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5-HT2A

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https://www.readbyqxmd.com/read/28529483/identification-of-a-novel-allosteric-inhibitory-site-on-tryptophan-hydroxylase-1-enabling-unprecedented-selectivity-over-all-related-hydroxylases
#1
Mike Petrassi, Rob Barber, Celine Be, Sarah Beach, Brian Cox, Anne-Marie D'Souza, Nick Duggan, Martin Hussey, Roy Fox, Peter Hunt, Gabor Jarai, Takatoshi Kosaka, Paul Oakley, Viral Patel, Neil Press, David Rowlands, Clemens Scheufler, Oliver Schmidt, Honnappa Srinivas, Mary Turner, Rob Turner, John Westwick, Alison Wolfreys, Nuzhat Pathan, Simon Watson, Matthew Thomas
Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements - SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28529043/the-impact-of-the-halogen-bonding-on-d2-and-5-ht1a-5-ht7-receptor-activity-of-azinesulfonamides-of-4-2-ethyl-piperidinyl-1-yl-phenylpiperazines-with-antipsychotic-and-antidepressant-properties
#2
Anna Partyka, Rafał Kurczab, Vittorio Canale, Grzegorz Satała, Krzysztof Marciniec, Agnieszka Pasierb, Magdalena Jastrzębska-Więsek, Maciej Pawłowski, Anna Wesołowska, Andrzej J Bojarski, Paweł Zajdel
A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D2 and serotoninergic 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline (21), which behaved as D2, 5-HT1A and 5-HT7 receptor antagonist...
May 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28525587/assessing-the-psychedelic-after-glow-in-ayahuasca-users-post-acute-neurometabolic-and-functional-connectivity-changes-are-associated-with-enhanced-mindfulness-capacities
#3
Frederic Sampedro, Mario de la Fuente Revenga, Marta Valle, Natalia Roberto, Elisabet Domínguez-Clavé, Matilde Elices, Luís Eduardo Luna, José Alexandre S Crippa, Jaime E C Hallak, Draulio B de Araujo, Pablo Friedlander, Steven A Barker, Enrique Álvarez, Joaquim Soler, Juan C Pascual, Amanda Feilding, Jordi Riba
Background: Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine (DMT) and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network (DMN), purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers, and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood...
May 19, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28521372/synthesis-and-characterization-of-new-azecine-derivatives-as-potential-neuroleptics
#4
Stephanie Zergiebel, Christian Fleck, Hans-Dieter Arndt, Christoph Enzensperger, Andreas Seeling
Dibenzo- and benzindolo-azecines represent a class of potential neuroleptics. To characterize the effectiveness at the dopamine and 5-HT2A-receptor representative structures were synthesized and tested by radio ligand binding studies, in vivo and in vitro studies.Neuroleptic potency and the risk of side effects of the prodrug 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-yl isobutyrate, an ester derivative of the most promising azecine 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404), was tested in vivo concerning conditioned avoidance response inhibition, locomotor activity and triggering of catalepsy vs...
May 18, 2017: Drug Research
https://www.readbyqxmd.com/read/28488759/association-between-t102c-5-ht2a-receptor-gene-polymorphism-and-5-year-mortality-risk-among-brazilian-amazon-riparian-elderly-population
#5
Tális O Silva, Ivo Jung, Alexis Trott, Cláudia G Bica, Jeferson N Casarin, Paola C Fortuna, Euler E Ribeiro, Fernanda D de Assis, Guilherme C Figueira, Fernanda Barbisan, Maria Fernanda Manica-Cattani, Beatriz S R Bonadiman, Lucien J Houenou, Pedro Antônio S do Prado-Lima, Ivana B M da Cruz
OBJECTIVE: Serotonin (5-HT) is a pleiotropic molecule that exerts several functions on brain and peripheral tissues via different receptors. The gene for the 5-HT2A receptor shows some variations, including a T102C polymorphism, that have been associated with increased risk of neuropsychiatric and vascular disorders. However, the potential impact of 5-HT2A imbalance caused by genetic variations on the human lifespan has not yet been established. METHODS: We performed a prospective study involving an Amazon riparian elderly free-living population in Maués City, Brazil, with a 5-year follow-up...
May 10, 2017: American Journal of Human Biology: the Official Journal of the Human Biology Council
https://www.readbyqxmd.com/read/28474719/-18-f-labelling-of-electron-rich-iodonium-ylides-application-to-the-radiosynthesis-of-potential-5-ht2a-receptor-pet-ligands
#6
I N Petersen, J Villadsen, H D Hansen, J Madsen, A A Jensen, N Gillings, S Lehel, M M Herth, G M Knudsen, J L Kristensen
(18)F-Labelling of aromatic moieties was limited to electron deficient aromatic systems for many years but recent developments have provided access to the direct labelling of electron rich aromatic systems. Herein we report the synthesis and (18)F-labelling of iodonium ylide precursors in the pursuit of (18)F-labelled 5-HT2A receptor agonist PET-ligands. Subsequent evaluation in pigs showed high brain uptake of the PET ligands but a blocking dose of ketanserin did not significantly reduce the signal in relevant brain regions - indicating that the ligands do not interact specifically with the 5-HT2A receptor in vivo...
