Isolation and biomimetic synthesis of phenylpropionyl phenylethylamines from Chloranthus henryi.

In this study, ten phenylpropionyl phenylethylamines, including five previously undescribed ones (1a/b, 2a/b, and 3), five known analogues (4-8), and two established phenylpropanoids precursors (9, 10) were isolated from the aerial parts of Chloranthus henryi Hemsl. Their structures, including absolute configurations, were determined by high-resolution mass spectrometry, enantio-separation, electronic circular dichroism calculation, and single crystal diffraction. Compounds 1a and 1b were the first examples of natural hetero-[2 + 2] cycloaddition products between phenylpropionyl phenylethylamine and phenylpropene. The plausible hetero-[2 + 2] biosynthesis pathway was confirmed by a photocatalytic biomimetic synthesis in eight steps, which also led to the production of three other potential natural homo-[2 + 2] adducts (1'a/b, 2', and 3'). Bioactivity screening indicated that these adducts bear medium inhibitory activity on nitric oxide generation, with IC50 values of 6-35 µM in RAW 264.7 macrophages.

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.

New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary.

New developments in the synthesis, resolution, and synthetic applications of chiral 1-phenylethylamine (α-PEA) reported in the last decade have been reviewed. In particular, improvements in the synthesis of α-PEA and its derivatives and chiral resolution, as well as their applications in the resolution of other compounds, were discussed. α-PEA was used as a chiral auxiliary in the diastereoselective synthesis of medicinal substances and natural products. Chiral ligands with α-PEA moieties were applied in asymmetric reactions, and effective modular chiral organocatalysts were constructed with α-PEA fragments and used in important synthetic reactions.

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

2,5-Dimethoxy-4-ethylphenethylamine (2C-E) is psychedelic phenylethylamine, with a chemical structure similar to mescaline, used as new psychoactive substance (NPS). It inhibits norepinephrine and serotonin uptake and, more relevant, acts as a partial agonist of the serotonin 2A (5-HT2 A), 2B (5-HT2 B), and (5-HT2 C) receptors. Consumers have reported that 2C-E induces mild-moderate psychedelic effects, but its pharmacology in humans, including pharmacological effects and pharmacokinetics, have not yet studied. To assess the acute effects of 2C-E on physiological and subjective effects and evaluate its pharmacokinetics, an observational study was carried-out. Ten recreational users of psychedelics self-administered a single oral dose of 2C-E (6.5, 8, 10, 15, or 25 mg). Blood pressure and heart rate were evaluated at baseline, 2, 4, and 6 h post-administration. Three rating scales were administered to evaluate subjective effects: a set of Visual Analog Scales (VAS), the 49-item short form version of the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2, 4, and 6 h after self-administration. To assess 2C-E concentrations oral fluid (saliva) was collected during 6 h. 2C-E induced primarily alterations in perceptions, hallucinations, and euphoric-mood. Saliva maximal concentrations were achieved 2 h after self-administration. Administration of oral 2C-E at recreational doses produces a group of psychedelic-like effects such to 2C-B and other serotonin-acting drugs.

ß-Phenylethylamine and various monomethylated and para-halogenated analogs. Acute toxicity studies in mice.

Phenylethylamine's acute toxic effects in a population of adult (10 to 12 weeks old; ∼30 g) Swiss male albino mice are significantly increased by para-position aromatic ring halogenation. LDLO, LD50, and LD100 values (mg/kg; x ± SEM) for p-F- (116.7 ± 3.3, 136.7 ± 1.7, and 160.0 ± 2.9), p-Br- (126.7 ± 3.3, 145.0 ± 2.9, and 163.3 ± 3.3), p-Cl- (133.3 ± 3.3, 146.7 ± 1.7, and 165.0 ± 2.9), and p-I-PEA (133.3 ± 3.3, 153.3 ± 1.7, and 168.3 ± 1.7), compared to PEA 203.3 ± 3.3, 226.7 ± 4.4, and 258.3 ± 8.8). Like PEA, the difference between LDLO and LD50, and LD50 and LD100 for individual amines were similar and in the range (10 to 20%). Toxicity variation between the various p-halogenatedPEAs also fell within a relatively narrow range (as a group: LDLO 116.7 ± 3.3 to 133.3 ± 3.3, LD50 136.7 ± 1.7 to 153.3 ± 1.7, and LD100 160.0 ± 2.9 to 168.3 ± 1.7 mg/kg). PEA methylation, (exception of its α-methyl derivative), results in relatively modest changes in acute toxicity. LDLO, LD50, and LD100 values (mg/kg; x ± SEM) for N-Me- (176.6 ± 3.3, 200.0 ± 2.9, and 221.7 ± 3.3), p-Me- (183.3 ± 3.3, 206.7 ± 3.3, and 225.0 ± 2.9), o-Me- (210.0 ± 5.8, 233.3 ± 3.3, and 258.3 ± 1.7), and ß-MePEA (220.0 ± 5.8, 243.3 ± 4.4, and 278.3 ± 44). Similar to PEA, and the p-HPEAs, the difference between LDLO and LD50 and LD50 and LD100 values for individual amines fell within a relatively narrow range (10 to 20%). Variation in toxicity among the methylatedPEAs also fell within a limited range (as a group: LDLO 176 ± 3.3 to 220 ± 5.8, LD50 200.0 ± 2.9 to 243.3 ± 4.4 and LD100 221.7 ± 3.3 to 278.3 ± 4.4 mg/kg). With the exception of PEA's methyl derivative (amphetamine) all the amines studied are rapidly metabolized by monoamine oxidase. This pharmacokinetics difference would help to explain the markedly higher amphetamine toxicity [(LDLO, LD50 and LD100 (mg/kg; x ± SEM) of 21.3 ± 0.9, 25.0 ± 0.6, and 29.3 ± 0.7, respectively)].

