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Megan Andrews, Babak Tousi, Marwan N Sabbagh
Alzheimer's disease is an important condition with a considerable and unmet disease burden in large need of continued research and more treatment options. The 5HT6 antagonists are a new class of medications to be offered. Because they are pro-cholinergic, these medications are to be used as adjuncts to acetylcholinesterase inhibitors (such as donepezil), further increasing acetylcholine in the central nervous system (CNS). Early trials of the 5HT6 antagonists showed improvements in cognition and activities of daily living when used as adjuncts to current therapies for Alzheimer's dementia...
May 2, 2018: Neurology and Therapy
Aarti Sawant-Basak, R Scott Obach, Angela Doran, Peter Lockwood, Klaas Schildknegt, Hongying Gao, Jessica Mancuso, Susanna Tse, Thomas A Comery
SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean C max and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively...
July 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Magdalena Kotańska, Klaudia Lustyk, Adam Bucki, Monika Marcinkowska, Joanna Śniecikowska, Marcin Kołaczkowski
Obesity, from early childhood onwards, is a common societal problem. The overconsumption of sweet, salty and high-fat products are the main factors that cause excessive weight gain. It is therefore necessary to search for new drugs that affect satiety centers and reduce the sense of hunger and caloric intake. It has been suggested that the blockade of 5-HT6 receptors may reduce food intake, and since idalopirdine is a clinically tested, selective 5HT6 receptor antagonist, it was chosen to be examined in animal models of obesity...
January 3, 2018: Metabolic Brain Disease
Magdalena Jastrzębska-Więsek, Agata Siwek, Anna Partyka, Marcin Kołaczkowski, Maria Walczak, Magdalena Smolik, Gniewomir Latacz, Katarzyna Kieć-Kononowicz, Anna Wesołowska
The effect of some antidepressants co-administered with EMD386088 in the modified forced swim test in rats was investigated. Additionally, the pharmacokinetics, metabolic stability, and the effect of EMD386088 on P450 cytochromes were determined. Intraperitoneal (i.p.) coadministration of EMD386088 (2.5 mg/kg) and imipramine (15 mg/kg), reboxetine (5 mg/kg), moclobemide (10 mg/kg), or bupropion (10 mg/kg) evoked significant antidepressant-like activity, whereas no effect was observed after joint administration of EMD386088 with s-citalopram (10 mg/kg)...
January 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Magdalena Dudek, Monika Marcinkowska, Adam Bucki, Adrian Olczyk, Marcin Kołaczkowski
5HT6 receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined...
December 2015: Metabolic Brain Disease
Christine A Parker, Eugenii A Rabiner, Roger N Gunn, Graham Searle, Laurent Martarello, Robert A Comley, Maria Davy, Alan A Wilson, Sylvain Houle, Romina Mizrahi, Marc Laruelle, Vincent J Cunningham
UNLABELLED: Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d)...
December 2015: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Z Naumovska, A K Nestorovska, A Filipce, Z Sterjev, K Brezovska, A Dimovski, L J Suturkova
Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety...
2015: Prilozi (Makedonska Akademija Na Naukite i Umetnostite. Oddelenie za Medicinski Nauki)
Kun-Cheng Liu, Jun-Yi Li, Hui-Hui Tan, Cheng-Xue Du, Wen Xie, Yu-Ming Zhang, Wei-Lin Ma, Li Zhang
Preclinical studies indicate both activation and blockade of serotonin6 (5-HT6) receptors may produce antidepressant-like effects. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT6 receptors in the dorsal hippocampus (DH) involve in the regulation of PD-associated depression. Unilateral 6-hydroxydopamine lesions of the medial forebrain bundle in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats...
August 2015: Neuropharmacology
Renny Abraham, Ramakrishna Nirogi, Anil Shinde
BACKGROUND: It is a well-known fact that 5HT6 ligands increase glutamate levels. In the current study we investigated whether a 5HT6 antagonist, SB399885 would show antidepressant like property at a dose which would significantly increase the glutamate levels. Further we studied if the combination of a 5HT6 antagonist and N-methyl-D-aspartate (NMDA) antagonist, memantine would restore the antidepressant property. As dementia and depression are co-morbid, we evaluated if this combination would have an effect on cognition...
June 2014: Pharmacological Reports: PR
Akos Tarcsay, Gábor Paragi, Márton Vass, Balázs Jójárt, Ferenc Bogár, György M Keserű
The formation of ligand-protein complexes requires simultaneous adaptation of the binding partners. In structure based virtual screening, high throughput docking approaches typically consider the ligand flexibility, but the conformational freedom of the protein is usually taken into account in a limited way. The goal of this study is to elaborate a methodology for incorporating protein flexibility to improve the virtual screening enrichments on GPCRs. Explicit-solvated molecular dynamics simulations (MD) were carried out in lipid bilayers to generate an ensemble of protein conformations for the X-ray structures and homology models of both aminergic and peptidergic GPCRs including the chemokine CXCR4, dopamine D3, histamine H4, and serotonin 5HT6 holo receptor complexes...
November 25, 2013: Journal of Chemical Information and Modeling
Margarita A Morozova, Taisiya A Lepilkina, Georgy E Rupchev, Allan G Beniashvily, Denis S Burminskiy, Sergey S Potanin, Evgeny V Bondarenko, Vasily I Kazey, Yan Lavrovsky, Alexandre V Ivachtchenko
UNLABELLED: The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia. OBJECTIVE: To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment. METHODS: A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed...
