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H3 antagonist

Jung Kim, Yongik Lee, Xiaodong Lu, Bing Song, Ka-Wing Fong, Qi Cao, Jonathan D Licht, Jonathan C Zhao, Jindan Yu
Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively...
December 4, 2018: Cell Reports
Steven T Szabo, Michael J Thorpy, Geert Mayer, John H Peever, Thomas S Kilduff
Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Although only a few drugs have received regulatory approval for narcolepsy to date, treatment involves diverse medications that affect multiple biochemical targets and neural circuits. Clinical trials have demonstrated efficacy for the following classes of drugs as narcolepsy treatments: alerting medications (amphetamine, methylphenidate, modafinil/armodafinil, solriamfetol [JZP-110]), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), sodium oxybate, and the H3 -receptor inverse agonist/antagonist pitolisant...
November 8, 2018: Sleep Medicine Reviews
A P Casani, G Guidetti, R Schoenhuber
Ménière's disease is a disorder of the inner ear that causes vertigo, tinnitus, fullness and hearing loss. Although several treatments are available, the success rate is reported to be around 70%, similar to placebo. Betahistine, a weak H1 receptor agonist and an effective H3 receptor antagonist, is frequently prescribed for Ménière's disease, especially to reduce recurrent vertigo attacks. The effects of this drug on hearing and other audiological symptoms remains unclear. Given the inconclusive reports in the literature, we proposed a consensus conference on the use of betahistine in Ménière's disease...
October 2018: Acta Otorhinolaryngologica Italica
James M Stafford, Chul-Hwan Lee, Philipp Voigt, Nicolas Descostes, Ricardo Saldaña-Meyer, Jia-Ray Yu, Gary Leroy, Ozgur Oksuz, Jessica R Chapman, Fernando Suarez, Aram S Modrek, N Sumru Bayin, Dimitris G Placantonakis, Matthias A Karajannis, Matija Snuderl, Beatrix Ueberheide, Danny Reinberg
A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M...
October 2018: Science Advances
Mizuki Watanabe, Takaaki Kobayashi, Yoshihiko Ito, Hayato Fukuda, Shizuo Yamada, Mitsuhiro Arisawa, Satoshi Shuto
We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3 /H4 antagonist, thioperamide...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Alaa Alachkar, Dorota Łażewska, Gniewomir Latacz, Annika Frank, Agata Siwek, Annamaria Lubelska, Ewelina Honkisz-Orzechowska, Jadwiga Handzlik, Holger Stark, Katarzyna Kieć-Kononowicz, Bassem Sadek
A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists ( 1 ⁻ 16 ) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2...
October 29, 2018: International Journal of Molecular Sciences
Bin Li, Yanan Zhu, Haiyun Chen, Hui Gao, Hangyuan He, Na Zuo, Linguo Pei, Wen Xie, Liaobin Chen, Ying Ao, Hui Wang
This study aimed to demonstrate that prenatal dexamethasone exposure (PDE) can induce kidney dysplasia in utero and adult glomerulosclerosis in male offspring, and to explore the underlying intrauterine programming mechanisms. Pregnant rats were subcutaneously administered dexamethasone 0.2 mg/kg.d from gestational day (GD) 9 to GD20. The male fetus on GD20 and the adult offspring at age of postnatal week 28 were analyzed. The adult offspring kidneys in the PDE group displayed glomerulosclerosis, elevated levels of serum creatinine and urine protein, ultrastructural damage of podocytes, the reduced expression levels of podocyte marker genes, nephrin and podocin...
October 22, 2018: Toxicology
Darren M Riddy, Anna E Cook, David M Shackleford, Tracie L Pierce, Elisabeth Mocaer, Clotilde Mannoury la Cour, Aurore Sors, William N Charman, Roger J Summers, Patrick M Sexton, Arthur Christopoulos, Christopher J Langmead
The histamine H3 receptor is a G protein-coupled receptor (GPCR) drug target that is highly expressed in the CNS, where it acts as both an auto- and hetero-receptor to regulate neurotransmission. As such, it has been considered as a relevant target in disorders as varied as Alzheimer's disease, schizophrenia, neuropathic pain and attention deficit hyperactivity disorder. A range of competitive antagonists/inverse agonists have progressed into clinical development, with pitolisant approved for the treatment of narcolepsy...
