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We report a scalable hydrogenation method for nitriles based on cost-effective materials in a very simple two-electrode setup under galvanostatic conditions. All components are commercially and readily available. The method is very easy to conduct and applicable to a variety of nitrile substrates, leading exclusively to primary amine products in yields of up to 89% using an easy work-up protocol. Importantly, this method is readily transferable from the milligram scale in batch-type screening cells to the multi-gram scale in a flow-type electrolyser. The transfer to flow electrolysis enabled us to achieve a notable 20 g day−1 productivity of phenylethylamine at a geometric current density of 50 mA cm−2 in a flow-type electrolyser with 48 cm2 electrodes. It is noteworthy that this method is sustainable in terms of process safety and reusability of components. [ABSTRACT FROM AUTHOR]

This brief review highlights some of the structure–activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines and certain tryptamines, which possess psychedelic activity in humans. Where they are known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of psychedelic molecules. With a focus on the 5‐HT2A receptor subtype, a G‐protein coupled receptor known to be the primary target of psychedelics, we refer to several X‐ray and cryoEM structures, with a variety of ligands bound, to illustrate the underlying atomistic basis for some of the known pharmacological observations of psychedelic drug actions. [ABSTRACT FROM AUTHOR]

The first total synthesis of phenethylamine alkaloid based natural products discolin A, B, E and bacillimidazole B is reported, which were isolated from marine sea bacteria Tenacibaculum discolor sv11 and marine sponge. Total syntheses of discolin A, B, E and bacillimidazole B are achieved in two linear steps including condensation reaction and N-alkylation reaction with an overall yield of 68%, 35%, 65%, and 32%, respectively. A total of 24 analogues are prepared with moderate to excellent yield. All the natural products and their analogues were screened for antibacterial activity. The most active compound showed an IC50 of 122.1 nM against P. aeruginosa. [ABSTRACT FROM AUTHOR]

The poor stability, high noise, and low detectivity (D*) of perovskite mesh nanowire (PMN) photodetectors (PDs) seriously hinder their practical applications. Here, a phenylethylamine iodine doping strategy (PIDS) is introduced to solve these problems. The PIDS leads to the formation of 2D perovskite PEA2MAx‐1PbxI3x+1 (PEA = phenylethylamine, MA = methylamine) within MAPbI3 PMN, which not only prevents water and oxygen erosion to thwart PMN degradation but also inhibits the transport of dark state carriers to reduce dark current. As a result, the noise, D*, and stability of the PMN PD are simultaneously improved. The device exhibits low noise current (7.61 × 10−15 A Hz−1/2) and high D* of 3.2 × 1014 Jones, the highest D* value for PMN PDs reported to date. Moreover, the unpacked device sustains 100% of its initial performance after 2880 h of storage in the air (45–55% humidity), enabling it as the most stable MAPbI3 perovskite micro/nanostructure PD reported to date. Furthermore, the flexible device with PIDS exhibits comparable performance to that of the rigid device as well as great mechanical stability. Finally, the flexible device with PIDS demonstrates excellent optical imaging capability and a higher precision optical imaging potential than the commercial silicon photodiode S2386. [ABSTRACT FROM AUTHOR]

Sodium borohydride induces the oxidative expansion of the imine derived from isatin and phenylethylamine to form 3-phenethylquinazoline-2,4(1H,3H)-dione. It has been proposed that this transformation occurs by in situ formation of hydroperoxyl anions by a reaction between sodium borohydride and atmospheric oxygen. To contribute to understanding this oxidative expansion, the reaction between the imine derived from isatin and phenylethylamine with hydrogen peroxide was studied in this work. From this reaction, 3-phenethylquinazoline-2,4(1H,3H)-dione was isolated and two by-products were identified: N-phenethyl-2-(3-phenethyl-ureido)-benzamide and methyl(2-(phenethylcarbamoyl)phenyl)carbamate. This article analyses the structure of these by-products and proposes a mechanism that explains the reaction. It was established that the reaction of the imine derived from isatin and phenylethylamine with hydrogen peroxide produces a mixture of three compounds: 3-phenethylquinazoline-2,4(1H,3H)-dione, N-phenethyl-2-(3-phenethyl-ureido)-benzamide and methyl(2-(phenethylcarbamoyl)phenyl)carbamate. A reaction mechanism is proposed that explains this behaviour [ABSTRACT FROM AUTHOR]

β‐Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N‐pyridinium aziridines as latent dual electrophiles for the synthesis of β‐phenethylamines. Bromide‐promoted ring opening generates β‐halopyridinium amines. Selective Ni‐catalyzed C−C cross‐coupling between organozinc nucleophiles and the benzylic C−Br electrophile affords a diverse family of β‐functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni‐catalyzed reductive N−N bond activation within the β‐functionalized phenethylaminopyridinium salts furnishes the products of formal olefin carboamination. Other reductive N−N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N‐centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of β‐phenethylamines and significantly expand the utility of N‐pyridinium aziridines as linchpins in chemical synthesis. [ABSTRACT FROM AUTHOR]

High-quality perovskite films (PFs) are crucial for achieving high-performance perovskite solar cells (PSCs). Herein, we report a dual-modification strategy via incorporating CsPbBr3 QDs into MAPbI3 perovskite bulk and capping the interface of the perovskite/hole transport layer (HTL) with phenylethylamine iodide (PEAI) to improve perovskite crystallinity and interface contact properties to acquire high-quality PFs with fewer defects. CsPbBr3 QDs promoted perovskite grain growth and reduced bulk defects, while PEAI surface modification passivated interfaces, improved hydrophobic properties, and prevented carrier recombination at the perovskite/HTL interface. Benefiting from growth control and the effective suppression of both bulk and interface carrier recombination, the resulting devices show a greatly improved photoelectric conversion efficiency (PCE) from 17.21% of the reference cells to 21.04% with a champion Voc of 1.15 V, Jsc of 23.30 mA/cm2, and fill factor (FF) of 78.6%. Furthermore, the dual-modification strategy endows PFs with promoted moisture tolerance, and the nonencapsulated PSCs retain 75% of their initial efficiency after aging for 30 days at 40% relative humidity and room temperature, which is significantly higher than the 59% value of the original PSCs. Good operational stability and the maintained efficiency of the target device over time suggest the potential for future commercialization. [ABSTRACT FROM AUTHOR]

