here, we report an example of enantioselective C-H alkenylation between β-alkyl phenylethylamine compounds and styrenes with Boc-L-lle-OH as the ligand and nosylamide as the directing group. This reaction is applicable to styrene containing various electron-deficient and electron-donating substitutions and may be utilized for the synthesis of benzoazepine compounds.

Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3.

Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters.

EXPERT RESEARCH OF SUBSTANCES OF GROUP OF DERIVATIVES OF PHENYLETHYLAMINE (ON EXAMPLE OF MESCALINE AND 2С-В)

General physical and chemical descriptions of phenylethylamine presented grosses-formulas, the molecular masses and indexes of chromatography maintenance of derivatives of phenylethylamine, register in the article, mescaline, and 2С-В behave to that. During expert research of substances of a group of derivatives of phenylethylamine, the task of quality authentication of research objects that have an alike molecular structure stands before experts. The analytical approach intended for authentication of the investigated substances envisages the use of a few unconnected inter se methods: methods of providing of high level of selectivity, middle and subzero level of selectivity. The brought analytical charts over, that give a scientifically reasonable result, when after every method positive result that confirms each other are arrived at. The aim of the research of this work is an analysis and approbation of existent methodologies of authentication of substances that have an alike molecular structure, and their quantitative research. The process of quality authentication of mescaline and 2С-В, or other derivatives of phenylethylamine, includes for itself extraction and preparation of the test. During realization of screening of the investigated psychotropic substances (mescaline, 2С-В) used: method of quality analytical reactions, method of TLC, method of ultraviolet spectroscopy, method of infra-red spectroscopy, method of gas mass-spectrometry. Quantitative determination of mescaline and 2С-В was conducted by the method of gas mass-spectrometry. At the research of substances of a group of derivatives to the phenylethylamine expert, it follows to follow the presence of corresponding literary sources and the presence of corresponding analytical equipment (GC, GC/MS, LC/MS, and others like that). In accordance with it, it’s needed to use those or other methodologies of research of substances. The indicated methodologies are subject to obligatory verification before application in a laboratory. Key words: phenylethylamine, mescaline, 2C-B, chromatography, spectrophotometry, chromato-mass spectroscopy.

New Synthetic Cathinones and Phenylethylamine Derivatives Analysis in Hair: A Review.

The analysis of psychoactive substances in hair is of great importance for both clinical and forensic toxicologists since it allows one to evaluate past and continuative exposure to xenobiotics. In particular, a new challenge is represented by new psychoactive substances: Among this new class of drugs of abuse, synthetic cathinone and phenethylamine derivatives are often detected in biological samples. Hence, there is a growing need to develop new analytical procedures or improve old ones in order to conduct evaluations of these emerging substances. This study is a systematic review of all the instrumental and experimental data available in the literature. A total of 32 articles were included in the review. Acidic solvents proved to be the most reliable solutions for extraction. Gas chromatography and liquid chromatography coupled to tandem mass spectrometric and high-resolution mass spectrometric systems represent the majority of the involved instrumental techniques. Sensitivity must be maintained at the pg/mg level to detect any occurrences up to occasional consumption. In total, 23 out of 32 articles reported real positive samples. The most frequently detected substance in hair was mephedrone, followed by butylone, methylone, MDPV, and α-pyrrolidinophenone-type substances.

Determination of 19 Psychoactive Substances in Premortem and Postmortem Whole Blood Samples Using Ultra-High-Performance Liquid Chromatography–Tandem Mass Spectrometry

An ever-increasing need exists within the forensic laboratories to develop analytical processes for the qualitative and quantitative determination of a broad spectrum of new psychoactive substances. Phenylethylamine derivatives are among the major classes of psychoactive substances available on the global market and include both amphetamine analogues and synthetic cathinones. In this work, an ultra-high-performance liquid chromatography-positive ion electrospray ionization tandem mass spectrometric method (UHPLC-ESI-MS/MS) has been developed and fully validated for the determination of 19 psychoactive substances, including nine amphetamine-type stimulants and 10 synthetic cathinone derivatives, in premortem and postmortem whole blood. The assay was based on the use of 1 mL premortem or postmortem whole blood, following solid phase extraction prior to the analysis. The separation was achieved on a Poroshell 120 EC-C18 analytical column with a gradient mobile phase of 0.1% formic acid in acetonitrile and 0.1% formic acid in water in 9 min. The dynamic multiple reaction monitoring used in this work allowed for limit of detection (LOD) and lower limit of quantitation (LOQ) values of 0.5 and 2 ng mL−1, respectively, for all analytes both in premortem and postmortem whole blood samples. A quadratic calibration model was used for the 12 quantitative analytes over the concentration range of 20–2000 ng mL−1, and the method was shown to be precise and accurate both in premortem and postmortem whole blood. The method was applied to the analysis of real cases and proved to be a valuable tool in forensic and clinical toxicology.