May 23, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28462720/homology-modeling-inspired-synthesis-of-5-ht2a-receptor-inhibitors-a-diazepine-analogue-of-the-atypical-antipsychotic-jl13
#7
Enrico Mongeau, Gengyang Yuan, Zachary Minden, Scott Waldron, Raymond Booth, Daniel Felsing, Mary Jo Ondrechen, Graham B Jones
The benzoxazepine JL13 is an analogue of the clozapine family which targets the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Following structure function analysis with a series of synthetic analogues, homology modeling was performed to determine key interaction sites with the receptor. An aza analogue was synthesized for evaluation, and demonstrated seventeen times greater affinity for the receptor. An improved synthetic route was developed to allow rapid modifications of the core and synthesis of related libraries...
April 26, 2017: Central Nervous System Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28459713/cardiac-outcomes-after-perinatal-sertraline-exposure-in-mice
#8
Sarah E Haskell, Cecilia Lo, Mitchell E Kent, Timothy M Eggleston, Kenneth A Volk, Benjamin E Reinking, Robert D Roghair
Selective serotonin reuptake inhibitors are prescribed to 6-10% of pregnant women in the United States. Using an intrauterine plus neonatal exposure model to represent exposure throughout human pregnancy, we hypothesized sertraline exposure would impact intracardiac serotonin signaling and lead to small left heart syndrome in the absence of maternal psychopathology. C57BL/6 adult female mice received sertraline (5 mg/kg/d IP) or saline throughout pregnancy to time of delivery. Pups maintained exposure on postnatal days 1-14 to encompass the developmental window analogous to human gestation...
April 25, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28459524/growing-evidence-for-heterogeneous-synaptic-localization-of-5-ht2a-receptors
#9
Carine Bécamel, Coralie Berthoux, Alexander Barre, Philippe Marin
The serotonin 2A (5-HT2A) receptor subtype continues to attract attention as a target for numerous psychoactive drugs including psychedelic hallucinogens, antidepressants, anxiolytics, and atypical antipsychotics. 5-HT2A receptors are a principal G protein-coupled receptor subtype mediating the excitatory effects of serotonin. Nonetheless, pre- vs postsynaptic localization of 5HT2A receptors, relative to glutamatergic synapses, has remained controversial. Here, we discuss recent findings highlighting the existence and roles of presynaptic 5-HT2A receptors in regulating glutamatergic transmission and cognition...
May 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28447622/modern-clinical-research-on-lsd
#10
REVIEW
Matthias E Liechti
All modern clinical studies using the classic hallucinogen lysergic acid diethylamide (LSD) in healthy subjects or patients in the last 25 years are reviewed herein. There were five recent studies in healthy participants and one in patients. In a controlled setting, LSD acutely induced bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. These subjective effects of LSD were mediated by the 5-HT2A receptor. LSD increased feelings of closeness to others, openness, trust, and suggestibility...
April 27, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28443529/selective-attention-and-mismatch-negativity-in-antipsychotic-na%C3%A3-ve-first-episode-schizophrenia-patients-before-and-after-6-months-of-antipsychotic-monotherapy
#11
B Oranje, B Aggernaes, H Rasmussen, B H Ebdrup, B Y Glenthøj
BACKGROUND: Attention deficits have been frequently reported in schizophrenia. It has been suggested that treatment with second-generation antipsychotics can ameliorate these deficits. In this study, the influence of 6 months treatment with quetiapine, a compound with less affinity for dopamine D2 receptors than for serotonergic 5-HT2A receptors, on electrophysiological parameters of attention was investigated in a group of antipsychotic-naïve, first-episode schizophrenia patients compared with a group of age- and gender-matched healthy controls...
April 26, 2017: Psychological Medicine
https://www.readbyqxmd.com/read/28428755/pharmacological-analysis-of-the-anti-epileptic-mechanisms-of-fenfluramine-in-scn1a-mutant-zebrafish
#12
Jo Sourbron, Ilse Smolders, Peter de Witte, Lieven Lagae
Dravet syndrome (DS) is a genetic encephalopathy that is characterized by severe seizures and prominent co-morbidities (e.g., physical, intellectual disabilities). More than 85% of the DS patients carry an SCN1A mutation (sodium channel, voltage gated, type I alpha subunit). Although numerous anti-epileptic drugs have entered the market since 1990, these drugs often fail to adequately control seizures in DS patients. Nonetheless, current clinical data shows significant seizure reduction in DS patients treated with the serotonergic (5-hydroxytryptamine, 5-HT) drug fenfluramine (FA)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28425496/3-4-methylenedioxymethamphetamine-increases-affiliative-behaviors-in-squirrel-monkeys-in-a-serotonin-2a-receptor-dependent-manner
#13
Elizabeth G Pitts, Adelaide R Minerva, Erika B Oliver, Jordan N Kohn, Meghan T Logun, Agnieszka Sulima, Kenner C Rice, Leonard L Howell
3,4-methylenedioxymethamphetamine (MDMA) increases sociality in humans and animals. Release of serotonin (5-HT) is thought to play an important role in the increase in social behaviors, but the mechanisms underlying these effects are poorly understood. Despite the advantages of nonhuman primate models, no studies have examined the mechanisms of the social effects of MDMA in nonhuman primates. The behavior and vocalizations of four group-housed squirrel monkeys were examined following administration of MDMA, its enantiomers, and methamphetamine...
