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Serotonin receptor 2c

Jianjun Cheng, John D McCorvy, Patrick M Giguère, Hu Zhu, Terry Kenakin, Bryan L Roth, Alan P Kozikowski
Based on the structural similarity of our previous 5-HT2C agonists with the melatonin receptor agonist tasimelteon, and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment...
October 11, 2016: Journal of Medicinal Chemistry
Steven F Grieco, Dmitry Velmeshev, Marco Magistri, Hagit Eldar-Finkelman, Mohammad A Faghihi, Richard S Jope, Eleonore Beurel
OBJECTIVES: We examined mechanisms that contribute to the rapid antidepressant effect of ketamine in mice that is dependent on glycogen synthase kinase-3 (GSK3) inhibition. METHODS: We measured serotonergic (5HT)-2C-receptor (5HTR2C) cluster microRNA (miRNA) levels in mouse hippocampus after administering an antidepressant dose of ketamine (10 mg/kg) in wild-type and GSK3 knockin mice, after GSK3 inhibition with L803-mts, and in learned helpless mice. RESULTS: Ketamine up-regulated cluster miRNAs 448-3p, 764-5p, 1264-3p, 1298-5p and 1912-3p (2- to 11-fold)...
October 10, 2016: World Journal of Biological Psychiatry
Raphaël Lafleur-Lambert, John Boukouvalas
The first enantioselective synthesis of the fungal metabolite (+)-O-methylasparvenone was achieved in eight steps and 22% overall yield from inexpensive 3,4,5-trimethoxybenzaldehyde dimethyl acetal. Key steps include (i) early-stage asymmetric alkynylation of an aromatic aldehyde with a propiolate, (ii) intramolecular Friedel-Crafts acylation, and (iii) site-selective cleavage of an aryl methyl ether.
September 21, 2016: Organic & Biomolecular Chemistry
Ronald Christopher, Mike Morgan, Jim Ferry, Bhaskar Rege, Yong Tang, Allan Kristensen, William Shanahan
PURPOSE: Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration-approved, extended-release, 20-mg once-daily formulation. METHODS: We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions...
September 27, 2016: Clinical Therapeutics
Kyoko Yoshida, Yasuhiro Go, Itaru Kushima, Atsushi Toyoda, Asao Fujiyama, Hiroo Imai, Nobuhito Saito, Atsushi Iriki, Norio Ozaki, Masaki Isoda
Atypical neurodevelopment in autism spectrum disorder is a mystery, defying explanation despite increasing attention. We report on a Japanese macaque that spontaneously exhibited autistic traits, namely, impaired social ability as well as restricted and repetitive behaviors, along with our single-neuron and genomic analyses. Its social ability was measured in a turn-taking task, where two monkeys monitor each other's actions for adaptive behavioral planning. In its brain, the medial frontal neurons responding to others' actions, abundant in the controls, were almost nonexistent...
September 2016: Science Advances
Yehuda Handelsman, Randi Fain, Zhixiao Wang, Xuan Li, Ken Fujioka, William Shanahan
OBJECTIVES: Lorcaserin is a serotonin 2C receptor agonist approved for chronic weight management. This analysis explores the number of patients needed to be treated (NNT) with lorcaserin for one more patient to achieve weight loss and glycemic goals. METHODS: This is a post hoc analysis of three Phase 3 studies in adults with and without type 2 diabetes mellitus (T2DM) treated with lorcaserin 10 mg BID or placebo. NNT is reported for patients achieving ≥5% or ≥10% weight loss, achievement of either HbA1c <5...
September 23, 2016: Postgraduate Medicine
Katherine M Serafine, Kenner C Rice, Charles P France
Lorcaserin is approved by the Food and Drug Administration for treating obesity and is under consideration for treating substance use disorders; it has agonist properties at serotonin (5-HT)2C receptors and might also have agonist properties at other 5-HT receptor subtypes. This study used drug discrimination to investigate the mechanism(s) of action of lorcaserin. Male Sprague-Dawley rats discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed-ratio 5 schedule for food. Lorcaserin (0...
September 2016: Journal of the Experimental Analysis of Behavior
F L Greenway, W Shanahan, R Fain, T Ma, D Rubino
Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials...
October 2016: Clinical Obesity
Ricardo de Oliveira, Rithiele Cristina de Oliveira, Luiz Luciano Falconi-Sobrinho, Raimundo da Silva Soares, Norberto Cysne Coimbra
The electrical stimulation of the dorsolateral columns of the periaquedutal grey matter (dlPAG) or deep layers of the superior colliculus (dlSC) evokes defensive behaviours followed by an antinociceptive response. Monoaminergic brainstem reticular nuclei are suggested to comprise the endogenous pain modulatory system. The aim of the present work was to investigate the role played by 5-HT2 subfamily of serotonergic receptors of the nucleus raphe magnus (NRM) and the gigantocellularis/paragigantocellularis pars α reticular nuclei (Gi/PGiα) in the elaboration of instinctive fear-induced antinociception elicited by electrical stimulation of dlPAG or of dlSC...
January 1, 2017: Behavioural Brain Research
Lingli Hu, Chunhua Liu, Minyan Dang, Bin Luo, Yiping Guo, Haitao Wang
The abundant forebrain serotonergic projections are believed to modulate the activities of cortical neurons. 5-HT2 receptor among multiple subtypes of serotonin receptors contributes to the modulation of excitability, synaptic transmissions and plasticity. In the present study, whole-cell patch-clamp recording was adopted to examine whether activation of 5-HT2A/2C receptors would have any impact on the excitability of cultured cortical neurons. We found that 2,5-Dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT2A/2C receptor agonist, rapidly and reversibly depressed spontaneous action potentials mimicking the effect of serotonin...