Ferrocene derivatives show a wide range of pharmacological activities in the medical field, especially in the anti‐tumor field, and can be used as candidate drugs or lead compounds for the treatment of tumors and other diseases. And α‐phenethylamine is an important intermediate for the preparation of fine chemical products. (R)‐(+)‐1‐Phenethylamine ferrocenecarboxylic acid/(S)‐(−)‐1‐phenethylamine ferrocenecarboxylic acid were prepared, named compounds 1 and 2, respectively. Single crystal X‐ray diffraction showed that compounds 1 and 2 crystallized in the orthorhombic system space group P212121, and the crystal structures of compounds 1 and 2 exhibited mirror symmetry. The inhibitory effect of two compounds on SW480, MDA‐MB‐231, and H1299 cells was tested by MTT colorimetry. The IC50 values of the compounds against cancer cells were also calculated. The anti‐cancer effect was more pronounced for compounds in the S‐configuration. Compound 2 made the wild‐type cancer cells undergo apoptosis, thus preventing cancer; it also had the function of helping the cell gene repair defects. [ABSTRACT FROM AUTHOR]

The identification of new psychoactive substances (compounds that mimic the effects of outlawed substances) poses a significant challenge due to their rapid emergence and continuous modifications. This phenomenon results in these molecules escaping legal regulation, allowing them to circumvent legislation. The phenethylamine class has garnered attention because its molecules replicate the effects of LSD and are associated with numerous cases of intoxication. In this study, we focused on three phenethylamines—2C-H, 25H-NBOH, and 25I-NBOMe—with crystallographic structures available in the Cambridge Crystallographic Data Center (CCDC) database. We conducted a systematic conformational analysis and compared the structural information obtained. Subsequently, we compared the spectra derived from this analysis with experimental details from the ENFSI database. Structural comparisons were made based on the RMSDs between the lower energy conformations and experimental crystallographic structures. Additionally, structures obtained from direct optimization were compared. We then simulated the spectra based on the X-ray structures and compared them with those in the experimental database. Interpretation was carried out using heat maps and PCA in Pirouette software. Combining in silico methods with experimental approaches provides a more comprehensive understanding of the characterization process of new psychoactive substances (NPSs). [ABSTRACT FROM AUTHOR]

The BF3⋅OEt2‐catalyzed reaction of azulene with N‐protected aziridines represents a general, efficient (up to 91% yield) and regioselective approach to phenethylamine‐azulene conjugates. Stereochemical studies and DFT calculations lend support to a concerted SN2‐type mechanism governing the ring‐opening of the aziridine. [ABSTRACT FROM AUTHOR]

The science of psychedelics is an intriguing, multi-disciplinary field that has recently been the subject of heightened public interest. This has mainly resulted from publicity associated with a number of high-profile investigations into psychedelic-assisted therapy for a range of difficult-totreat mental health conditions. With many psychedelic substances known, including natural, semisynthetic and fully synthetic, and a rangeof receptors, enzymes and transporters implicated in their modes of action, although very interesting, the field can appear daunting to newcomers to the area. This Primer Review is designed to give an overview of the chemistry and pharmacology of psychedelics. It is hoped that it will provide a useful resource for science undergraduates, postgraduates and their instructors, and experienced scientists who require a comprehensive and up-to-date summary of the field. The Review begins with a summary of the important classes of psychedelics and then goes on to summarise the known history of their traditional human use, dating back to prehistoric times. Following that, important classes of psychedelics are examined in more detail, namely the ergolines, such as lysergic acid diethylamide (LSD), tryptamines like psilocybin and N,N-dimethyltryptamine, phenethylamines typified by mescaline and 3,4- methylenedioxymethamphetamine (MDMA), arylcyclohexylamines including ketamine and phenylcyclohexylpiperidine (PCP), and a group of naturally occurring drugs that do not belong to any of these three classes, examples being muscimol and salvinorin A. The contributions made by early pioneers like Albert Hofmann and Alexander Shulgin are briefly summarised. References to primary literature and more specialised reviews are provided throughout. [ABSTRACT FROM AUTHOR]

Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson's disease, and addiction. Synthetic phenethylamines can have psychoactive and hallucinogenic effects due to their high affinity with the 5-HT2A receptor. Evidence indicates phenethylamines can directly alter the microtubule cytoskeleton being structurally similar to the microtubule destabilizing agent colchicine, however little work has been done on this interaction. As microtubules provide neuron structure, intracellular transport, and influence synaptic plasticity the interaction of phenethylamines with microtubules is important for understanding the potential harms, or potential pharmaceutical use of phenethylamines. We investigated 110 phenethylamines and their interaction with microtubules. Here we performed molecular docking of these compounds at the colchicine binding site and ranked them via binding energy. The top 10% of phenethylamines were further screened based on pharmacokinetic and physicochemical properties derived from SwissADME and LightBBB. Based on these properties 25B-NBF, 25C-NBF, and DMBMPP were tested in in vitro microtubule polymerization assays showing that they alter microtubule polymerization dynamics in a dose dependent manner. As these compounds can rapidly cross the blood brain barrier and directly affect cytoskeletal dynamics, they have the potential to modulate cytoskeletal based neural plasticity. Further investigations into these mechanisms are warranted. [ABSTRACT FROM AUTHOR]

