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CNS Drug Reviews 2001Phenibut (beta-phenyl-gamma-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has... (Review)
Review
Phenibut (beta-phenyl-gamma-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA-mimetic, primarily at GABA(B) and, to some extent, at GABA(A) receptors. It also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut. This article reviews the structure-activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre- or post-operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post-traumatic stress, stuttering and vestibular disorders.
Topics: Animals; Anticonvulsants; Baclofen; Brain; Diazepam; Dopamine Agonists; Dyskinesias; Emotions; GABA Agonists; Humans; Mental Disorders; Nootropic Agents; Phenethylamines; Piracetam; Stereoisomerism; Structure-Activity Relationship; Tranquilizing Agents; gamma-Aminobutyric Acid
PubMed: 11830761
DOI: 10.1111/j.1527-3458.2001.tb00211.x -
Nature Communications Aug 2023The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota...
The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis.
Topics: Humans; Animals; Mice; Insulin Resistance; Metabolic Syndrome; Irritable Bowel Syndrome; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Dysbiosis; Phenethylamines; Tryptamines
PubMed: 37591886
DOI: 10.1038/s41467-023-40552-y -
The Journal of Organic Chemistry Jan 2015LiTMP metalated dimethyl N-Boc-phosphoramidates derived from 1-phenylethylamine and 1,2,3,4-tetrahydronaphthalen-1-ylamine highly selectively at the CH3O group to...
LiTMP metalated dimethyl N-Boc-phosphoramidates derived from 1-phenylethylamine and 1,2,3,4-tetrahydronaphthalen-1-ylamine highly selectively at the CH3O group to generate short-lived oxymethyllithiums. These isomerized to diastereomeric hydroxymethylphosphonamidates (phosphate–phosphonate rearrangement). However, s-BuLi converted the dimethyl N-Boc-phosphoramidate derived from 1-phenylethylamine to the N-Boc α-aminophosphonate preferentially. Only s-BuLi deprotonated dimethyl hydroxymethylphosphonamidates at the benzylic position and dimethyl N-Boc α-aminophosphonates at the CH3O group to induce phosphonate–phosphinate rearrangements. In the former case, the migration of the phosphorus substituent from the nitrogen to the carbon atom followed a retentive course with some racemization because of the involvement of a benzyllithium as an intermediate.
Topics: Amides; Biochemical Phenomena; Lithium Compounds; Molecular Structure; Organophosphonates; Phenethylamines; Phosphoric Acids; Tetrahydronaphthalenes
PubMed: 25525945
DOI: 10.1021/jo502567j -
Brain, Behavior and Evolution 2020Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result... (Review)
Review
Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result in rhabdomyolysis, coagulopathy, and even death. Here, we review recent evidence that suggests a potential link between the gut-brain axis and PIH. Within the preoptic area of the hypothalamus, phenethylamines lead to changes in catecholamine levels, that activate the sympathetic nervous system (SNS) and increase the peripheral levels of norepinephrine (NE), resulting in: (1) the loss of heat dissipation through α1 adrenergic receptor (α1-AR)-mediated vasoconstriction, (2) heat generation through β-AR activation and subsequent free fatty acid (FFA) activation of uncoupling proteins (UCPs) in brown and white adipose tissue, and (3) alteration of the gut microbiome and its link to the gut-brain axis. Recent studies have shown that phenethylamine derivatives can influence the composition of the gut microbiome and thus its metabolic potential. Phenethylamines increase the relative level of Proteuswhich has been linked to enhanced NE turnover. Bidirectional fecal microbial transplants (FMT) between PIH-tolerant and PIH-naïve rats demonstrated that the transplantation of gut microbiome can confer phenotypic hyperthermic and tolerant responses to phenethylamines. These phenethylamine-mediated changes in the gut microbiome were also associated with epigenetic changes in the mediators of thermogenesis. Given the significant role that the microbiome has been shown to play in the maintenance of body temperature, we outline current studies demonstrating the effects of phenethylamines on the gut microbiome and how these microbiome changes may mechanistically contribute to alterations in body temperature.
Topics: Animals; Gastrointestinal Microbiome; Hyperthermia; Phenethylamines; Rats; Thermogenesis
PubMed: 33472193
DOI: 10.1159/000512098 -
Molecules (Basel, Switzerland) Jan 2023A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this... (Review)
Review
A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this motif are enumerated in key therapeutic targets, listing medicinal chemistry hits and appealing screening compounds. Latest reports in discovering new bioactive 2-phenethylamines by research groups are covered too.
Topics: Chemistry, Pharmaceutical; Receptors, G-Protein-Coupled; Phenethylamines; Receptors, Dopamine D2
PubMed: 36677913
DOI: 10.3390/molecules28020855 -
Tidsskrift For Den Norske Laegeforening... May 2016There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel... (Review)
Review
There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel Psychoactive Substances, and are mainly sold over the Internet. Uncertain dosage of potent substances entails a risk of accidental overdose, and therefore serious intoxication and death. In this article we provide an overview of current knowledge with regard to these substances.
Topics: Alkaloids; Cannabinoids; Designer Drugs; Humans; Illicit Drugs; Phenethylamines; Piperazines; Psychotropic Drugs; Substance-Related Disorders; Tryptamines
PubMed: 27143461
DOI: 10.4045/tidsskr.15.1278 -
JACC. Clinical Electrophysiology Dec 2016
Topics: Anti-Arrhythmia Agents; Phenethylamines; Sulfonamides
PubMed: 29759760
DOI: 10.1016/j.jacep.2016.06.005 -
Forensic Toxicology Jan 2023The present review aims to provide an overview of methods for the quantification of 2,5-dimethoxy-amphetamines and -phenethylamines in different biological matrices,... (Review)
Review
PURPOSE
The present review aims to provide an overview of methods for the quantification of 2,5-dimethoxy-amphetamines and -phenethylamines in different biological matrices, both traditional and alternative ones.
METHODS
A complete literature search was carried out with PubMed, Scopus and the World Wide Web using relevant keywords, e.g., designer drugs, amphetamines, phenethylamines, and biological matrices.
RESULTS
Synthetic phenethylamines represent one of the largest classes of "designer drugs", obtained through chemical structure modifications of psychoactive substances to increase their pharmacological activities. This practice is also favored by the fact that every new synthetic compound is not considered illegal by existing legislation. Generally, in a toxicological laboratory, the first monitoring of drugs of abuse is made by rapid screening tests that sometimes can occur in false positive or false negative results. To reduce evaluation errors, it is mandatory to submit the positive samples to confirmatory methods, such as gas chromatography or liquid chromatography combined to mass spectrometry, for a more specific qualitative and quantitative analysis.
CONCLUSIONS
This review highlights the great need for updated comprehensive analytical methods, particularly when analyzing biological matrices, both traditional and alternative ones, for the search of newly emerging designer drugs.
Topics: Phenethylamines; Gas Chromatography-Mass Spectrometry; Amphetamines; Mass Spectrometry; Chromatography, Liquid
PubMed: 36652064
DOI: 10.1007/s11419-022-00638-6 -
International Journal of Molecular... Aug 2022Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this...
Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 () as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.
Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Mice; Phenethylamines; Sulfonamides
PubMed: 35955741
DOI: 10.3390/ijms23158607 -
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