August 2014: CNS Spectrums
Núria Cruz, Eduard Vieta
DEVELOPMENT: Asenapine, recently marketed in United States and ready to be so in Europe, is a multimodal action second-generation antipsychotic, with high affinity for multiple dopaminergic (D2, D3 y D4), serotonergic (5HT2A, 5HT2B, 5HT2C, 5HT6 and 5HT7) and adrenergic (α1A, α2A, α2B and α2C) receptors. Asenapine has to be administered sublingually. After going through succesfully the preliminary phases of development, several clinical trials have been completed in two main indications: schizophrenia and mania...
April 2011: Revista de Psiquiatrí́a y Salud Mental
Sarah M Guadiana, Susan Semple-Rowland, Daniel Daroszewski, Irina Madorsky, Joshua J Breunig, Kirk Mykytyn, Matthew R Sarkisian
The formation of primary cilia is a highly choreographed process that can be disrupted in developing neurons by overexpressing neuromodulatory G-protein-coupled receptors GPCRs or by blocking intraflagellar transport. Here, we examined the effects of overexpressing the ciliary GPCRs, 5HT6 and SSTR3, on cilia structure and the differentiation of neocortical neurons. Neuronal overexpression of 5HT6 and SSTR3 was achieved by electroporating mouse embryo cortex in utero with vectors encoding these receptors. We found that overexpression of ciliary GPCRs in cortical neurons, especially 5HT6, induced the formation of long (>30 μm) and often forked cilia...
February 6, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Adrián Llerena, Roland Berecz, Eva Peñas-Lledó, Agnes Süveges, Humberto Fariñas
Despite risperidone's proven safety and efficacy, existing pharmacogenetic knowledge could be applied to improve its clinical use. The present work aims to summarize the information about genetic polymorphisms affecting risperidone adverse reactions and efficacy during routine clinical practice. The most relevant genes involved in the metabolism of the drug (i.e., CYP2D6, CYP3A and ABCB1) appear to have the greatest potential to predict differences in plasma concentrations of the drug and its interactions, but also relate to side effects, such as neuroleptic syndrome, weight gain or polydipsia...
January 2013: Pharmacogenomics
Charlotte K Callaghan, Vincent Hok, Andrea Della-Chiesa, David J Virley, Neil Upton, Shane M O'Mara
Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system in particular plays an important role in attention, alertness and cognition. Disturbances in serotonergic function have been implicated in differing neurological and neuropsychiatric disorders including depression, psychosis aggression and dementia. The serotonin receptor subtype 5HT6 is distributed within CNS regions relevant to learning and memory, including the striatum, cortex and hippocampus...
October 2012: Neuropharmacology
Sabina Cevoli, Nadia Marzocchi, Sabina Capellari, Chiara Scapoli, Giulia Pierangeli, Daniela Grimaldi, Federica Naldi, L Alberto Pini, Pasquale Montagna, Pietro Cortelli
Serotonin is involved in several central nervous system functions including pain threshold, mood regulation and drug reward. Overuse of acute medications is commonly identified as a causative factor for medication overuse headache (MOH). Apparently, MOH shares with other kinds of drug addiction some common neurobiological pathways. The objective of this study is to assess the role of serotonin metabolism genes in the genetic liability to MOH. We performed a genetic association study using polymorphisms of five serotonin metabolism-related genes: serotonin transporter (5HTT), serotonin receptor 1A(5-HT1A), serotonin receptor 1B (5-HT1B), serotonin receptor 2A (5-HT2A) and serotonin receptor 6 (5HT6)genes...
February 2010: Journal of Headache and Pain
Shrinivas K Kulkarni, Ashish Dhir
BACKGROUND: The World Health Organization (WHO) report has predicted that major depression will become a key cause of illness-induced disability by the year 2020, second only to ischemic heart diseases. OBJECTIVES/METHODS: Although a large number of antidepressant drugs (from monoamine oxidase inhibitors and tricyclic antidepressants to dual reuptake inhibitors) are available for treatment of the disease, approximately 30% of patients failed to respond to this therapy...
June 2009: Expert Opinion on Investigational Drugs
Stephen R Morairty, Linda Hedley, Judith Flores, Renee Martin, Thomas S Kilduff
STUDY OBJECTIVES: Serotonin (5-HT) has long been implicated in the control of sleep and wakefulness. This study evaluated the hypnotic efficacy of the 5-HT6 antagonist RO4368554 (RO) and the 5-HT2A receptor antagonist MDL100907 (MDL) relative to zolpidem. DESIGN: A randomized, repeated-measures design was utilized in which Wistar rats received intraperitoneal injections of RO (1.0, 3.0, and 10 mg/kg), MDL (0.1, 1.0 and 3.0 mg/kg), zolpidem (10 mg/kg), or vehicle in the middle of the dark (active) period...
January 2008: Sleep
Remigiusz Zieba
This review summarizes data on currently used antiobesity drugs and new compounds under clinical development. Three antiobesity drugs are currently accepted for long-term use. Sibutramine is a noradrenaline and serotonin reuptake inhibitor which reduces body weight by about 4-5 kg but increases heart rate and arterial blood pressure. Orlistat is a gastrointestinal lipase inhibitor which results in mean weight loss by about 3 kg and reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance; however, adverse gastrointestinal effects have been observed...
October 19, 2007: Postȩpy Higieny i Medycyny Doświadczalnej
Najam A Sharif, Michelle Senchyna
PURPOSE: To determine the relative density and tissue localization of mRNAs for serotonin (5-hydroxytryptamine; 5HT) receptor subtypes in human ocular tissues and correlate with their possible functions in the eye. METHODS: Total RNA was extracted from human ocular tissues samples from multiple donors and transcribed into cDNA. An optimized reverse transcriptase polymerase chain reaction (RT-PCR) procedure was then used to amplify the signals using primers designed against human 5HT receptor cDNAs...
2006: Molecular Vision
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