The structures of four salt forms of dopamine are reported. These are dopamine [2‐(3,4‐dihydroxyphenyl)ethan‐1‐aminium] benzoate, C8H12NO2+·C7H5O2−, I, dopamine 4‐nitrobenzoate, C8H12NO2+·C7H4NO4−, II, dopamine ethanedisulfonate, 2C8H12NO2+·C2H4O6S22−, III, and dopamine 4‐hydroxybenzenesulfonate monohydrate, C8H12NO2+·C6H5O4S−·H2O, IV. In all four structures, the dopamine cation adopts an extended conformation. Intermolecular interaction motifs that are common in the salt forms of tyramine can be found in related dopamine structures, but hydrogen bonding in the dopamine structures appear to be more variable and less predictable than for tyramine. Packing analysis discovered three dopamine‐containing groups of structures that can be described as isostructural with regards to the cation positions. Two of these groups contain both dopamine and tyramine species, and one of these is also highly variable in other ways too, containing anhydrous and hydrated forms, different anion types and ionized and neutral phenylethylamine species. As such, the group illustrates that packing behaviour can be robust and similar even where intermolecular interactions such as hydrogen bonds are very different. [ABSTRACT FROM AUTHOR]

As a Zn2+ fluorescent probe, we have designed and synthesized a new type of calixarene Schiff-base ligand (L) possessing a 1-phenylethylamine group as the fluorophore and the receptor. As only Zn2+ caused a significant increase in fluorescence emission intensity at 480 nm and the limit of detection (LOD) reached 4.8 x 10-7 M, the synthesized fluorescent probe L demonstrated high selectivity and sensitivity towards Zn2+ compared to other metal ions. In addition, the formation of a 1:1 complex between probe L and Zn2+ was determined. As a consequence, it was determined that probe L can be utilized for the detection and monitoring of Zn2+ in the environment. [ABSTRACT FROM AUTHOR]

With a growing global population and increased environmental concerns around animal agriculture, it is essential to humanely maximize animal performance and reduce environmental emissions. This study aims to determine the efficacy of feeding ractopamine hydrochloride (RAC), an orally active, β 1-adrenergic agonist (β1AA), to feedlot steers in the last 42 d of finishing to reduce ammonia (NH3) emissions and improve animal performance. A randomized complete block design was used to allocate 112 Angus and crossbred Angus steers (initial body weight [BW] = 566.0 ± 10.4 kg) to 8 cattle pen enclosures. Pens (n = 4 per treatment, 14 steers per pen, and 56 steers per treatment) were randomly assigned to one of two treatments: 1) CON; finishing ration containing no RAC, 2) RAC; finishing ration containing 27.3 g/907 kg dry matter (DM) basis RAC. Steers were weighed on day -1 and 0 before treatment and day 14, 28, and 42 during treatment. Treatment rations were mixed and delivered daily by masked personnel. Measured emissions included NH3, nitrous oxide (N2O), methane (CH4), hydrogen sulfide (H2S), and carbon dioxide (CO2). The primary response variables assessed were emissions standardized by live weight (LW) and hot carcass weight (HCW). Steers were harvested on day 43 and carcass data were collected on day 43 and 44. Steers fed RAC reduced NH3 emissions by 17.21% from day 0 to 28 (P = 0.032) and tended to reduce NH3 from day 0 to 42 by 11.07% (P = 0.070) vs. CON. When standardized for LW, NH3 was reduced by 23.88% from day 0 to 14 (P = 0.018), 17.80% from day 0 to 28 (P = 0.006), and 12.50% for day 0 to 42 (P = 0.027) in steers fed RAC vs. CON. Steers fed RAC had 14.05% (P = 0.013) lower cumulative NH3 emissions when standardized by HCW vs. CON. Feeding RAC to Steers reduced H2S by 29.49% from day 0 to 14 (P = 0.009) and tended to reduce H2S over day 0 to 28 by 11.14% (P = 0.086) vs. CON. When H2S emissions were standardized for LW, RAC fed steers had a 28.81% reduction from day 0 to 14 (P = 0.008) vs. CON. From day 0 to 42 the RAC fed steers tended to have a 0.24 kg/d greater average daily gain (ADG) (P = 0.066) and tended to eat 4.27% less (P = 0.069) on a DM basis vs. CON. The RAC fed steers had a 19.95% greater gain to feed ratio (G:F) compared to CON (P = 0.012). Steers fed RAC had an average of 12.52 kg greater HCW (P = 0.006) and an increase of 1.93 percentage units in dressing percent (DP) (P = 0.004) vs. CON. Ractopamine is an effective medicated feed additive for reducing NH3 and improving end product performance through HCW yields.

A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.

The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology, and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability, and immature phenotype of the iPSC-CM platform. The rationale for combining translation and classification tasks is because the most likely application of the deep learning technology we describe here is to translate iPSC-CMs following application of a perturbation. The deep learning network was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter.

Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is still poorly understood, despite several reports highlighting cases of acute intoxication, with brain and liver toxicity. Thus, in this study, mescaline, 2C-N (insertion of a nitro in the para position of the 2C phenethylamines aromatic ring) and 2C-B (insertion of a bromide in the para position of the 2C phenethylamines aromatic ring) and their corresponding NBOMe counterparts, mescaline-NBOMe, 25N-NBOMe and 25B-NBOMe, were synthetized and the in vitro neuro- and hepatocytotoxicity evaluated in differentiated SH-SY5Y and HepG2 cell lines, respectively. Cytotoxicity, oxidative stress, metabolic and energetic studies were performed to evaluate the main pathways involved in their toxicity. Our results demonstrated that the presence of the N-2-methoxybenzyl group significantly increased the in vitro cytotoxicity of 2C phenethylamines drugs in both cell lines, with the NBOMe drugs presenting lower EC50 values when compared to their counterparts. Consistently, our data showed a correlation between the drug's lipophilicity and the EC50 values, except for 2C-B. The 2C-B presented higher cytotoxic effects in both cell lines than mescaline-NBOMe, a result that can be explained by its higher passive permeability. All the NBOMe derivatives were able to cross the blood–brain barrier. Considering metabolic studies, the cytotoxicity of these drugs was shown to be influenced by inhibition of cytochrome P450 (CYP), which suggests a potential role of this enzyme complex, especially CYP3A4 and CYP2D6 isoenzymes in SH-SY5Y cells, in their detoxification or bioactivation. Furthermore, in differentiated SH-SY5Y cells, the drugs were able to induce mitochondrial membrane depolarization, and to disrupt GSH and ATP intracellular levels, these effects being concentration dependent and more pronounced for the NBOMe derivatives. No ROS overproduction was detected for any of the drugs in the tested experimental conditions. A correlation between a drug's lipophilicity and the EC50 values in both cell lines, except for 2C-B, was also obtained. In summary, the introduction of a NBOMe moiety to the parent drugs significantly increases their lipophilicity, brain permeability and cytotoxic effects, with GSH and ATP homeostasis disruption. The inhibition of CYP3A4 and CYP2D6 emphasized that CYP-mediated metabolism impacts the toxicity of these drugs. [ABSTRACT FROM AUTHOR]

