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Neuroscience Letters Jun 2024Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the...
Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis.
Topics: Animals; Rats, Wistar; Male; Sepsis; Depression; Rats; Hallucinogens; Phenethylamines; Prefrontal Cortex; Sepsis-Associated Encephalopathy
PubMed: 38821202
DOI: 10.1016/j.neulet.2024.137845 -
Biomedical Chromatography : BMC Feb 2022The misuse of 2-phenylethylamine (PEA) in sporting competitions is prohibited by the World Anti-Doping Agency. As it is endogenously produced, a method is required to...
The misuse of 2-phenylethylamine (PEA) in sporting competitions is prohibited by the World Anti-Doping Agency. As it is endogenously produced, a method is required to differentiate between naturally elevated levels of PEA and the illicit administration of the drug. In 2015, a sulfo-conjugated metabolite [2-(2-hydroxyphenyl)acetamide sulfate (M1)] was identified, and pilot study data suggested that the ratio M1/PEA could be used as a marker indicating the oral application of PEA. Within this project, the required reference material of M1 was synthesized, single and multiple dose elimination studies were conducted and 369 native urine samples of athletes were analyzed as a reference population. While the oral administration of only 100 mg PEA did not affect urinary PEA concentrations, an increase in urinary concentrations of M1 was observed for all volunteers. However, urinary concentrations of both PEA and M1 showed relatively large inter-individual differences and establishing a cut-off-level for M1/PEA proved difficult. Consequently, a second metabolite, phenylacetylglutamine, was considered. Binary logistic regression demonstrated a significant (P < 0.05) correlation of the urinary M1 and phenylacetylglutamine concentrations with an oral administration of PEA, suggesting that assessing both analytes can assist doping control laboratories in identifying PEA misuse.
Topics: Adult; Biomarkers; Chromatography, Liquid; Doping in Sports; Female; Humans; Limit of Detection; Linear Models; Male; Middle Aged; Phenethylamines; Reproducibility of Results; Substance Abuse Detection; Tandem Mass Spectrometry; Young Adult
PubMed: 34729800
DOI: 10.1002/bmc.5274 -
Molecules (Basel, Switzerland) Oct 2021The 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...
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.
Topics: Alkaloids; Chromatography, Liquid; Forensic Toxicology; Gas Chromatography-Mass Spectrometry; Hair; Humans; Illicit Drugs; Limit of Detection; Phenethylamines; Substance Abuse Detection; Tandem Mass Spectrometry
PubMed: 34684725
DOI: 10.3390/molecules26206143 -
Journal of Pharmaceutical and... May 2024The types and quantities of new psychoactive substances synthesized based on structural modifications have increased rapidly in recent years and pose a great challenge...
The types and quantities of new psychoactive substances synthesized based on structural modifications have increased rapidly in recent years and pose a great challenge to clinical and forensic laboratories. N-benzyl derivatives of phenethylamines, 25B-NBOH, 25E-NBOH, 25H-NBOH, and 25iP-NBOMe have begun to flow into the black market and have caused several poisoning cases and even fatal cases. The aim of this study was to avoid false negative results by detecting the parent drug and its metabolites to extend the detection window in biological matrices and provide basic data for the simultaneous determination of illegal drugs and metabolites in forensic and emergency cases. To facilitate the comparison of metabolic characteristics, we divided the four compounds into two groups of types, 25X-NBOH and 25X-NBOMe. The in vitro phase I and phase II metabolism of these four compounds was investigated by incubating 10 mg mL pooled human liver microsomes with co-substrates for 180 min at 37 ℃, and then analyzing the reaction mixture using ultrahigh-performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry. In total, 70 metabolites were obtained for the four compounds. The major biotransformations were O-demethylation, hydroxylation, dehydrogenation, N-dehydroxybenzyl, N-demethoxybenzyl, oxidate transformation to ketone and carboxylate, glucuronidation, and their combination reactions. We recommended the major metabolites with high peak area ratio as biomarkers, B2-1 (56.61%), B2-2 (17.43%) and B6 (17.78%) for 25B-NBOH, E2-1 (42.81%), E2-2 (34.90%) and E8-2 (10.18%) for 25E-NBOH, H5 (49.28%), H2-1 (21.54%), and H1 (18.37%) for 25H-NBOH, P3-1 (10.94%), P3-2 (33.18%), P3-3 (14.85%) and P12-2 (23.00%) for 25iP-NBOMe. This is a study to evaluate their metabolic characteristics in detail. Comparative analysis of the N-benzyl derivatives of phenethylamines provided basic data for elucidating their pharmacology and toxicity. Timely analysis of the metabolic profiles of compounds with abuse potential will facilitate the early development of regulatory measures.