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.

Death after 25C-NBOMe and 25H-NBOMe consumption.

A teenager male was found dead in a waterway after he was spotted jumping off into the water stream. The boy looked agitated and confused after a party with friends. At the gathering place, investigators seized packages of blotter papers. A complete autopsy and a histological evaluation of the main tissues were performed; although the death occurred by drowning, the prosecutor requested toxicological exams, in order to evaluate the potential role of drugs of abuse in the episode. Blood (both peripheral and central) and urine samples as well as seized blotter papers were collected and analyzed as follows. The blotter paper, analyzed through a GC-MS method, revealed the presence of 25-NBOMes. A liquid chromatography tandem mass spectrometric (LC-MS/MS) system was used to identify and quantify 5 different 25-NBOMes (namely 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25H-NBOMe, 25I-NBOMe) in blood and urine. 25E-NBOMe was used as internal standard (IS). 1mL of urine and 1mL of blood (both peripheral and cardiac) were diluted in 2mL phosphate buffer at pH 6.0, containing IS and purified on a solid phase extraction (SPE) cartridge. LOD and LOQ for the five 25-NBOMes were calculated at 0.05 and 0.1ng/mL respectively. Linearity, accuracy, precision, ion suppression, carry over and recovery were tested and all parameters fulfilled the acceptance criteria. Blood and urine provided positive results for 25C-NBOMe and 25H-NBOMe. Eventually, the seized blotter papers were analyzed by means of LC-MS/MS and the presence of the two NBOMes was confirmed: 25C-NBOMe and 25H-NBOMe were measured at the concentration of 2.80 and 0.29ng/mL in peripheral blood, of 1.43 and 0.13ng/mL in central blood and of 0.94 and 0.14ng/mL in urine, respectively. THC and THCCOOH were also detected in biological fluids, at the concentration of 15.5 and 56.0ng/mL in peripheral blood, 9.9 and 8.5ng/mL in central blood, respectively. NBOMes can produce severe hallucination even at very low doses, and the 25C-NBOMe levels measured in the subject's blood are considered potentially toxic.

4-bromo-2, 5-dimetoxifeniletilamina (2CB) un riesgo en nuestro medio: serie de casos / The risk of 2, 5-dimethoxy-4-bromophenylethylamine (2C-B): Case series / 4-bromo-2, 5-dimetoxifeniletilamina (2CB) um risco em nosso meio: série de casos

En Medellín, la prevalencia de consumo de drogas en el último año es del 3.6% y es el grupo de edad más predominante entre los 19 y 29 años. Sin embargo, hay un subregistro relevante sobre el consumo de las nuevas drogas que son vendidas como alternativas legales a las drogas clásicas de abuso. El objetivo de este reporte es mostrar tres casos que muestran las complicaciones cardiovasculares, neurológicas y musculares asociadas con 4-bromo-2,5-dimetoxifeniletilamina (2CB), sustancia conocida en Colombia desde 2007. El consumo de 2CB está en aumento y es prioritario que los profesionales de la salud reconozcan sus riesgos.

The prevalence of drug consumption in Medellin over the last year was 3.6%, where the principal age group was between 19 and 29 years. The phenomenon of the consumption of new drugs being sold as legal alternatives to the classic drugs of abuse has been greatly underreported. The objective of this report is to show three cases with muscular, neurological, and cardiovascular complications associated with 2,5-dimethoxy-4-bromophenylethylamine (2C-B), a substance known in Colombia since 2007. The consumption of 2C-B is on the rise and must become a priority for health professionals due to the risks involved.

Em Medellín, a prevalência de consumo de drogas no último ano é de 3.6% e é o grupo de idade mais predominante entre os 19 e 29 anos. Porém, há um sub-registro relevante sobre o consumo das novas drogas que sao vendidas como alternativas legais às drogas clássicas de abuso. O objetivo deste relatório é mostrar três casos que mostram as complicações cardiovasculares, neurológicas e musculares associadas com 4-bromo-2,5-dimetoxifeniletilamina (2CB), substância conhecida na Colômbia desde 2007. O consumo de 2CB está em aumento e é prioritário que os profissionais da saúde reconheçam seus riscos.

Case series: toxicity from 25B-NBOMe--a cluster of N-bomb cases.