Knowing the stability of drugs is important to ensure accurate and reliable results of drug concentrations. This study evaluated the stability of ten new psychoactive substances (NPSs) in urine and methanol/water at different storage temperatures. Quantitative analyses were performed using liquid chromatography-tandem mass spectrometry. Three replicates of each storage condition were analyzed at day 0 and after 7, 14-, 30-, 60-, and 90 days with storage at +25°C, +4°C, and −20°C. For each analyte, the percent difference at each time interval from day 0 was calculated for each storage condition. Para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), deschloroketamine (DCK), and 2-fluorodeschloroketamine (2-FDCK) were stable in urine, even when stored for 90-day periods at various temperatures. For synthetic cathinones, the concentrations declined over time at room temperature (+25°C) in urine but were relatively stable in methanol solvent with 0.1% formic acid. The significant degradation was found at +25°C, and the most excellent stability was shown by samples stored at −20°C. Phenethylamines (PMA and PMMA) and ketamine substitutes (DCK and 2-FDCK) were relatively more stable than synthetic cathinones (mephedrone, butylone, pentylone, ephylone, 4-MEAPP, and eutylone). [ABSTRACT FROM AUTHOR]

Background: The prevalence and incidence of Parkinson's disease (PD) is increasing due to a prolonged life expectancy. The cardinal features of PD include resting tremor, rigidity, bradykinesia, and postural instability. In rodents the 2,4,5-trihydroxyphenylethylamine [6-hydroxydopamine (6-OHDA)] induced lesion of the nigrostriatal system showed retrograde degeneration and structural changes in the corpus striatum under transmission the electron microscope (TEM). Aim and Objectives: To study the ultra-structure of normal and 6-OHDA lesioned corpus striatum in Wistar albino rats under the transmission electron microscope. Material and Methods: Wistar albino male adult rats received unilateral stereotaxical injection of 6-OHDA on the right side of striatum and were sacrificed after 120 days. The following stereotaxic co-ordinates were used to target the dorsolateral part of the striatum: AP = 0.2 mm, ML = 3.2 mm, DV = 4.5 mm from the bregma. Another target was the dorsomedial part of striatum: AP = 1.1 mm, ML = 2.4 mm and DV = 3.5 mm. The motor behavior was monitored in cylinder which was counted for a period of 60 min. Results and Conclusion: Our TEM finding in the control rats demonstrated that nucleus was round and comparatively large in proportion to the cell body and lies in the centre of the nerve cell in the striatum. Occasionally one or two dense nucleoli were located eccentrically in the nucleoplasm. Additionally, in the cytoplasm around the nucleus, the conspicuous organelles along with the numerous ribosomes which were mostly free and appear as rosettes or clusters, some of which were attached to the endoplasmic reticulum. Furthermore, few short of granular endoplasmic reticula were seen. Interestingly, the lesioned rats showed neuronal and glial cells damage at the ultra-structural level in striatum under TEM observation. [ABSTRACT FROM AUTHOR]

Multidrug efflux pumps are among the main Pseudomonas aeruginosa antibiotic‐resistance determinants. Besides, efflux pumps are also involved in other relevant activities of bacterial physiology, including the quorum sensing‐mediated regulation of bacterial virulence. Nevertheless, despite the relevance of efflux pumps in bacterial physiology, their interconnection with bacterial metabolism remains obscure. The effect of several metabolites on the expression of P. aeruginosa efflux pumps, and on the virulence and antibiotic resistance of this bacterium, was studied. Phenylethylamine was found to be both inducer and substrate of MexCD‐OprJ, an efflux pump involved in P. aeruginosa antibiotic resistance and in extrusion of precursors of quorum‐sensing signals. Phenylethylamine did not increase antibiotic resistance; however, the production of the toxin pyocyanin, the tissue‐damaging protease LasB and swarming motility were reduced in the presence of this metabolite. This decrease in virulence potential was mediated by a reduction of lasI and pqsABCDE expression, which encode the proteins that synthesise the signalling molecules of two quorum‐sensing regulatory pathways. This work sheds light on the interconnection between virulence and antibiotic‐resistance determinants, mediated by bacterial metabolism, and points to phenylethylamine as an anti‐virulence metabolite to be considered in the study of therapies against P. aeruginosa infections. [ABSTRACT FROM AUTHOR]

A relevant role has been attributed to phenethylamine in depressive disorders. It has been measured in human urine and rat brain in pathological conditions and after drug administration. Furthermore, a clinical correlation has been proposed between urinary elimination and depressive symptoms. Furthermore, its metabolic predecessor, D-phenylalanine, has been used as an antidepressant drug in the treatment of depressive disorders. The use of this amino acid has been realized alone, or in combination with classical antidepressants. In the present study, we tried to characterize its behavioural profile comparing it with imipramine and fluoxetine. Antidepressant drugs have been studied using diverse animal models. We used here the Porsolt test, or Forced Swimming Test (FST), measuring times of climbing, swimming and resting. When a comparison was performed between groups in climbing behaviour, significant differences were observed between imipramine treated group and saline controls (p < 0.05), and imipramine versus fluoxetine and D-phenylalanine (p < 0.01). When swimming was evaluated, clear differences between D-phenylalanine and the other groups were observed (p < 0.001). Additionally, a significant difference was also observed between imipramine and fluoxetine (p < 0.01). When resting was evaluated, high differences between D-phenylalanine versus all other groups were shown (p < 0.001). Observed behavioural profile was according to serotonergic antidepressant drugs effects. It is supported by the fact that swimming behaviours were increased, and a correlative decrease in resting was also present. We conclude that D-phenylalanine showed higher antidepressant potency than other classical antidepressants, at least at the doses used. [ABSTRACT FROM AUTHOR]