April 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28411124/m3-muscarinic-acetylcholine-receptor-facilitates-the-endocytosis-of-mu-opioid-receptor-mediated-by-morphine-independently-of-the-formation-of-heteromeric-complexes
#14
Juan F Lopez-Gimenez, Elisa Alvarez-Curto, Graeme Milligan
Morphine inefficiency to induce the internalization of mu opioid (MOP) receptors observed in numerous experimental models constitutes a paradigm of G-protein coupled receptor (GPCR) functional selectivity. We recently described that activation of Gαq/11 proteins through 5-HT2A serotonin receptors co-expressed in the same cells facilitates MOP receptor endocytosis promoted by morphine. In order to explore whether a different Gαq/11 coupled GPCR would emulate this effect, a double stable Flp-In T-REx HEK293 cell line permanently expressing MOP-YFP receptors along with FLAG-M3-Cerulean receptors expressed in an inducible manner was generated...
April 11, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28404690/pharmacologic-characterization-of-valbenazine-nbi-98854-and-its-metabolites
#15
Dimitri E Grigoriadis, Evan Smith, Sam R J Hoare, Ajay Madan, Haig Bozigian
The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is being developed for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)-α-dihydrotetrabenazine (R,R,R-DHTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand binding studies were conducted to assess and compare valbenazine, tetrabenazine and their respective metabolites in their abilities to selectively and potently inhibit [(3)H]-DHTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28401524/chemistry-and-structure-activity-relationships-of-psychedelics
#16
David E Nichols
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-HT2A 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...
March 26, 2017: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/28397671/-flibanserin-as-pharmacological-therapy-of-inhibited-sexual-desire-in-women
#17
Anne Sofie Eldon, Annamaria Giraldi
Flibanserin was approved by the Food and Drug Administration in the USA in August 2015 as the first drug for the treatment of American women with the dysfunction hypoactive sexual desire disorder (HSDD) and is a 5-HT1A agonist and 5-HT2A antagonist. The neurophysiological effects of flibanserin on these receptors are consistent with the clinical effects, i.e. significantly increasing sexual desire and frequency of satisfying sexual experiences. As such, shifting the balance between inhibitory and excitatory neurotransmitters of importance to sexual desire, flibanserin pharmacologically broaches a possible new approach to the treatment of HSDD...
February 13, 2017: Ugeskrift for Laeger
https://www.readbyqxmd.com/read/28394294/relationship-between-occupational-stress-5-ht2a-receptor-polymorphisms-and-mental-health-in-petroleum-workers-in-the-xinjiang-arid-desert-a-cross-sectional-study
#18
Ting Jiang, Hua Ge, Jian Sun, Rong Li, Rui Han, Jiwen Liu
At present, there is growing interest in research examining the relationship between occupational stress and mental health. Owing to the socioeconomic impact of occupational stress and the unique environment of petroleum workers in Xinjiang, a cross-sectional study was carried out between April and December 2015 to investigate the relationship between occupational stress, 5-hydroxytryptamine receptor (5-HTR2A) genotype, and mental health. A total of 1485 workers were selected. The Symptom Checklist 90 was used to assess nine classes of psychological symptoms...
April 10, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/28386699/dreamlike-effects-of-lsd-on-waking-imagery-in-humans-depend-on-serotonin-2a-receptor-activation
#19
Rainer Kraehenmann, Dan Pokorny, Leonie Vollenweider, Katrin H Preller, Thomas Pokorny, Erich Seifritz, Franz X Vollenweider
RATIONALE: Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming. OBJECTIVES: This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects. METHODS: Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally)...
April 7, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28380327/interaction-between-harmane-a-class-of-%C3%AE-carboline-alkaloids-and-the-ca1-serotonergic-system-in-modulation-of-memory-acquisition
#20
Mohammad Nasehi, Fatemeh Ghadimi, Fatemeh Khakpai, Mohammad-Reza Zarrindast
This study set to assess the involvement of dorsal hippocampus (CA1) serotonergic system on harmane induced memory acquisition deficit. We used one trial step-down inhibitory avoidancetask to evaluate memory retention and then, open field test to evaluate locomotor activity in adult male NMRI mice. The results showed that pre-training intra-peritoneal (i.p.) administration of harmane (12mg/kg) induced impairment of memory acquisition. Pre-training intra-CA1 administration of 5-HT1B/1D receptor agonist (CP94253; 0...
April 2, 2017: Neuroscience Research
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