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Journal of Analytical Toxicology Jan 2021NBOMes are N-benzylmethoxy derivatives of the 2C family compounds with N-2-methoxybenzyl moiety substituted by the methoxy group at the 2- and 5-position and the halogen...
NBOMes are N-benzylmethoxy derivatives of the 2C family compounds with N-2-methoxybenzyl moiety substituted by the methoxy group at the 2- and 5-position and the halogen group at the 4-position of the phenyl ring. These substances are a new class of potent serotonin 5-HT2A receptor agonist hallucinogens with potential harmful effects. The substitution with halogen of the already psychoactive phenethylamine produces a derivative (2C-I) with increased hallucinogenic effects. This class of hallucinogens has chemical structures very similar to natural hallucinogenic alkaloid mescaline and these are sold mainly via internet as a 'legal' alternative to other hallucinogenic drug-lysergic acid diethylamide (LSD). 25I-NBOMe is the first synthesized and one of the most common compound from NBOMes. Knowledge of pharmacological properties of 25I-NBOMe is very limited so far. There are only a few in vivo and in vitro so far published studies. The behavioral experiments are mainly related with the hallucinogenic effect of 25I-NBOMe while the in vitro studies concerning mainly the affinity for 5-HT2A receptors. The 25I-NBOMe Critical Review 2016 reported 51 non-fatal intoxications and 21 deaths associated with 25I-NBOMe across Europe. Case reports describe various toxic effects of 25I-NBOMe usage including tachycardia, hypertension, hallucinations, rhabdomyolysis, acute kidney injury and death. The growing number of fatal and non-fatal intoxication cases indicates that 25I-NBOMe should be considered as a serious danger to public health. This review aims to present the current state of knowledge on pharmacological effects and chemical properties of 25I-NBOMe and to describe reported clinical cases and analytical methods available for identification of this agent in biological material.
Topics: Benzylamines; Designer Drugs; Dimethoxyphenylethylamine; Europe; Hallucinogens; Humans; Phenethylamines
PubMed: 32128596
DOI: 10.1093/jat/bkaa022 -
Critical Reviews in Toxicology Jan 2023Recently, a growing number of reports have indicated a positive effect of hallucinogenic-based therapies in different neuropsychiatric disorders. However, hallucinogens... (Review)
Review
Recently, a growing number of reports have indicated a positive effect of hallucinogenic-based therapies in different neuropsychiatric disorders. However, hallucinogens belonging to the group of new psychoactive substances (NPS) may produce high toxicity. NPS, due to their multi-receptors affinity, are extremely dangerous for the human body and mental health. An example of hallucinogens that have been lately responsible for many severe intoxications and deaths are 25X-NBOMes - -(2-methoxybenzyl)-2,5-dimethoxy-4-substituted phenethylamines, synthetic compounds with strong hallucinogenic properties. 25X-NBOMes exhibit a high binding affinity to serotonin receptors but also to dopamine, adrenergic and histamine receptors. Apart from their influence on perception, many case reports point out systemic and neurological poisoning with these compounds. In humans, the most frequent side effects are tachycardia, anxiety, hypertension and seizures. Moreover, preclinical studies confirm that 25X-NBOMes cause developmental impairments, cytotoxicity, cardiovascular toxicity and changes in behavior of animals. Metabolism of NBOMes seems to be very complex and involves many metabolic pathways. This fact may explain the observed high toxicity. In addition, many analytical methods have been applied in order to identify these compounds and their metabolites. The presented review summarized the current knowledge about 25X-NBOMes, especially in the context of toxicity.
Topics: Animals; Humans; Hallucinogens; Phenethylamines; Seizures; Dopamine
PubMed: 37115704
DOI: 10.1080/10408444.2023.2194907 -
Current Opinion in Neurobiology Oct 2015Trace amine-associated receptors (TAARs) are G Protein-Coupled Receptors that function as vertebrate olfactory receptors. Like odorant receptors, TAARs constitute an... (Review)
Review
Trace amine-associated receptors (TAARs) are G Protein-Coupled Receptors that function as vertebrate olfactory receptors. Like odorant receptors, TAARs constitute an ever-evolving sensory subsystem, with individual TAARs recognizing particular chemicals and some evoking stereotyped behaviors. Several TAARs mediate aversion or attraction towards volatile amines that include the mouse odor trimethylamine, the predator odor 2-phenylethylamine, and the death-associated odor cadaverine. TAAR-expressing sensory neurons achieve monoallelic receptor expression, use canonical olfactory signaling molecules, and target a dedicated olfactory bulb region. In mouse, TAAR4 and TAAR5 are encoded by adjacent genes and localize to adjacent glomeruli, yet mediate opposing behaviors. Future studies are needed to understand how TAAR-expressing sensory neurons engage higher-order neural circuits to encode odor valence.