New Isocoumarin Analogues from the Marine-Derived Fungus Paraphoma sp. CUGBMF180003.

Nine new secondary metabolites, including six isocoumarin analogues, 7-hydroxyoospolactone (1), 7-methoxyoospolactone (2), 7-methoxy-9-hydroxyoospolactone (3), 10-acetoxy-9-hydroxyoospolactone (4), 6-dehydroxysescandelin (5), parapholactone (6), and three compounds with a rare skeleton of isocoumarin coupled with phenylethylamine, namely paraphamide A (12), paraphamide B (13), and paraphamide C (14), together with five known compounds, oospolactone (7), 8-O-methyloospolactone (8), 10-hydroxyoospolactone (9), 9,10-dihydroxyoospolactone (10), and oospoglycol (11), were isolated and identified from the marine-derived fungus Paraphoma sp. CUGBMF180003. Their chemical structures were determined using spectroscopic data, including HRESIMS and 1D and 2D NMR techniques. Furthermore, the stereogenic carbons in 5 and 14 were determined by comparing the experimental and calculated electronic circular dichroism (ECD) spectra. The carbon skeleton of 12–14 was identified as the first example of isocoumarin coupled with phenylethylamine derivatives. All of these compounds were examined for antimicrobial activities against Candida albicans and Staphylococcus aureus. Both 1 and 6 showed antibacterial activity against S. aureus with MIC values of 12.5 μg/mL.

Rational Anode Engineering Enables Progresses for Different Types of Organic Solar Cells

AbstractAnode modification is vital for improving device performance of organic solar cells (OSCs). PEDOT:PSS is the most widely applied hole transport layer (HTL) in OSCs. In this work, three kinds of modified HTLs, namely PEDOT:PSS‐PA, PEDOT:PSS‐TA, and PEDOT:PSS‐DA are readily prepared via simple doping of phenylethylamine derivatives into commercially available Al 4083, by modulating the number of hydroxyl groups on the adulterant molecules. All of them exhibit enhanced work functions (WFs) and conductivities. Matching with PM6:Y6 composed active layers, PEDOT:PSS‐TA based devices achieves the highest performance with a power conversion efficiency (PCE) of 17.10%, while the PM6:ITC‐2Cl system demonstrates a highest PCE of 14.17% in devices with PEDOT:PSS‐DA, and the optimal PCE of PM6:PIDTC‐T based OSCs is equal to 9.55% while the HTL is PEDOT:PSS‐PA. Further investigations reveal that the different adulterants formed various amount of hydrogen bonds in HTLs, inducing dissimilar interfacial morphology and mobility, and thus unidentical degrees of change in recombination. Afterwards, the doping strategy is extended to a newly proposed high‐performance system PM6:PY‐IT, and successfully drags its efficiency from 14.78% to 15.62%, another world‐class breakthrough for all‐polymer solar cells. In summary, this study not only achieves a series of OSCs with improved PCEs, but also delivers a deep understanding of PEDOT:PSS improvement.

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

Psychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a K m of 24.3 µM and a v max of 642 pmol × mg protein−1 × min−1. Transport was modestly reduced in variants *2 and *7, more strongly reduced in *3 and *4, and lowest in *5 and *6, while *8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with K m values in the range of 7.9–46.0 µM and v max values between 70.7 and 570 pmol × mg protein−1 × min−1. Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the Km being 21-fold and the v max 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity.

A Systematic Review on Analytical Methods to Determine Chiral and Achiral Forms of Venlafaxine and its Metabolite O-desmethylvenlafaxine

Background: Venlafaxine (VEN) is a bicyclic phenylethylamine derivative and possesses a marked structural difference from other antidepressant drugs present in the market. It works by eliciting the neurotransmitter action in CNS. It occurs in two enantiomeric forms i.e. R and S VEN. After the first pass metabolism, it gets metabolized into more active form O-desmethylvenlafaxine (ODV) which also exist in the enantiomeric forms. So it is important to develop a suitable analytical and bioanalytical method for the determination of VEN and its metabolite to quantify them accurately. Methods and Results: The current review summarizes methods to determine chiral and achiral forms of VEN and ODV. According to the literature, it is clear that most widely used method for the determination of VEN and ODV is liquid chromatography-mass spectroscopy, other methods used for routine analysis include UV spectroscopy, reverse phase high-performance liquid chromatography with PDA detector. For the determination of enantiomeric forms of VEN and ODV, different chiral columns have been utilized. Capillary electrophoresis with charged cyclodextrins is also used to determine the enantiomeric forms. Conclusion: Various analytical methods for determining VEN and its metabolite in different matrices have been discussed thoroughly in the present review.