5-(2-Aminopropyl)benzofuran (5-APB), also known as "Benzo Fury," is a novel psychoactive substance (NPS) belonging to a new class of synthetic phenethylamines. It acts by disrupting serotonergic circuits as a serotonin–norepinephrine–dopamine reuptake inhibitor and is classified as an entactogen, similar to MDMA and MDA. Despite its popularity among users, recent toxicity events have been associated with the consumption of 5-APB and other benzofurans, highlighting the need for a better understanding of their pharmacodynamics and toxicity. One way to achieve this is by developing the synthesis of 5-APB metabolites as biomarkers of exposure. In this study, we present a six-step synthesis for one of the 5-APB metabolites, 2-(5-(2-aminopropyl)-2-hydroxyphenyl)acetic acid (1), involving methylation, formylation, Aldol-type condensation, reduction, and hydrolysis reactions. The compound was obtained in an overall yield of 11%. [ABSTRACT FROM AUTHOR]

RationaleDrug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery.ObjectiveTo predict the impact of a drug from the drug chemistry on the cardiac rhythm.Methods and resultsIn a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction.ConclusionsWe present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.

The science of psychedelics is an intriguing, multi-disciplinary field that has recently been the subject of heightened public interest. This has mainly resulted from publicity associated with a number of high-profile investigations into psychedelic-assisted therapy for a range of difficult-to-treat mental health conditions. With many psychedelic substances known, including natural, semi-synthetic and fully synthetic, and a rangeof receptors, enzymes and transporters implicated in their modes of action, although very interesting, the field can appear daunting to newcomers to the area. This Primer Review is designed to give an overview of the chemistry and pharmacology of psychedelics. It is hoped that it will provide a useful resource for science undergraduates, postgraduates and their instructors, and experienced scientists who require a comprehensive and up-to-date summary of the field. The Review begins with a summary of the important classes of psychedelics and then goes on to summarise the known history of their traditional human use, dating back to prehistoric times. Following that, important classes of psychedelics are examined in more detail, namely the ergolines, such as lysergic acid diethylamide (LSD), tryptamines like psilocybin and N,N-dimethyltryptamine, phenethylamines typified by mescaline and 3,4-methylenedioxymethamphetamine (MDMA), arylcyclohexylamines including ketamine and phe-nylcyclohexylpiperidine (PCP), and a group of naturally occurring drugs that do not belong to any of these three classes, examples being muscimol and salvinorin A. The contributions made by early pioneers like Albert Hofmann and Alexander Shulgin are briefly summarised. References to primary literature and more specialised reviews are provided throughout. [ABSTRACT FROM AUTHOR]

In this study, new pyridine-based imine compounds (8-10) were synthesized and docking studies of these compounds against D2 Dopamine receptor (6CM4) were performed. The structures of these compounds, which were synthesized using the microwave method, were determined by 1H-NMR, 13C-NMR and elemental analysis techniques. The binding energy values vary range from -6.79 to -7.07 kcal/mol with D2 Dopamine Receptor/PDB: 6MC4. Compound 10 (-7.07 kcal mol-1) showed better binding energy than 9 (-6.95 kcal mol-1) and 8 (-6.79 kcal/mol). [ABSTRACT FROM AUTHOR]

A register‐based cohort study conducted in Sweden found that lisdexamfetamine was the only studied treatment associated with reduced risk of hospitalization and death in patients with amphetamine or methamphetamine use disorder. Use of benzodiazepines was associated with significantly higher risk of hospitalization and death, the investigators reported. Study results were published online Nov. 16, 2022, in JAMA Psychiatry. [ABSTRACT FROM AUTHOR]

This work investigates the effect of passivation on the electronic properties of inorganic perovskite CsPbI3 materials by using first-principles calculations with density functional theory (DFT). The passivation effect after the addition of Phenylethylamine (PEA+) molecule to CsPbI3 (110) surface is studied. The results of density of states (DOS) calculations show that the CsPbI3 (110) surface model with I atom terminated reveals new electronic DOS peaks (surface states) near the Fermi level. These surface states are mainly due to the contribution of I-5p orbital and are harmful to the CsPbI3-based solar cells because they reduce the photoelectric conversion efficiency. The surface states near the Fermi level are significantly reduced, and the decline rate reaches 38.8% with the addition with PEA+ molecule to the CsPbI3 (110) surface. [ABSTRACT FROM AUTHOR]

Introduction: NBOMes and NBOHs are psychoactive drugs derived from phenethylamines and have hallucinogenic effects due to their strong agonism to serotonin 5-HT2A receptors. Although cases of toxicity associated with the recreational use of substituted phenethylamines are frequently reported, there is a lack of information on the possible neurotoxic effects of NBOMe and NBOH in the brain hippocampus, a major neurogenesis region. Objectives: This study aimed at assessing the phenotypic and molecular effects of prolonged exposure of the hippocampus to the drugs 25H-NBOMe and 25H-NBOH. Methods: The ex vivo organotypic culture model of hippocampal slices (OHC) was used to investigate, by immunofluorescence and confocal microscopy, and transcriptome analyses, the mechanisms associated with the neurotoxicity of 25H-NBOMe and 25H-NBOH. Results: Reduction in the density of mature neurons in the OHCs occurred after two and seven days of exposure to 25H-NBOMe and 25H-NBOH, respectively. After the withdrawal of 25H-NBOMe, the density of mature neurons in the OHCs stabilized. In contrast, up to seven days after 25H-NBOH removal from the culture medium, progressive neuron loss was still observed in the OHCs. Interestingly, the exposure to 25H-NBOH induced progenitor cell differentiation, increasing the density of post-mitotic neurons in the OHCs. Corroborating these findings, the functional enrichment analysis of differentially expressed genes in the OHCs exposed to 25H-NBOH revealed the activation of WNT/Beta-catenin pathway components associated with neurogenesis. During and after the exposure to 25H-NBOMe or 25H-NBOH, gene expression patterns related to the activation of synaptic transmission and excitability of neurons were identified. Furthermore, activation of signaling pathways and biological processes related to addiction and oxidative stress and inhibition of the inflammatory response were observed after the period of drug exposure. Conclusion: 25H-NBOMe and 25H-NBOH disrupt the balance between neurogenesis and neuronal death in the hippocampus and, although chemically similar, have distinct neurotoxicity mechanisms.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias.