Topics: Animals; Behavior; Cadaverine; Humans; Ligands; Olfactory Receptor Neurons; Phenethylamines; Receptors, G-Protein-Coupled
PubMed: 25616211
DOI: 10.1016/j.conb.2015.01.001 -
ACS Chemical Neuroscience Jul 2022Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory...
Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish () is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel -benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -OCH, -OCF, -F, -Cl, and -Br substitutions in the position of the phenyl ring of the -benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the -benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H-NBOMe(F) and 34H-NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, including anxiogenic/hypolocomotor (24H-NBF, 24H-NBOMe, and 34H-NBF), behaviorally inert (34H-NBBr, 34H-NBCl, and 34H-NBOMe), anxiogenic/hallucinogenic-like (24H-NBBr, 24H-NBCl, and 24H-NBOMe(F)), and anxiolytic/hallucinogenic-like (34H-NBOMe(F)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse.
Topics: Animals; Artificial Intelligence; Behavior, Animal; Hallucinogens; Phenethylamines; Zebrafish
PubMed: 35671176
DOI: 10.1021/acschemneuro.2c00123 -
Journal of Natural Products Apr 2022The bacterial genus has been associated with various ecological roles in marine environments. Members of this genus can act, for example, as pathogens, predators, or... (Review)
Review
The bacterial genus has been associated with various ecological roles in marine environments. Members of this genus can act, for example, as pathogens, predators, or episymbionts. However, natural products produced by these bacteria are still unknown. In the present work, we investigated a strain for the production of antimicrobial metabolites. Six new phenethylamine (PEA)-containing alkaloids, discolins A and B ( and ), dispyridine (), dispyrrolopyridine A and B ( and ), and dispyrrole (), were isolated from media produced by the predatory bacterium sv11. Chemical structures were elucidated by analysis of spectroscopic data. Alkaloids and exhibited strong activity against Gram-positive DSM10, ATCC607, DSM20600, and ATCC25923, with minimum inhibitory concentration (MIC) values ranging from 0.5 to 4 μg/mL, and moderate activity against FH2173 and ATCC9170. Compound displayed moderate antibacterial activities against Gram-positive bacteria. Dispyrrolopyridine A () was active against efflux pump deficient ATCC25922 Δ, with an MIC value of 8 μg/mL, as well as against N2 with an MIC value of 32 μg/mL. Other compounds were inactive against these microorganisms. The biosynthetic route toward discolins A and B ( and ) was investigated using and experiments. It comprises an enzymatic decarboxylation of phenylalanine to PEA catalyzed by DisA, followed by a nonenzymatic condensation to form the central imidazolium ring. This spontaneous formation of the imidazolium core was verified by means of a synthetic one-pot reaction using the respective building blocks. Six additional strains belonging to three species were able to produce discolins, and several DisA analogues were identified in various marine flavobacterial genera, suggesting the widespread presence of PEA-derived compounds in marine ecosystems.
Topics: Alkaloids; Anti-Bacterial Agents; Anti-Infective Agents; Ecosystem; Escherichia coli; Flavobacterium; Microbial Sensitivity Tests; Phenethylamines; Tenacibaculum
PubMed: 35416664
DOI: 10.1021/acs.jnatprod.1c01173 -
Therapeutic Drug Monitoring Apr 2020The novel phenethylamines 4-fluoroamphetamine (4-FA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B) fall in the top 10 most used new psychoactive substances (NPSs) among...
BACKGROUND
The novel phenethylamines 4-fluoroamphetamine (4-FA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B) fall in the top 10 most used new psychoactive substances (NPSs) among high-risk substance users. Various phenethylamines and NPS are also highly used in populations with mental disorders, depression, or attention deficit hyperactivity disorder (ADHD). Moreover, NPS use is highly prevalent among men and women with risky sexual behavior. Considering these specific populations and their frequent concurrent use of drugs, such as antidepressants, ADHD medication, and antiretrovirals, reports on potential interactions between these drugs, and phenethylamines 4-FA and 2C-B, were reviewed.
METHODS
The authors performed a systematic literature review on 4-FA and 2C-B interactions with antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, bupropion, venlafaxine, phenelzine, moclobemide, and tranylcypromine), ADHD medications (atomoxetine, dexamphetamine, methylphenidate, and modafinil), and antiretrovirals.