Background A new class of hallucinogens called NBOMes has emerged. This class includes analogues 25I-NBOMe, 25C-NBOMe and 25B-NBOMe. Case reports and judicial seizures indicate that 25I-NBOMe and 25C-NBOMe are more prevalently abused. There have been a few confirmed reports of 25B-NBOMe use or toxicity. Report Observational case series. This report describes a series of 10 patients who suffered adverse effects from 25B-NBOMe. Hallucinations and violent agitation predominate along with serotonergic/stimulant signs such as mydriasis, tachycardia, hypertension and hyperthermia. The majority (7/10) required sedation with benzodiazepines. Analytical method 25B-NBOMe concentrations in plasma and urine were quantified in all patients using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Peak plasma levels were measured between 0.7-10.1 ng/ml. Discussion The NBOMes are desired by users because of their hallucinogenic and stimulant effects. They are often sold as LSD or synthetic LSD. Reported cases of 25B- NBOMe toxicity are reviewed and compared to our series. Seizures and one pharmacological death have been described but neither were observed in our series. Based on our experience with cases of mild to moderate toxicity, we suggest that management should be supportive and focused on preventing further (self) harm. High doses of benzodiazepines may be required to control agitation. Patients who develop significant hyperthermia need to be actively managed. Conclusions Effects from 25B-NBOMe in our series were similar to previous individual case reports. The clinical features were also similar to effects from other analogues in the class (25I-NBOMe, 25C-NBOMe). Violent agitation frequently present along with signs of serotonergic stimulation. Hyperthermia, rhabdomyolysis and kidney injury were also observed.

Fast separation of selected cathinones and phenylethylamines by supercritical fluid chromatography.

The chromatographic behaviour of eleven synthetic cathinones and four phenylethylamines under supercritical/subcritical fluid conditions was investigated. Four stationary phases with sub-2µm particles (Waters Acquity UPC(2) BEH silica, BEH 2-ethylpyridine, CSH Fluoro-Phenyl, and HSS C18SB) were evaluated in terms of isomer resolution, chromatographic peak shape, and analysis time. Methanol, water, formic acid, ammonium hydroxide, ammonium acetate, and ammonium formate were mixed with carbon dioxide to test their influence on analyte retention and peak shapes. Methanol and ammonium cations were essential for successful separations. Efficient separations of four isomeric pairs (R>1), and most of the remaining analytes, were achieved in less than 3.3min on BEH and Fluoro-Phenyl columns with gradient of methanolic ammonium hydroxide in CO2. Drugs were detected by positive electrospray ionization-triple quadrupole mass spectrometry in selected reaction monitoring mode. Added detection specificity and faster separation of isomers on the BEH column using a steep gradient and high flow rate reduced analysis time of the mixture of 15 drugs to 1.6min.

"Not for human consumption": a review of emerging designer drugs.

Synthetic, or "designer" drugs, are created by manipulating the chemical structures of other psychoactive drugs so that the resulting product is structurally similar but not identical to illegal psychoactive drugs. Originally developed in the 1960s as a way to evade existing drug laws, the use of designer drugs has increased dramatically over the past few years. These drugs are deceptively packaged as "research chemicals," "incense," "bath salts," or "plant food," among other names, with labels that may contain warnings such as "not for human consumption" or "not for sale to minors." The clinical effects of most new designer drugs can be described as either hallucinogenic, stimulant, or opioid-like. They may also have a combination of these effects due to designer side-chain substitutions. The easy accessibility and rapid emergence of new designer drugs have created challenges for health care providers when treating patients presenting with acute toxicity from these substances, many of which can produce significant and/or life-threatening adverse effects. Moreover, the health care provider has no way to verify the contents and/or potency of the agent ingested because it can vary between packages and distributors. Therefore, a thorough knowledge of the available designer drugs, common signs and symptoms of toxicity associated with these agents, and potential effective treatment modalities are essential to appropriately manage these patients.

Phenylethylamines from Browningia candelaris (Cactaceae) / Feniletilaminas de Browningia candelaris (Cactaceae)

The analysis by gas chromatography coupled with mass spectrometry (GC-MS) of the alkaloidal extract of Browningia candelaris (Cactaceae) showed the presence of N-acetyl-3,4-dimethoxyphenylethylamine; N,N-dimethyl-3,4-dimethoxyphenylethylamine; N,N-dimethyl-4-methoxyphenylethylamine; and 4-methoxyamphetamine. The presence of these psychoactive compounds is discussed in terms of their possible ritual use in Andean cultures of Northern Chile.

El análisis por medio de cromatografía de gases acoplada a espectrometría de masas (CG-EM) del extracto alcaloidal de Browningia candelaris (Cactaceae) mostró la presencia de N-acetil-3,4-dimetoxifeniletilamina; N,N-dimetil-3,4-dimetoxifeniletilamina; N,N-dimetil-4-metoxifeniletilamina y 4-metoxianfetamina. La presencia de estos compuestos psicoactivos se discute en términos de su posible utilización en ceremonias mágico-religiosas por culturas andinas del norte de Chile.