October 6, 2016: Neuroscience Letters
D Weissmann, S van der Laan, M D Underwood, N Salvetat, L Cavarec, L Vincent, F Molina, J J Mann, V Arango, J F Pujol
Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT2CR receptor editing in suicide is region-specific...
2016: Translational Psychiatry
Ruiyong Wu, Jun Gao, Shinnyi Chou, Collin Davis, Ming Li
As a highly motivated social behavior, maternal behavior in rats has been routinely used to study psychoactive drugs for clinical, neuroscience and pharmacological purposes. Recent evidence indicates that acute activation of serotonin 2C (5-HT2C) receptors causes a disruption of rat maternal behavior. The present study was designed to elucidate the behavioral, pharmacological mechanisms and neuroanatomical basis of this 5-HT2C effect. First, we replicated the finding that acute MK212 injection (2.0mg/kg, a highly selective 5-HT2C agonist) disrupts maternal behavior, especially on pup retrieval...
November 2016: Psychoneuroendocrinology
Erum Shireen
Antipsychotic drugs are extensively prescribed for the treatment of schizophrenia and other related psychiatric disorders. These drugs produced their action by blocking dopamine (DA) receptors, and these receptors are widely present throughout the brain. Therefore, extended antipsychotic use also leads to severe extrapyramidal side effects. The short-term effects include parkinsonism and the later appearing tardive dyskinesia. Currently available treatments for these disorders are mostly symptomatic and insufficient, and are often linked with a number of detrimental side effects...
2016: Journal of Experimental Pharmacology
Pingwen Xu, Yanlin He, Xuehong Cao, Lourdes Valencia-Torres, Xiaofeng Yan, Kenji Saito, Chunmei Wang, Yongjie Yang, Antentor Hinton, Liangru Zhu, Gang Shu, Martin G Myers, Qi Wu, Qingchun Tong, Lora K Heisler, Yong Xu
BACKGROUND: Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. METHODS: We combined neuroanatomic, pharmacologic, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-hydroxytryptamine (5-HT) 2C receptor (5-HT2CR) expressed by dopamine (DA) neurons in the regulation of binge-like eating behavior in mice. RESULTS: We showed that 5-HT stimulates DA neural activity through a 5-HT2CR-mediated mechanism, and activation of this midbrain 5-HT→DA neural circuit effectively inhibits binge-like eating behavior in mice...
June 9, 2016: Biological Psychiatry
M Wierucka-Rybak, M Wolak, M Juszczak, J Drobnik, E Bojanowska
Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0...
June 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Carlos M Villalón, Antoinette Maassen VanDenBrink
Migraine is a highly prevalent neurovascular disorder. Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5 HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder...
July 28, 2016: Mini Reviews in Medicinal Chemistry
D J David, D Gourion
Antidepressant therapy aims to reach remission of depressive symptoms while reducing the complications and risks of relapse. Even though they have proven their efficacy, it takes several weeks for antidepressants to demonstrate full effectiveness, and adverse effects occur more quickly or (quicker) which can be a source of poor compliance. This latest aspect often leads to dose reduction and/or change of molecule that have the effect of delaying remission. This review attempts to present, from the pharmacological properties of the major classes of antidepressants (monoamine oxidase inhibitor [MAOI], tricyclic antidepressants [TCA], selective serotonin reuptake inhibitor [SSRI] and serotonin and noradrenaline reuptake inhibitor [SNRI]), to the pharmacological mechanisms involved in adverse effects by focusing on sexual dysfunction, nausea/vomiting, and weight changes...
July 13, 2016: L'Encéphale
Zhaiyi Zhang, Manli Shen, Paul J Gresch, Masoud Ghamari-Langroudi, Alexander G Rabchevsky, Ronald B Emeson, Stefan Stamm
The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full-length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full-length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full-length, constitutively active receptor at the cell surface...
2016: EMBO Molecular Medicine
Olivia M Farr, Jagriti Upadhyay, Anna Gavrieli, Michelle Camp, Nikolaos Spyrou, Harper Kaye, Hannah Mathew, Maria Vamvini, Anastasia Koniaris, Holly Kilim, Alexandra Srnka, Alexandra Migdal, Christos S Mantzoros
Lorcaserin is a serotonin 5-hydroxytryptamine 2c receptor agonist effective in treating obesity. Studies in rodents have shown that lorcaserin acts in the brain to exert its weight-reducing effects, but this has not yet been studied in humans. We performed a randomized, placebo-controlled, double-blind trial with 48 obese participants and used functional MRI to study the effects of lorcaserin on the brain. Subjects taking lorcaserin had decreased brain activations in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state...
October 2016: Diabetes
Jaya Thomas, R Khanam, Divya Vohora
Agomelatine is a novel antidepressant with agonistic actions at melatonergic (MT1 and MT2 receptors) and antagonistic actions at 5HT-2C receptors. Venlafaxine, a serotonin norepinephrine reuptake inhibitor, is a widely prescribed drug in depression. The present study evaluated the low dose combinations of venlafaxine and agomelatine in chronic forced swim test (chronic FST) and tail suspension test (TST) in mice. Further, the effect of above drugs and their combination was evaluated on serum pro-inflammatory cytokines and hippocampal indole amine 2, 3 dioxygenase (IDO) activity by calculating the ratios of kynurenine/tryptophan (KYN/TRP) and serotonin/tryptophan (5HT/TRP)...
October 2016: Neurochemistry International
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