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Nature Dec 2023Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic...
Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA) as well as methamphetamine, an abused substance that has posed a severe threat to human health and society. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and β-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HTR (refs. ). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.
Topics: Humans; Ligands; Methamphetamine; Nervous System Diseases; Phenethylamines; Receptors, G-Protein-Coupled; Substance-Related Disorders; Heterotrimeric GTP-Binding Proteins; Polypharmacology; Hydrogen Bonding
PubMed: 37935377
DOI: 10.1038/s41586-023-06775-1 -
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 -
Expert Review of Clinical Pharmacology 2023The renewed interest in considering a range of stimulants, psychedelics and dissociatives as therapeutics emphasizes the need to draft an updated overview of these... (Review)
Review
INTRODUCTION
The renewed interest in considering a range of stimulants, psychedelics and dissociatives as therapeutics emphasizes the need to draft an updated overview of these drugs' clinical and pharmacological issues.
AREAS COVERED
The focus here was on: stimulants (e.g. amphetamines, methamphetamine, and pseudoephedrine; phenethylamines; synthetic cathinones; benzofurans; piperazines; aminoindanes; aminorex derivatives; phenmetrazine derivatives; phenidates); classical (e.g. ergolines; tryptamines; psychedelic phenethylamines), and atypical (e.g. PCP/ketamine-like dissociatives) psychedelics.Stimulant and psychedelics are associated with: a) increased central DA levels (psychedelic phenethylamines, synthetic cathinones and stimulants); b) 5-HT receptor subtypes' activation (psychedelic phenethylamines; recent tryptamine and lysergamide derivatives); and c) antagonist activity at NMDA receptors, (phencyclidine-like dissociatives).
EXPERT OPINION
Clinicians should be regularly informed about the range of NPS and their medical, psychobiological and psychopathological risks both in the acute and long term. Future research should focus on an integrative model in which pro-drug websites' analyses are combined with advanced research approaches, including computational chemistry studies so that in vitro and in vivo preclinical studies of index novel psychoactives can be organized. The future of psychedelic research should focus on identifying robust study designs to convincingly assess the potential therapeutic benefits of psychedelics, molecules likely to present with limited dependence liability levels.
Topics: Humans; Hallucinogens; Psychotropic Drugs; Central Nervous System Stimulants; Phenethylamines; Methamphetamine
PubMed: 37968919
DOI: 10.1080/17512433.2023.2279192 -
Current Topics in Behavioral... 2018This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three... (Review)
Review
This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT receptor is the principal mechanism of action for psychedelics, compounds with 5-HT agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.
Topics: Animals; Ergolines; Hallucinogens; Humans; Phenethylamines; Receptor, Serotonin, 5-HT2A; Structure-Activity Relationship; Tryptamines
PubMed: 28401524
DOI: 10.1007/7854_2017_475 -
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 -
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 -
Drug Testing and Analysis 2014Sixteen phenethylamines are now included in Schedules I and II of the United Nations 1971 Convention on Psychotropic Substances. Most of the ring-substituted compounds... (Review)
Review
Sixteen phenethylamines are now included in Schedules I and II of the United Nations 1971 Convention on Psychotropic Substances. Most of the ring-substituted compounds are in Schedule I, whereas 2C-B, amphetamine, and methamphetamine are listed in Schedule II. Substances in Schedule IV (e.g. benzphetamine) are now regarded as obsolete pharmaceutical products. They all represent the 'old phenethylamines'. By 2013, nearly 100 illicit phenethylamines had been found in the European Union (EU). Of these, nine (MBDB, 4-MTA, PMMA, 2C-I, 2C-T-2, 2C-T-7, TMA-2, 5-IT and 4-MA) were submitted for risk assessment by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). All except MBDB were recommended for EU-wide control. Of the 'new phenethylamines', 2C-B was the most commonly reported, but other 2C compounds were widespread. Many of the ring-substituted phenethylamines are described in the 1991 book PIHKAL. Many fused ring phenethylamines have appeared in the past few years; they include further benzofurans (e.g. 5-and 6-APB), indanylalkylamines (e.g. 5-IAP), dibenzofurans (e.g. 2C-B-FLY) and 2-aminopropylindoles (e.g.5-IT). The recent and rapid rise of phenethylamines with bulky N-substituents (e.g. 25I-NBOMe) has been particularly significant. Although not phenethylamines, it is notable that the thiophene bioisosteres of amphetamine and methamphetamine as well as certain conformationally-restricted variants (e.g. aminoindanes) have been found in recent drug seizures. In the United Kingdom Misuse of Drugs Act, most ring-substituted phenethylamines are either listed by name or are covered by generic definitions dating from 1977. In 2013, temporary generic legislation included a number of benzofurans, indanylalkylamines and certain 'NBOMe' compounds.
Topics: Animals; Europe; Humans; Illicit Drugs; Phenethylamines; Psychotropic Drugs; Substance Abuse Detection
PubMed: 24574327
DOI: 10.1002/dta.1570 -
New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents.Archives of Toxicology Apr 20212C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs... (Comparative Study)
Comparative Study
2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.
Topics: Animals; Designer Drugs; Dopamine; Dose-Response Relationship, Drug; Inflammation; Locomotion; Male; Mice; Mice, Inbred C57BL; Neurotoxicity Syndromes; Nucleus Accumbens; Phenethylamines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley
PubMed: 33515270
DOI: 10.1007/s00204-021-02980-x -
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