Topics: Humans; Phenethylamines; Chromatography, High Pressure Liquid; Microsomes, Liver; Designer Drugs; Hallucinogens
PubMed: 38359493
DOI: 10.1016/j.jpba.2024.116020 -
Scientific Reports Dec 2017GABAergic and dopaminergic pathways are co-localized in several areas of the central nervous system and recently several reports have shown co-release of both...
GABAergic and dopaminergic pathways are co-localized in several areas of the central nervous system and recently several reports have shown co-release of both neurotransmitters. The GABA-A receptor (β and ρ1 subunits) is modulated by dopamine (DA) and, interestingly, GABAρ1 can be modulated by several biogenic amines. Here we explored the effects of the metabolites of the dopaminergic pathway and other structural analogues of DA on GABAρ1 and the DA gated ion channel (LGC-53) from Caenorhabditis elegans expressed in Xenopus laevis oocytes. Our findings show an antagonistic effect of the metabolite 3-Methoxytyramine (3-MT, IC = 285 ± 30 µM) with similar potency compared to DA on induced GABA currents; however, it was inactive on LGC-53. The structural DA analogues and metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 2-phenylethylamine (β-PEA) and 4-amino-1-butanol (4-AM-1-OH), antagonized GABAρ1 currents, whereas β-PEA acted as partial agonists on LGC-53, indicating that the putative binding sites of both receptors may share structural characteristics. These results suggest that the DA metabolites 3-MT, DOPAC and HVA modulate GABAρ1 and possibly affect the activity of the receptors that include this subunit in vivo.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopamine; GABA-A Receptor Antagonists; Homovanillic Acid; Humans; Molecular Docking Simulation; Oocytes; Phenethylamines; Protein Conformation; Receptors, Biogenic Amine; Receptors, GABA-A; Xenopus laevis
PubMed: 29234054
DOI: 10.1038/s41598-017-17530-8 -
Neurotoxicity Research Apr 20214-Bromo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25B-NBOMe) is a hallucinogen exhibiting high binding affinity for 5-HT serotonin receptors. In the present work,...
4-Bromo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25B-NBOMe) is a hallucinogen exhibiting high binding affinity for 5-HT serotonin receptors. In the present work, we investigated its effect on dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release in the rat frontal cortex, striatum, and nucleus accumbens. Hallucinogenic activity, impact on cognitive and motor functions, and anxiogenic/anxiolytic properties of this compound were also tested. The release of DA, 5-HT, ACh, and glutamate was studied using microdialysis in freely moving animals. Hallucinogenic activity was investigated using head and body twitch response (WDS), cognitive functions were examined with the novel object recognition test (NOR), locomotor activity was studied in the open field (OF), while anxiogenic/anxiolytic effect was tested using the light/dark box (LDB). Neurotoxicity was evaluated with the comet assay. 25B-NBOMe increased DA, 5-HT, and glutamate release in all studied brain regions, induced hallucinogenic activity, and lowered the recognition index (Ri) vs. control in the NOR test. It also decreased locomotor activity of rats in the OF test. The effect of 25B-NBOMe in the NOR test was inhibited by scopolamine. In the LDB test, the time spent in the dark zone was longer in comparison to control and was dose-dependent. In contrast to MDMA, 25B-NBOMe showed subtle genotoxic effect observed in the comet assay.Our findings indicate that 25B-NBOMe shows hallucinogenic activity in the wide range of doses. The changes in neurotransmitter levels may be related to 25B-NBOMe affinity for 5-HT receptor. Alterations in the NOR, OF, and LDB indicate that 25B-NBOMe impacts short-term memory, locomotion, and may be anxiogenic.
Topics: Animals; Anisoles; Behavior, Animal; Brain; Brain Chemistry; Hallucinogens; Locomotion; Male; Memory; Phenethylamines; Rats, Wistar; Rats
PubMed: 33337517
DOI: 10.1007/s12640-020-00297-8 -
Forensic Science International Sep 2015DESIGNER: phenethylamines (PEAs) and cathinones have been encountered worldwide. Complete characterization of these substances can be challenging due to their chirality...
Regioisomeric and enantiomeric analyses of 24 designer cathinones and phenethylamines using ultra high performance liquid chromatography and capillary electrophoresis with added cyclodextrins.