Adolescent exposures to traditional and novel psychoactive drugs, reported to National Poison Data System (NPDS), 2007–2017

BackgroundSurvey data on adolescent drug use trends have limitations evaluating the impact of drug use on health and may lag current trends. The objective was to describe National Poison Data System (NPDS) trends, medical outcomes, and healthcare encounters from adolescent exposures of traditional and novel psychoactive drugs. MethodsRetrospective review of adolescent (10–18 years of age) exposure calls to all U.S. poison centers, from January 1, 2007 through December 31, 2017, using generic codes for traditional and novel psychoactive drugs. Descriptive statistics and univariate Poisson regression modeling were used for analysis. ResultsThere were 49,757 exposure calls for the included psychoactive drugs. The median age was 16 years (IQR 15,17), 64% were male, and the majority were evaluated in a healthcare facility (92%). Marijuana had the most exposure calls (36.6%), followed by synthetic cannabinoids (e.g., spice; 21.3%). There were 181 (<1%) deaths; the highest fatality rates were from fentanyl, 2C drugs (phenylethylamine derivatives), and heroin. LSD exposure calls have had the most significant increase over the past 10 years. ConclusionU.S. Poison Centers reported almost 50,000 exposure calls and 181 deaths over 10 years for adolescent exposures of both traditional and novel psychoactive drugs, demonstrating the significant health impact on this vulnerable population. Opioids and 2C drugs contributed to the highest mortality rates, moderate/major symptoms and healthcare utilization, and LSD had the most significant increase in calls. Multi-source surveillance methodology is critical in understanding the public health impact on drug abuse in the adolescent population.

Propylphosphonic anhydride (T3P®) mediated synthesis of 3-oxoisoindoline-1-carboxamides from 2-formylbenzoic acid, amines, and isocyanides. Preparation of isoindolinone alkaloids

Propylphosphonic anhydride (T3P®) was successfully applied to the synthesis of an isoindolinone library by the utilization of an Ugi four-center, three-component reaction (Ugi-4C-3CR). The use of T3P® significantly shortened the required reaction time and the corresponding products were obtained in good to high yields. Moreover, a side-reaction was observed when phenylethylamine derivatives and tryptamine were used as the amine component. The latter reaction was applied to the microwave-assisted, one-pot synthesis of the isoquinoline alkaloid (±)-nuevamine. Surprisingly, the traditional Ugi four-component reaction (Ugi-4CR) was unsuccessful in the presence of T3P®. In this case an α-amino amide was produced excluding the carboxylic acid from the multicomponent reaction.

Visible Light-Mediated Decarboxylation Rearrangement Cascade of ω-Aryl- N-(acyloxy)phthalimides.

A Smiles-type radical rearrangement induced by visible-light-mediated decarboxylation of ω-aryl- N-(acyloxy)phthalimides was developed, giving rise to pharmacologically important substance classes: phenylethylamine derivatives, dihydroisoquinolinones, and benzoazepinones were synthesized on the basis of readily available benzoic acids or benzaldehydes and β- or γ-amino acids. This methodology facilitates the synthesis of enantiopure D-amphetamine and of precursors of capsazepinoid bronchodilators.

Acute Pharmacological Effects of 2C-B in Humans: An Observational Study.

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenylethylamine derivative, structurally similar to mescaline. It is a serotonin 5-hydroxytryptamine-2A (5-HT2A), 5-hydroxytryptamine-2B (5-HT2B), and 5-hydroxytryptamine-2C (5-HT2C) receptor partial agonist used recreationally as a new psychoactive substance. It has been reported that 2C-B induces mild psychedelic effects, although its acute pharmacological effects and pharmacokinetics have not yet been fully studied in humans. An observational study was conducted to assess the acute subjective and physiological effects, as well as pharmacokinetics of 2C-B. Sixteen healthy, experienced drug users self-administered an oral dose of 2C-B (10, 15, or 20 mg). Vital signs (blood pressure and heart rate) were measured at baseline 1, 2, 3, 4, and 6 hours (h). Each participant completed subjective effects using three rating scales: the visual analog scale (VAS), the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2–3 and 6 h after self-administration (maximum effects along 6 h), and the Hallucinogenic Rating Scale (maximum effects along 6 h). Oral fluid (saliva) was collected to assess 2C-B and cortisol concentrations during 24 h. Acute administration of 2C-B increased blood pressure and heart rate. Scores of scales related to euphoria increased (high, liking, and stimulated), and changes in perceptions (distances, colors, shapes, and lights) and different body feelings/surrounding were produced. Mild hallucinating effects were described in five subjects. Maximum concentrations of 2C-B and cortisol were reached at 1 and 3 h after self-administration, respectively. Oral 2C-B at recreational doses induces a constellation of psychedelic/psychostimulant-like effects similar to those associated with serotonin-acting drugs.