RESULTS
Limited literature exists on the pharmacokinetics and drug-drug interactions of 2C-B and 4-FA. Only one case report indicated a possible interaction between 4-FA and ADHD medication. Although pharmacokinetic interactions between 4-FA and prescription drugs remain speculative, their pharmacodynamic points toward interactions between 4-FA and ADHD medication and antidepressants. The pharmacokinetic and pharmacodynamic profile of 2C-B also points toward such interactions, between 2C-B and prescription drugs such as antidepressants and ADHD medication.
CONCLUSIONS
A drug-drug (phenethylamine-prescription drug) interaction potential is anticipated, mainly involving monoamine oxidases for 2C-B and 4-FA, with monoamine transporters being more specific to 4-FA.
Topics: Amphetamines; Antidepressive Agents; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Depressive Disorder; Dimethoxyphenylethylamine; Drug Interactions; Humans; Phenethylamines; Prescription Drugs
PubMed: 32022784
DOI: 10.1097/FTD.0000000000000725 -
Microbial Cell Factories Oct 2015Hydroxycinnamic acids (HCAs) including cinnamic acid, p-coumaric acid, caffeic acid, and ferulic acid, are C6-C3 phenolic compounds that are synthesized via the...
BACKGROUND
Hydroxycinnamic acids (HCAs) including cinnamic acid, p-coumaric acid, caffeic acid, and ferulic acid, are C6-C3 phenolic compounds that are synthesized via the phenylpropanoid pathway. HCAs serve as precursors for the synthesis of lignins, flavonoids, anthocyanins, stilbenes and other phenolic compounds. HCAs can also be conjugated with diverse compounds including quinic acid, hydroxyl acids, and amines. Hydroxycinnamoyl (HC) amine conjugates such as N-HC tyramines and N-HC phenethylamines have been considered as potential starting materials to develop antiviral and anticancer drugs.
RESULTS
We synthesized N-HC tyramines and N-HC phenethylamines using three different approaches in Escherichia coli. Five N-HC phenethylamines and eight N-HC tyramines were synthesized by feeding HCAs and phenethylamine or tyramine to E. coli harboring 4CL (encoding 4-coumarate CoA:ligase) and either SHT (encoding phenethylamine N-HC transferase) or THT (encoding tyramine N-HC transferase). Also, N-(p-coumaroyl) phenethylamine and N-(p-coumaroyl) tyramine were synthesized from p-coumaric acid using E. coli harboring an additional gene, PDC (encoding phenylalanine decarboxylase) or TDC (encoding tyrosine decarboxylase). Finally, we synthesized N-(p-coumaroyl) phenethylamine and N-(p-coumaroyl) tyramine from glucose by reconstructing the metabolic pathways for their synthesis in E. coli. Productivity was maximized by optimizing the cell concentration and incubation temperature.
CONCLUSIONS
We reconstructed the metabolic pathways for synthesis of N-HC tyramines and N-HC phenethylamines by expressing several genes including 4CL, TST or SHT, PDC or TDC, and TAL (encoding tyrosine ammonia lyase) and engineering the shikimate metabolic pathway to increase endogenous tyrosine concentration in E. coli. Approximately 101.9 mg/L N-(p-coumaroyl) phenethylamine and 495.4 mg/L N-(p-coumaroyl) tyramine were synthesized from p-coumaric acid. Furthermore, 152.5 mg/L N-(p-coumaroyl) phenethylamine and 94.7 mg/L N-(p-coumaroyl) tyramine were synthesized from glucose.
Topics: Coenzyme A Ligases; Coumaric Acids; Escherichia coli; Escherichia coli Proteins; Mass Spectrometry; Metabolic Engineering; Phenethylamines; Plasmids; Transferases; Tyramine
PubMed: 26463041
DOI: 10.1186/s12934-015-0353-y -
Journal of Pharmaceutical and... May 2023A rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the targeted analysis of 75 phenethylamines...
A rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the targeted analysis of 75 phenethylamines and their derivatives from the hair matrix. The monitored classes of phenethylamines included the 2C series, D series, N-benzyl derivatives, mescaline-derived compounds, MDMA analogs, and benzodifurans. Approximately 20 mg of hair was weighed and pulverized with 0.1% formic acid in methanol by cryogenic grinding. After ultrasonication, centrifugation, and filtration, the supernatant was analyzed by LC-MS/MS operating in the scheduled multiple reaction monitoring mode. Phenethylamines and their derivatives were separated in 13 min on a biphenyl column (2.6 µm, 100 Å, 100 × 3.0 mm) using a gradient eluting mobile phase composed of 0.1% formic acid in water and acetonitrile. The developed and validated method showed good selectivity, sensitivity (LOD: 0.5-10 pg/mg and LOQ: 1-20 pg/mg), linearity (R > 0.997), accuracy and precision (< 20%), and stability. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of phenethylamines in hair from authentic forensic cases.