DESIGNER: phenethylamines (PEAs) and cathinones have been encountered worldwide. Complete characterization of these substances can be challenging due to their chirality and variably substituted phenyl rings. In this study, 24 PEAs and cathinones were analyzed by ultra high performance liquid chromatography with photo diode array detection (UHPLC-PDA) on a variety of stationary phases, and by capillary electrophoresis on a dynamically coated capillary with PDA detection (CE-PDA). In the UHPLC-PDA study, a BEH Phenyl column resolved 18 of the 24 regioisomers in 8min, with good discrimination of the PEAs. In contrast, capillary zone electrophoresis (CZE) on a dynamically coated capillary partially or baseline resolved only 10 of the 24 regioisomers, but with improved discrimination of mono-substituted cathinones. A second series of CE-PDA experiments using 80mM (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) in the run buffer resolved all 24 regioisomers and all but two sets of enantiomers within 18min. Five illicit samples were successfully analyzed using the described methods.
Topics: Alkaloids; Chromatography, Liquid; Designer Drugs; Electrophoresis, Capillary; Molecular Structure; Phenethylamines; Stereoisomerism
PubMed: 26232847
DOI: 10.1016/j.forsciint.2015.06.026 -
Journal of Agricultural and Food... May 2020In this study, the metabolic pathway of phenethylamine synthesis was reconstructed by chromosomal integration and overexpression of the gene encoding phenylalanine...
In this study, the metabolic pathway of phenethylamine synthesis was reconstructed by chromosomal integration and overexpression of the gene encoding phenylalanine decarboxylase in . The genes encoding 3-deoxy-d-arabinoheptulosonate-7-phosphate synthase (), shikimate kinase II (), chorismate mutase/prephenate dehydratase (), and tyrosine aminotransferase () in the phenethylamine synthetic pathway were sequentially chromosomally overexpressed. The phosphotransferase system was replaced by deleting the -- genes and chromosomally overexpressing the genes encoding galactose permease () and glucokinase (). In addition, the gene encoding glucose-6-phosphate dehydrogenase in the pentose phosphate pathway was chromosomally overexpressed, generating the final engineered strain AUD9. The AUD9 strain produced 2.65 g L phenethylamine with a yield of 0.27 g of phenethylamine g glucose in batch fermentation; fed-batch fermentation of AUD9 produced 38.82 g L phenethylamine with a productivity of 1.08 g L h phenethylamine, demonstrating its potential for industrial fermentative production of phenethylamine.
Topics: Biosynthetic Pathways; Escherichia coli; Escherichia coli Proteins; Glucokinase; Glucose; Metabolic Engineering; Metabolic Networks and Pathways; Monosaccharide Transport Proteins; Phenethylamines; Prephenate Dehydratase
PubMed: 32367713
DOI: 10.1021/acs.jafc.0c01706 -
Nature Aug 2017Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and...
Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and 'pharmacoterrorism' in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects. Here we develop a 'dissection through vaccination' approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.
Topics: Amphetamine; Amphetamines; Animals; Biological Products; Central Nervous System Stimulants; Chemical Fractionation; Cytochrome P-450 Enzyme System; Drug Synergism; Haptens; Hemocyanins; Illicit Drugs; Male; Mice; Phenethylamines; Theophylline; Vaccines
PubMed: 28813419
DOI: 10.1038/nature23464 -
Neuropharmacology May 20184-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs...
BACKGROUND
4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine receptor and transporter interaction profiles of a series of 2C-T drugs.
METHODS
We determined the binding affinities of 2C-T drugs at monoamine receptors and transporters in human cells that were transfected with the respective receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT) and 5-HT receptors, activation of human trace amine-associated receptor 1 (TAAR), and inhibition of monoamine uptake transporters.
RESULTS
2C-T drugs had high affinity for 5-HT and 5-HT receptors (1-54 nM and 40-350 nM, respectively). With activation potencies of 1-53 nM and 44-370 nM, the drugs were potent 5-HT receptor and 5-HT receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT receptor (EC > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT and adrenergic receptors. The compounds had high affinity for the rat TAAR (5-68 nM) and interacted with the mouse but not human TAAR. The 2C-T drugs did not potently interact with monoamine transporters (K > 4000 nM).
CONCLUSION
The receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT receptor interactions. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
Topics: Animals; Biogenic Amines; HEK293 Cells; Humans; Membrane Transport Proteins; Mice; Molecular Structure; Phenethylamines; Protein Binding; Psychotropic Drugs; Radioligand Assay; Rats; Receptors, Biogenic Amine; Transfection
PubMed: 28720478
DOI: 10.1016/j.neuropharm.2017.07.012