Total Synthesis and Stereochemical Assignment of Delavatine A: Rh-Catalyzed Asymmetric Hydrogenation of Indene-Type Tetrasubstituted Olefins and Kinetic Resolution through Pd-Catalyzed Triflamide-Directed C–H Olefination

Delavatine A (1) is a structurally unusual isoquinoline alkaloid isolated from Incarvillea delavayi. The first and gram-scale total synthesis of 1 was accomplished in 13 steps (the longest linear sequence) from commercially available starting materials. We exploited an isoquinoline construction strategy and developed two reactions, namely Rh-catalyzed asymmetric hydrogenation of indene-type tetrasubstituted olefins and kinetic resolution of β-alkyl phenylethylamine derivatives through Pd-catalyzed triflamide-directed C-H olefination. The substrate scope of the first reaction covered unfunctionalized olefins and those containing polar functionalities such as sulfonamides. The kinetic resolution provided a collection of enantioenriched indane- and tetralin-based triflamides, including those bearing quaternary chiral centers. The selectivity factor (s) exceeded 100 for a number of substrates. These reactions enabled two different yet related approaches to a key intermediate 28 in excellent enantiopurity. In the synthesis, the triflamide served as not only an effective directing group for C-H bond activation but also a versatile functional group for further elaborations. The relative and absolute configurations of delavatine A were unambiguously assigned by the syntheses of the natural product and its three stereoisomers. Their cytotoxicity against a series of cancer cell lines was evaluated.

Risk assessment of synephrine in dietary supplements

Synephrine is asympathomimetic phenylethylamine derivative that occurs naturally in citrus fruits. It is often added to dietary supplements intended for weight loss and enhancement of sports performance, typically in the form of Citrus aurantium extracts and in many cases in combination with caffeine. The health risks of synephrine were evaluated on the basis of the available toxicological data and in accordance to the EFSA guidance on the safety assessment of botanicals and botanical preparations intended for use in food supplements. In animal studies, orally applied synephrine induced adrenergic effects on the cardiovascular system (increase of blood pressure, ventricular arrhythmias), which were enhanced by the concomitant application of caffeine as well as physical activity. Some human intervention studies investigating the acute effects of synephrine on blood pressure and heart rate of healthy, normotensive test persons indicate that synephrine can induce cardiovascular effects in humans. Aseries of published case reports of adverse cardiovascular effects (hypertension, cardiac arrhythmia, myocardial infarction) were associated with consumption of synephrine- and caffeine-containing dietary supplements. In conclusion, consumption of high amounts of synephrine, especially in combination with caffeine and physical exercise, is associated with an increased risk of adverse effects on the cardiovascular system. According to the assessment by the BfR (Bundesinstitut für Risikobewertung), daily intake of synephrine through dietary supplements should not exceed the median intake from conventional foods.

Palladium(ii)-catalyzed ortho-C–H olefination of phenylalanine and phenylethylamine derivatives directed by removable picolinamide group

Palladium-catalyzed ortho-C–H olefination of phenylalanine and phenylethylamine derivatives assisted by a removable picolinamide group has been achieved.

Bidentate Lewis Acid Catalyzed Domino Diels-Alder Reaction of Phthalazine for the Synthesis of Bridged Oligocyclic Tetrahydronaphthalenes.

A domino process consisting of an inverse and a normal electron-demand Diels-Alder reaction is presented for the formation of bridged tri- and tetracyclic 1,2,3,4-tetrahydronaphthalenes catalyzed by a bidentate Lewis acid. The products were synthesized in a one-pot reaction from commercially available starting materials and contain up to six stereogenic centers. The tetrahydronaphthalenes were isolated as single diastereomers and are derivatives of phenylethylamine, which is well-known as a scaffold of amphetamine or dopamine.