October 22, 2018: Neuropharmacology
Ekaterini Tiligada, Madeleine Ennis
Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho) physiological processes. It elicits its multifaceted modulatory functions by activating four types of G-protein-coupled receptors, designated as H1-4 . Despite the heterogeneity and the complexity of histamine receptor pharmacology, many discoveries over the past 100 years resulted in the development of H1 antihistamines and H2 -targeting 'blockbuster' therapeutics for the management of allergies and gastrointestinal disorders, respectively...
October 19, 2018: British Journal of Pharmacology
Jian Xin, Min Hu, Qian Liu, Tian Tai Zhang, Dong Mei Wang, Song Wu
Histamine H3 receptor (H3 R), a kind of G-protein coupled receptor (GPCR), is expressed mainly in the central nervous system (CNS) and plays a vital role in homoeostatic control. This study describes the design and synthesis of a series of novel H3 R antagonists based on the iso-flavone scaffold. The results of the bioactivity evaluation show that four compounds (1c, 2c, 2h, and 2o) possess significant H3 R inhibitory activities. Molecular docking indicates that a salt bridge, π-π T-shape interactions, and hydrophobic interaction all contribute to the interaction between compound 2h and H3 R...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Tamara A M Mocking, Eléonore W E Verweij, Henry F Vischer, Rob Leurs
Receptor-binding affinity and ligand-receptor residence time are key parameters for the selection of drug candidates and are routinely determined using radioligand competition-binding assays. Recently, a novel bioluminescence resonance energy transfer (BRET) method utilizing a NanoLuc-fused receptor was introduced to detect fluorescent ligand binding. Moreover, this NanoBRET method gives the opportunity to follow fluorescent ligand binding on intact cells in real time, and therefore, results might better reflect in vivo conditions as compared with the routinely used cell homogenates or purified membrane fractions...
December 2018: Molecular Pharmacology
Claire-Marie Rangon, Anne-Laure Schang, Juliette Van Steenwinckel, Leslie Schwendimann, Sophie Lebon, Tingting Fu, Libo Chen, Veronique Beneton, Nathalie Journiac, Pierrette Young-Ten, Thomas Bourgeois, Johanna Maze, Boris Matrot, Ana A Baburamani, Veena Supramaniam, Carina Mallard, Lionel Trottet, A David Edwards, Henrik Hagberg, Bobbi Fleiss, Jingjun Li, Tsu Tshen Chuang, Pierre Gressens
Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination...
September 12, 2018: Brain, Behavior, and Immunity
Evelyn M Guilherme, Bruna Silva-Marques, Carlos Eduardo M Fernandes, Thiago L Russo, Rosana Mattioli, Anna C Gianlorenço
The neural histaminergic system innervates the cerebellum, with a high density of fibers in the vermis and flocculus. The cerebellum participates in motor functions, but the role of the histaminergic system in this function is unclear. In the present study, we investigated the effects of intracerebellar histamine injections and H1, H2 and H3 receptor antagonist injections (chlorpheniramine, ranitidine, and thioperamide, respectively) and H4 receptor agonist (VUF-8430) on locomotor and exploratory behaviors in mice...
September 12, 2018: Neuroscience Letters
Ming Gao, Xiu-Ling Deng, Zhen-Hua Liu, Hui-Jie Song, Juan Zheng, Zhen-Hai Cui, Kang-Li Xiao, Lu-Lu Chen, Hui-Qing Li
AIMS: Catch-up growth after a period of nutritional deprivation in adulthood is related to the onset of metabolic disorders. This process involves chromatin remodelling of the Pdx-1 gene in pancreas. The objective of this study was to determine the chromatin remodelling mechanism of GLP-1 analogue Liraglutide upon Pdx-1 in catch-up growth rats in vivo and in vitro. METHODS: Five-week-old male specific pathogen free (SPF) Wistar rats were randomly divided into normal group, catch-up growth group and Liraglutide group...