BackgroundThere is evidence that mGlu2/3 receptors regulate 5-HT2A signaling, interactions that have been theorized to play a role in the antipsychotic-like effects of mGlu2/3 agonists as well as the hallucinogenic effects of 5-HT2A agonists. One approach to unraveling this interaction is through the chronic administration of agonists at the two receptors, which should influence the functional properties of the targeted receptor due to receptor downregulation or desensitization and thereby alter crosstalk between the two receptors. In this study, we investigated whether chronic treatment with the mGlu2/3 agonist LY379268 would alter the behavioral response to a phenethylamine hallucinogen, 25CN-NBOH, which acts as a selective 5-HT2A agonist.MethodsWe first conducted a dose response of 25CN-NBOH (0.1, 0.3, 1, 3, or 10 mg/kg) to confirm the effects on head-twitch response (HTR) and then blockade studies with either the M100907 (0.1 mg/kg) or SB242084 (0.1, 0.3, or 1 mg/kg) to determine the contribution of 5-HT2A and 5-HT2C to 25CN-NBOH-induced HTR, respectively. To determine whether an mGlu2/3 agonist could block 25CN-NBOH-induced HTR, mice were pretreated with vehicle or LY379268 (0.1, 1, or 10 mg/kg) prior to 25CN-NBOH, and HTR was assessed. The effects of chronic LY379268 on 5-HT2A agonist-induced HTR were evaluated by treating mice with either vehicle or LY379268 (10 mg/kg) for 21 days and measuring 25CN-NBOH-induced HTR 48 h after the final LY379268 treatment. The following day (72 h after the final LY379268 treatment), the ability of acute LY379268 to block PCP-induced locomotor activity was assessed.Results25CN-NBOH dose-dependently increased the HTR, a 5-HT2A-mediated behavior, in mice. The selective 5-HT2A antagonist M100907 completely blocked the HTR induced by 25CN-NBOH, whereas the selective 5-HT2C antagonist SB242084 had no effect on the HTR. Administration of LY379268 (10 mg/kg SC) attenuated the HTR induced by 1 mg/kg 25CN-NBOH by ~ 50%. Chronic treatment (21 days) with LY379268 also attenuated the HTR response to 25CN-NBOH when tested 48 h after the last dose of LY379268. In locomotor tests, acute LY379268 significantly attenuated PCP-induced locomotor activity in the chronic vehicle treatment group; by contrast, there was only a trend for an overall interaction in the chronic LY379268 group, with LY379268 blocking the locomotor-stimulating effects of PCP only during the last 20 min.ConclusionsThese data are consistent with a functional interaction between mGlu2/3 and 5-HT2A receptors, although the specific mechanism for the interaction is not known. These data support the hypothesis that mGlu2/3 receptors play a prominent role in modulating the behavioral response to 5-HT2A receptor activation.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias.

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. [ABSTRACT FROM AUTHOR]

Psychedelics are experiencing a strong renaissance and will soon be incorporated into clinical practice. However, there is uncertainty about how much harm they can cause at what doses. This review aimed to collect information on the health-hazardous doses of psychedelic substances, to be aware of the risks to which patients may be subjected. We focused on ergolamines, simple tryptamines, and phenylethylamines. We reviewed articles published in major medical and scientific databases. Studies reporting toxic or lethal doses in humans and animals were included. We followed PRISMA criteria for revisions. We identified 3032 manuscripts for inclusion. Of these, 33 were ultimately useful and gave relevant information about effects associated with high psychedelics doses. Despite having different molecular structures and different mechanisms of action, psychedelics are effective at very low doses, are not addictive, and are harmful at extremely high doses. For LSD and psilocybin, no dose has been established above which the lives of users are endangered. In contrast, MDMA appears to be the most dangerous substance, although reports are biased by recreational missuses. It seems that it is not only the dose that makes the poison. In the case of psychedelics, the set and setting make the poison. [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]

In this study, the analytical characterization of three cathinones and one N‐pyrrolidinyl‐substituted amphetamine derivative is described: 1‐([3,4‐methylenedioxyphenyl])‐2‐(propylamino)butan‐1‐one (N‐propyl norbutylone 1), 1‐([3,4‐methylenedioxyphenyl])‐2‐(butylamino)butan‐1‐one (N‐butyl norbutylone 2), 2‐(benzylamino)‐1‐phenylheptan‐1‐one (N‐benzyl norheptedrone 3), and 1‐(1‐[3,4‐dimethoxyphenyl]propan‐2‐yl)pyrrolidine (N‐pyrrolidinyl‐3,4‐DMA 4). The identification was based on ultra‐high‐performance liquid chromatography–quadrupole time‐of‐flight–mass spectrometry (UHPLC–QTOF–MS), gas chromatography‐orbitrap MS (GC‐Orbitrap‐MS), nuclear magnetic resonance spectroscopy (NMR), and Fourier transform infrared (FT‐IR). GC‐Orbitrap‐MS, with higher mass accuracy, benefit more on the accurate structure elucidation of product ions compared with the low‐resolution GC–MS. The collision‐induced dissociation (CID) and electron ionization (EI) pathways of these compounds were examined to assist forensic laboratories in elucidating the structure of new psychoactive substances (NPS) with similar structure in their case work. In addition, electron activated dissociation (EAD) was applied to analyze N‐benzyl norheptedrone, which showed only one product ion in the CID mode. The result showed that for compound with limited product ions in the CID mode, the EAD mode can give more complementary information for structure elucidation. In addition, quantitative NMR (qNMR) was applied for the quantification of four powdered/crystal and two herbal blend seized samples. To our knowledge, no analytical data about the compounds 3 and 4 have appeared until now, making this the first report on these compounds. [ABSTRACT FROM AUTHOR]