Topics: Chromatography, Liquid; Phenethylamines; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Hair
PubMed: 37018959
DOI: 10.1016/j.jpba.2023.115367 -
NBOMe: new potent hallucinogens--pharmacology, analytical methods, toxicities, fatalities: a review.European Review For Medical and... Sep 2015NBOMe is a class of emerging new psychoactive substances that has recently gained prominence in the drug abuse market. NBOMes are N-2-methoxy-benzyl substituted 2C class... (Review)
Review
OBJECTIVE
NBOMe is a class of emerging new psychoactive substances that has recently gained prominence in the drug abuse market. NBOMes are N-2-methoxy-benzyl substituted 2C class of hallucinogens, currently being marked online as "research chemicals" under various names: N-bomb, Smiles, Solaris, and Cimbi. This article reviews available literature on the pharmacology; the analytical methods currently used for the detection and quantification of NBOMe in biological matrices and blotters, together with intoxication cases and NBOMe-related fatalities.
MATERIALS AND METHODS
Relevant scientific articles were identified from Medline, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE and Google Scholar, through June 2015 using the following keywords: "NBOMe", "Nbomb", "Smiles", "intoxication", "toxicity" "fatalities", "death", "pharmacology", "5-HT2A receptor", "analysis" and "analytical methods". The main key word "NBOMe" was individually searched in association to each of the others.
RESULTS
The review of the literature allowed us to identify 43 citations on pharmacology, analytical methods and NBOMe-related toxicities and fatalities.
CONCLUSIONS
The high potency of NBOMes (potent agonists of 5-HT2A receptor) has led to several severe intoxications, overdose and traumatic fatalities; thus, their increase raises significant public health concerns. Moreover, due to the high potency and ease of synthesis, it is likely that their recreational use will become more widespread in the future. The publication of new data, case reports and evaluation of the NBOMes metabolites is necessary in order to improve knowledge and awareness within the forensic community.
Topics: Benzylamines; Drug Overdose; Hallucinogens; Humans; Phenethylamines; Substance-Related Disorders
PubMed: 26400534
DOI: No ID Found -
Biochemical Pharmacology Dec 2018The use of new psychoactive substituted 2,5-dimethoxy-N-benzylphenethylamines is associated with abuse and toxicity in the United States and elsewhere and their...
The use of new psychoactive substituted 2,5-dimethoxy-N-benzylphenethylamines is associated with abuse and toxicity in the United States and elsewhere and their pharmacology is not well known. This study compares the mechanisms of action of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe), 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe), 2-(((4-iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH); and 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) with hallucinogens and stimulants. Mammalian cells heterologously expressing 5-HT, 5-HT, 5-HT or 5-HT receptors, or dopamine, serotonin or norepinephrine transporters (DAT, SERT and NET, respectively) were used to assess drug affinities at radioligand binding sites. Potencies and efficacies were determined using [S]GTPγS binding assays (5-HT), inositol-phosphate accumulation assays (5-HT 5-HT and 5-HT), and uptake and release assays (transporters). The substituted phenethylamines were very low potency and low efficacy agonists at the 5-HT receptor. 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOH and 25N-NBOMe had very high affinity for, and full efficacy at, 5-HT and 5-HT receptors. In the 5-HT receptor functional assay, 25D-NBOMe, 25E-NBOMe, 25I-NBOH and 25N-NBOMe had subnanomolar to low nanomolar potencies similar to (+)lysergic acid diethylamide (LSD) while 25H-NBOMe had lower potency, similar to serotonin. At the 5-HT receptor, four had very high potencies, similar to LSD and serotonin, while 25H-NBOMe had lower potency. At the 5-HT receptor, the compounds had lower affinity, potency and efficacy compared to 5-HT or 5-HT The phenethylamines had low to mid micromolar affinities and potencies at the transporters. These results demonstrate that these -NBOMe and -NBOH substituted phenethylamines have a biochemical pharmacology consistent with hallucinogenic activity, with little psychostimulant activity.
Topics: Dose-Response Relationship, Drug; HEK293 Cells; Humans; Phenethylamines; Psychotropic Drugs; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists
PubMed: 30261175
DOI: 10.1016/j.bcp.2018.09.024