-
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 -
International Journal of Molecular... Dec 2020Psychedelic and stimulating phenethylamines belong to the family of new psychoactive substances (NPS). The acute toxicity framework has begun to be investigated, while...
Psychedelic and stimulating phenethylamines belong to the family of new psychoactive substances (NPS). The acute toxicity framework has begun to be investigated, while studies showing genotoxic potential are very limited or not available. Therefore, in order to fill this gap, the aim of the present work was to evaluate the genotoxicity by treating TK6 cells with 2C-H, 2C-I, 2C-B, 25B-NBOMe, and the popular 3,4-Methylenedioxymethylamphetamine (MDMA). On the basis of cytotoxicity and cytostasis results, we selected the concentrations (6.25-35 µM) to be used in genotoxicity analysis. We used the micronucleus (MN) as indicator of genetic damage and analyzed the MNi frequency fold increase by an automated flow cytometric protocol. All substances, except MDMA, resulted genotoxic; therefore, we evaluated reactive oxygen species (ROS) induction as a possible mechanism at the basis of the demonstrated genotoxicity. The obtained results showed a statistically significant increase in ROS levels for all genotoxic phenethylamines confirming this hypothesis. Our results highlight the importance of genotoxicity evaluation for a complete assessment of the risk associated also with NPS exposure. Indeed, the subjects who do not have hazardous behaviors or require hospitalization by using active but still "safe" doses could run into genotoxicity and in the well-known long-term effects associated.
Topics: Anisoles; Apoptosis; Cell Line; Cell Survival; Dimethoxyphenylethylamine; Flow Cytometry; Genes; Hallucinogens; Humans; Micronuclei, Chromosome-Defective; Micronucleus Tests; N-Methyl-3,4-methylenedioxyamphetamine; Phenethylamines; Psychotropic Drugs; Reactive Oxygen Species
PubMed: 33348640
DOI: 10.3390/ijms21249616 -
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 -
Biochemical Pharmacology Jan 2008Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic... (Review)
Review
Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds.
Topics: Animals; Behavior, Animal; Discrimination Learning; Dopamine; Glutamic Acid; Hallucinogens; Humans; Lysergic Acid Diethylamide; Phenethylamines; Receptors, Serotonin; Self Administration; Structure-Activity Relationship; Tryptamines
PubMed: 17977517
DOI: 10.1016/j.bcp.2007.07.018 -
Critical Reviews in Food Science and... 2012Tyramine poisoning is caused by the ingestion of food containing high levels of tyramine, a biogenic amine. Any foods containing free tyrosine are subject to tyramine... (Review)
Review
Tyramine poisoning is caused by the ingestion of food containing high levels of tyramine, a biogenic amine. Any foods containing free tyrosine are subject to tyramine formation if poor sanitation and low quality foods are used or if the food is subject to temperature abuse or extended storage time. Tyramine is generated by decarboxylation of the tyrosine through tyrosine decarboxylase (TDC) enzymes derived from the bacteria present in the food. Bacterial TDC have been only unequivocally identified and characterized in Gram-positive bacteria, especially in lactic acid bacteria. Pyridoxal phosphate (PLP)-dependent TDC encoding genes (tyrDC) appeared flanked by a similar genetic organization in several species of lactic acid bacteria, suggesting a common origin by a single mobile genetic element. Bacterial TDC are also able to decarboxylate phenylalanine to produce phenylethylamine (PEA), another biogenic amine. The molecular knowledge of the genes involved in tyramine production has led to the development of molecular methods for the detection of bacteria able to produce tyramine and PEA. These rapid and simple methods could be used for the analysis of the ability to form tyramine by bacteria in order to evaluate the potential risk of tyramine biosynthesis in food products.
Topics: Adrenergic Uptake Inhibitors; Aromatic-L-Amino-Acid Decarboxylases; Bacterial Proteins; Bacterial Typing Techniques; Food Inspection; Food Microbiology; Gram-Negative Bacteria; Gram-Positive Bacteria; Phenethylamines; Tyramine; Tyrosine Decarboxylase; Vasoconstrictor Agents
PubMed: 22369263
DOI: 10.1080/10408398.2010.500545 -
Psychopharmacology Mar 2014Psychoactive-substituted phenethylamines 2,5-dimethoxy-4-chlorophenethylamine (2C-C); 2,5-dimethoxy-4-methylphenethylamine (2C-D); 2,5-dimethoxy-4-ethylphenethylamine...
Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function.
RATIONALE
Psychoactive-substituted phenethylamines 2,5-dimethoxy-4-chlorophenethylamine (2C-C); 2,5-dimethoxy-4-methylphenethylamine (2C-D); 2,5-dimethoxy-4-ethylphenethylamine (2C-E); 2,5-dimethoxy-4-iodophenethylamine (2C-I); 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2); and 2,5-dimethoxy-4-chloroamphetamine (DOC) are used recreationally and may have deleterious side effects.