As a key intermediate in natural products and pharmaceutics, N-(R, R)-phenethyl-1-indane was directly prepared by one-pot reductive amination of 1-indanone and R-(+)-α-phenethylamine using abundant molecular hydrogen as a reductant. Compared with the traditional noble metal catalyst, the Co-VB1(1:2)/C-900 catalysts showed higher selectivity in this reaction, and generated the N-(R, R)-phenethyl-1-indane with high yield. The Co-VB1(1:2)/C-900 catalysts were prepared by the modification of thiamine hydrochloride (VB1) as nitrogen and sulfur sources. At the same time, the catalyst was reusable for several times. The synthesis of N-(R, R)-phenethyl-1-indane was cost-effective and atom-economical. The catalyst also presented moderate to good catalytic activities in reductive amination for a series substrate, ranging from aldehydes or ketones, to giving access to various valuable compounds. [ABSTRACT FROM AUTHOR]

The abuse of new psychoactive substances is attracting a lot of attention from the world public. There is an increasing use among young people, who are not aware of the harmful effects of this substances. Some of these substances may have been around for years, but have reemerged in the market in altered chemical forms and launched as legal alternatives to common drugs of abuse. This paper describes application of gas chromatography coupled with mass spectrometry method (GC-MS) to identify 2,5-dimetoxy-4-bromophenethylamine (2C-B) compound in urine sample after solid phase extraxtion and derivatization with N-methyl-bis-trifluoroacetamide (MBTFA). Gas chromatographic separation of TFA derivative of 2C-B (2C-B TFA) was successfully performed using DB-5MS capillary column (5% diphenyl-95% dimethilsiloxane). Selected ion monitoring (SIM) technique was used for quantitative analyses which was performed using matrix matched calibratores, whereby good results were achieved. Urine sample which contained 2C-B was obtained within International Quality Assurance Programme-International Collaborative Exercises (ICE) program organized by the scientific department of United Nations Office on Drugs and Crime (UNODC). The aim of this study was to develop a simple and sensitive method of gas chromatography mass spectrometry (GC-EI-MS) for the identification, extraction and quantitative analysis of 2C-B in the urine sample, which is near the blood remains a priority analyzed matrix in clinical and forensic toxicology.

New bis(N,N-diethylamino)(phenethyl)methylsilane and 1,2-bis(N,N-diethylamino)-1,2-di(phenethyl)-1,2-dimethyldisilane were synthesized by the reaction of diethylamine with (phenethyl)methyldichlorosilane. Structure of the obtained compounds was confirmed by 1Н, 13С, and 29Si NMR spectroscopy data. [ABSTRACT FROM AUTHOR]

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Rationale: Synthetic phenethylamine (PEA) analogs, such as β-methylphenethylamine (BMPEA) and N,α-diethylphenethylamine (DEPEA), are often found in dietary supplements, despite regulations prohibiting their sale. PEA analogs are structurally related to amphetamine, and we have shown that BMPEA and DEPEA produce cardiovascular stimulation mimicking the effects of amphetamine. However, few studies have examined behavioral effects of BMPEA, DEPEA, and other PEA analogs. Objectives: Here, we examined the reinforcing effects of α-ethylphenethylamine (AEPEA, 1 mg/kg/injection), DEPEA (1 mg/kg/injection), and BMPEA (3 mg/kg/injection) as compared to amphetamine (0.1 mg/kg/injection) using a fixed-ratio 1 self-administration paradigm in male rats. Methods: Male rats were trained in self-administration chambers containing 2 nose-poke holes. A nose-poke response in the active hole delivered drug or saline, whereas a nose-poke response in the inactive hole had no programmed consequence. Four groups of rats were initially trained for 10 days with the doses noted above. Upon acquisition of drug self-administration, a dose–effect function was determined by training rats on 3 additional doses for 3 days each. A separate group of rats was trained with saline. Results: Male rats self-administered each PEA analog and amphetamine, as shown by significant increases in active responses versus inactive responses. Subsequent dose–response testing showed clear differences in potency of the compounds. Amphetamine showed a typical inverted U-shaped dose–effect function, peaking at 0.1 mg/kg/injection. AEPEA and DEPEA also showed inverted dose–effect functions, with each peaking at 0.3 mg/kg/injection. BMPEA did not show an inverted U-shaped dose–effect function, but active responding slowly increased up to a dose of 6 mg/kg/injection. Conclusions: Taken together, our findings indicate that dietary supplements containing PEA analogs may have significant abuse liability when used recreationally. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Carbon dots (CDs), as a new type of photoluminescent nanomaterial, have attracted extensive attention in various fields because of their unique luminescence properties. However, CDs will exhibit fluorescence quenching in the solid state or aggregate state, which limits their application. In this paper, a unique strategy is proposed to regulate solutions to achieve multicolour fluorescence of CDs in the solid state. We report the successful preparation of orange, green and blue solid fluorescent CDs using citric acid, urea and phenylethylamine as precursors and methanol, ethanol and water as solvents, respectively. The solid-state fluorescence of CDs may be caused by the linkage of the phenylethyl structure to the surface of CDs during formation, which effectively disperses the CDs and prevents π–π interactions between graphitized nuclei. Meanwhile, multicolour solid fluorescent CDs are realized by adjusting the solvent in the preparation process. Based on the excellent fluorescence properties of CDs, orange, green and blue light-emitting diodes (LEDs) are prepared. A white LED (WLED) can be obtained by mixing the three colours of solid fluorescent CDs, which shows the application potential of CDs in display lighting equipment. [ABSTRACT FROM AUTHOR]