November 2018: Journal of Diabetes and its Complications
Nermin Eissa, Petrilla Jayaprakash, Sheikh Azimullah, Shreesh K Ojha, Mohammed Al-Houqani, Fakhreya Y Jalal, Dorota Łażewska, Katarzyna Kieć-Kononowicz, Bassem Sadek
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i...
August 30, 2018: Scientific Reports
Linda J Kay, S Kim Suvarna, Peter T Peachell
The diverse effects of histamine are mediated by discrete histamine receptors. The principal repository of histamine in the body is the mast cell. However, the effects of histamine on mast cells, especially those of human origin, have not been fully elucidated. In this study, the expression of histamine receptors in human lung mast cells was evaluated. Moreover, the effects of histamine receptor engagement on both mediator release and chemotaxis were investigated. Mast cells were isolated and purified from human lung tissue...
August 24, 2018: European Journal of Pharmacology
Jie Zheng, Cesar Corzo, Mi Ra Chang, Jinsai Shang, Vinh Q Lam, Richard Brust, Anne-Laure Blayo, John B Bruning, Theodore M Kamenecka, Douglas J Kojetin, Patrick R Griffin
Peroxisome proliferator-activated receptors (PPARs) are pharmacological targets for the treatment of metabolic disorders. Previously, we demonstrated the anti-diabetic effects of SR1664, a PPARγ modulator lacking classical transcriptional agonism, despite its poor pharmacokinetic properties. Here, we report identification of the antagonist SR11023 as a potent insulin sensitizer with significant plasma exposure following oral administration. To determine the structural mechanism of ligand-dependent antagonism of PPARγ, we employed an integrated approach combining solution-phase biophysical techniques to monitor activation helix (helix 12) conformational dynamics...
November 6, 2018: Structure
Nasir Niaz, Gokcen Guvenc, Burcin Altinbas, Mehmed Berk Toker, Begum Aydin, Duygu Udum-Kucuksen, Selim Alcay, Elif Gokce, Burcu Ustuner, Murat Yalcin
Brain histamine holds a key position in the regulation of behavioral states, biological rhythms, body weight, energy metabolism, thermoregulation, fluid balance, stress and reproduction in female animals. However, it is not clear whether central histamine exerts any effect on hypothalamic-pituitary-testicular in male rats and if so, the involvement of type of central histamine receptors. The current study was designed to determine the effect of centrally administrated histamine on plasma gonadotropin hormone-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone level, and sperm parameters, and to show the mediation of the central histaminergic H1, H2 and H3/H4 receptors on histamine-evoked hormonal and sperm parameters' effects...
August 18, 2018: Brain Research
Abhinav Adhikari, Judith Davie
BACKGROUND: JARID2 is a non-catalytic member of the polycomb repressive complex 2 (PRC2), which is known to regulate developmental target genes in embryonic stem cells. Here, we provide mechanistic insight into the modulation of Wnt signaling by JARID2 during murine skeletal muscle differentiation. RESULTS: We show that JARID2 is expressed in proliferating myoblasts, but downregulated upon muscle differentiation. Unexpectedly, depletion of JARID2 or the catalytic subunit of the PRC2 complex, EZH2, inhibited differentiation, suggesting that JARID2 and the PRC2 complex are required to initiate this process...
August 17, 2018: Epigenetics & Chromatin
Betina González, Oscar V Torres, Subramaniam Jayanthi, Natalia Gomez, Máximo H Sosa, Alejandra Bernardi, Francisco J Urbano, Edgar García-Rill, Jean-Lud Cadet, Verónica Bisagno
METH use causes neuroadaptations that negatively impact the prefrontal cortex (PFC) leading to addiction and associated cognitive decline in animals and humans. In contrast, modafinil enhances cognition by increasing PFC function. Accumulated evidence indicates that psychostimulant drugs, including modafinil and METH, regulate gene expression via epigenetic modifications. In this study, we measured the effects of single-dose injections of modafinil and METH on the protein levels of acetylated histone H3 (H3ac) and H4ac, deacetylases HDAC1 and HDAC2, and of the NMDA subunit GluN1 in the medial PFC (mPFC) of mice euthanized 1 h after drug administration...
January 10, 2019: Progress in Neuro-psychopharmacology & Biological Psychiatry
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