OBJECTIVES
This study compares the behavioral effects and the mechanisms of action of these substituted phenethylamines with those of hallucinogens and a stimulant.
METHODS
The effects of these compounds on mouse locomotor activity and in rats trained to discriminate dimethyltryptamine, (-)-DOM, (+)-LSD, (±)-MDMA, and S(+)-methamphetamine were assessed. Binding and functional activity of the phenethylamines at 5-HT1A, 5-HT2A, 5-HT2C receptors and monoamine transporters were assessed using cells heterologously expressing these proteins.
RESULTS
The phenethylamines depressed mouse locomotor activity, although 2C-D and 2C-E stimulated activity at low doses. The phenethylamines except 2C-T-2 fully substituted for at least one hallucinogenic training compound, but none fully substituted for (+)-methamphetamine. At 5-HT1A receptors, only 2C-T-2 and 2C-I were partial-to-full very low potency agonists. In 5-HT2A arachidonic acid release assays, the phenethylamines were partial to full agonists except 2C-I which was an antagonist. All compounds were full agonists at 5-HT2A and 5-HT2C receptor inositol phosphate assays. Only 2C-I had moderate affinity for, and very low potency at, the serotonin transporter.
CONCLUSIONS
The discriminative stimulus effects of 2C-C, 2C-D, 2C-E, 2C-I, and DOC were similar to those of several hallucinogens, but not methamphetamine. Additionally, the substituted phenethylamines were full agonists at 5-HT2A and 5-HT2C receptors, but for 2C-T-2, this was not sufficient to produce hallucinogen-like discriminative stimulus effects. Additionally, the 5-HT2A inositol phosphate pathway may be important in 2C-I's psychoactive properties.
Topics: Animals; Discrimination, Psychological; Male; Methamphetamine; Mice; Motor Activity; N,N-Dimethyltryptamine; Phenethylamines; Psychotropic Drugs; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Vesicular Monoamine Transport Proteins
PubMed: 24142203
DOI: 10.1007/s00213-013-3303-6 -
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 -
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 -
Journal of Medical Toxicology :... Jun 2013New groups of synthetic "designer drugs" have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit... (Review)
Review
New groups of synthetic "designer drugs" have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit drugs but are advertised as "legal" highs and are sold over the internet, at raves and night clubs, and in head shops. The 2C series drugs are ring-substituted phenethylamines that belong to a group of designer agents similar in structure to 3,4-methylenedioxy-N-methylamphetamine (MDMA, Ecstasy). Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for these patients. This review focuses on the pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication based on available published literature. Multiple names under which 2C drugs are sold were identified and tabulated. Common features identified in patients intoxicated with 2Cs included hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia. Patients may exhibit sympathomimetic symptoms or symptoms consistent with serotonin toxicity, but an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs; at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. 2C drugs are a group of designer intoxicants, many of which are marketed as legal, but may carry risks that consumers are unaware of. These drugs may be characterized by either serotonergic toxicity or a sympathomimetic toxidrome, but a presentation consistent with excited delirium is consistent amongst the reported 2C-related deaths. Treatment of 2C intoxication is primarily supportive, but immediate action is required in the context of excited delirium, hyperthermia, and seizure activity.
Topics: Animals; Central Nervous System Stimulants; Designer Drugs; Drug Overdose; Fever; Hallucinogens; Humans; Phenethylamines
PubMed: 23494844
DOI: 10.1007/s13181-013-0295-x -
Human Psychopharmacology Jan 2020The number of novel psychedelic phenethylamines and tryptamines has continued to increase, but little academic research has focused on the effects of these substances....
OBJECTIVE
The number of novel psychedelic phenethylamines and tryptamines has continued to increase, but little academic research has focused on the effects of these substances. We sought to determine and compare the subjective effects of various substances.
METHODS
We conducted in-depth interviews with 39 adults (75.4% male and 87.2% White) who reported experience using psychedelic phenethylamines and/or tryptamines. Participants described the effects of compounds they have used. We examined the subjective drug effects in a qualitative descriptive manner.
RESULTS
Participants reported on the use of 36 compounds. The majority (64.1%) reported the use of 2C series drugs, with 2C-B use being most prevalent; 38.5% reported the use of NBOMe, and 25.6% reported the use of DOx. With regard to tryptamines, 46.2% reported use, and 4-AcO-DMT was the most prevalent drug used in this class. 2C-B was often described as being more favorable than other 2C series compounds with the effects described as being comparable with MDMA and LSD. NBOMe effects were generally described in an unfavorable manner, and the effects of DOx were often described as lasting too long (12-36 hr). The effects of 4-AcO-DMT were often described as mimicking psilocybin.
CONCLUSION
Knowing the effects of various compounds can inform education, prevention, and harm reduction efforts regarding the use of these drugs.
Topics: Adolescent; Adult; Drug Users; Female; Hallucinogens; Humans; Male; Phenethylamines; Qualitative Research; Self Report; Tryptamines; Young Adult
PubMed: 31909513
DOI: 10.1002/hup.2719