While a few derivatives of cinnamamides exhibited anti-inflammatory and/ or analgesic activity, in this study, we developed a highly efficient method for the synthesis of cinnamamides from methyl cinnamates and phenylethylamines catalyzed by Lipozyme® TL IM in continuous-flow microreactors. The reaction parameters and broad substrate range of the new method was studied. Maximum conversion (91.3%) was obtained under the optimal condition of substrate molar ratio of 1:2 (methyl 4-chlorocinnamate: phenylethylamine) at 45 ° C for about 40 min. The remarkable features of this work include short residence time, mild reaction conditions, easy control of the reaction process, and that the catalyst can be recycled or reused, which provide a rapid and economical strategy for the synthesis and design of cinnamamide derivatives for further research on drug activity. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in SCN1B, the gene encoding voltage-gated sodium channel b1/b1B subunits are associated with a spectrum of epileptic disorders. This study describes a child with early myoclonic encephalopathy and a compound heterozygous variant in the SCN1B gene (p.Arg85Cys and c.3G>C/p.Met1), along with the child's clinical response to anti-seizure medications (ASMs) and the ketogenic diet. We reviewed the current clinical literature pertinent to SCN1B-related epilepsy. Methods: We described the evaluation and management of a patient with SCN1B-related developmental and epileptic encephalopathy (DEE). We used the Medline and Pubmed databases to review the various neurological manifestations associated with SCN1B genetic variants, and summarize the functional studies performed on SCN1B variants. Results: We identified 20 families and six individuals (including the index case described herein) reported to have SCN1B-related epilepsy. Individuals with monoallelic pathogenic variants in SCN1B often present with genetic epilepsy with febrile seizures plus (GEFS+), while those with biallelic pathogenic variants may present with developmental and epileptic encephalopathy (DEE). Individuals with DEE present with seizures of various semiologies (commonly myoclonic seizures) and status epilepticus at early infancy and are treated with various antiseizure medications. In our index case, adjunctive fenfluramine was started at 8 months of age at 0.2 mg/kg/day with gradual incremental increases to the final dose of 0.7 mg/kg/day over 5 weeks. Fenfluramine was effective in the treatment of seizures, resulting in a 50% reduction in myoclonic seizures, status epilepticus, and generalized tonic-clonic seizures, as well as a 70–90% reduction in focal seizures, with no significant adverse effects. Following the initiation of fenfluramine at eight months of age, there was also a 50% reduction in the rate of hospitalizations. Conclusions: SCN1B pathogenic variants cause epilepsy and neurodevelopmental impairment with variable expressivity and incomplete penetrance. The severity of disease is associated with the zygosity of the pathogenic variants. Biallelic variants in SCN1B can result in early myoclonic encephalopathy, and adjunctive treatment with fenfluramine may be an effective treatment for SCN1B-related DEE. Further research on the efficacy and safety of using newer ASMs, such as fenfluramine in patients under the age of 2 years is needed. [ABSTRACT FROM AUTHOR]

The illicit drug market of novel psychoactive substances (NPSs) is expanding, becoming an alarming threat due to increasing intoxication cases and insufficient (if any) knowledge of their effects. Phenethylamine 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) and synthetic cathinone 3,4-methylenedioxy-α-pyrrolidinohexanophenone (3,4-MDPHP) are new, emerging NPSs suggested to be particularly dangerous. This study verified whether these two new drugs (i) possess abuse liability, (ii) alter plasma corticosterone levels, and (iii) interfere with dopaminergic transmission; male and female adolescent rats were included to evaluate potential sex differences in the drug-induced effects. Findings show that the two NPSs are not able to sustain reliable self-administration behavior in rats, with cumulatively earned injections of drugs being not significantly different from cumulatively earned injections of saline in control groups. Yet, at the end of the self-administration training, females (but not males) exhibited higher plasma corticosterone levels after chronic exposure to low levels of 3,4-MDPHP (but not of 2-Cl-4,5-MDMA). Finally, electrophysiological patch-clamp recordings in the rostral ventral tegmental area (rVTA) showed that both drugs are able to increase the firing rate of rVTA dopaminergic neurons in males but not in females, confirming the sex dimorphic effects of these two NPSs. Altogether, this study demonstrates that 3,4-MDPHP and 2-Cl-4,5-MDMA are unlikely to induce dependence in occasional users but can induce other effects at both central and peripheral levels that may significantly differ between males and females. [ABSTRACT FROM AUTHOR]

N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT2A agonists containing substances emerging on the illicit drug market as a replacement for N,N-diethyllysergamide (LSD). Despite the increasing use of NBOMes for diagnostic, research and recreational purposes, only a limited number of studies have focussed on their in vivo effect. Here, we investigated pharmacokinetics, systemic toxicity, thermoregulation in individually and group-housed animals, and acute behavioural effects after subcutaneous administration of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe; 0.2, 1, and 5 mg/kg) in Wistar rats. Drug concentration peaked 1 h after the administration of 5 mg/kg in both blood serum and brain tissue with a half-life of 1.88 and 2.28 h, respectively. According to Organisation for Economic Co-operation and Development 423 toxicity assay, the drug is classified into category 3 with a lethal dose of 300 mg/kg and an estimated LD50 value of 200 mg/kg. Histological examination of organs collected from rats injected with the lethal dose revealed subtle pathological changes, highly suggestive of acute cardiovascular arrest due to malignant arrhythmia. Altered thermoregulation after 5 mg/kg was demonstrated by reduced body temperature in individually housed rats (p < 0.01). Behavioural effects assessed by the Open Field test and Prepulse Inhibition of Startle Response revealed that the two lower doses (0.2 and 1 mg/kg) caused a reduction in locomotor activity (p < 0.01), increased anxiety (p < 0.05) and 5 mg/kg additionally impaired sensorimotor gating (p < 0.001). In summary, 25CN-NBOMe readily passes the blood-brain barrier and exhibits a moderate level of toxicity and behavioural effect comparable with other NBOMes. [ABSTRACT FROM AUTHOR]