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H3 antagonist

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, Eleonore 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 results might therefore better reflect in vivo conditions as compared to the routinely used cell homogenates or purified membrane fractions...
September 24, 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...
August 8, 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
Na Liu, Wenfang Zhou, Yue Guo, Junmei Wang, Weitao Fu, Huiyong Sun, Dan Li, Mojie Duan, Tingjun Hou
The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2...
August 27, 2018: Journal of Chemical Information and Modeling
Adam Schafer, Han Cheng, Rui Xiong, Veronica Soloveva, Cary Retterer, Feiyan Mo, Sina Bavari, Gregory Thatcher, Lijun Rong
Ebola and Marburg are filoviruses and biosafety level 4 pathogens responsible for causing severe hemorrhagic fevers in humans with mortality rates up to 90%. The most recent outbreak in West Africa resulted in approximately 11,310 deaths in 28,616 reported cases. Currently there are no FDA-approved vaccines or therapeutics to treat infections of these deadly viruses. Recently we screened an FDA-approved drug library and identified numerous G protein-coupled receptor (GPCR) antagonists including antihistamines possessing anti-filovirus properties...
September 2018: Antiviral Research
Mohammad A Khanfar, David Reiner, Stefanie Hagenow, Holger Stark
Histamine H3 receptor (H3 R) is largely expressed in the CNS and modulation of the H3 R function can affect histamine synthesis and liberation, and modulate the release of many other neurotransmitters. Targeting H3 R with antagonists/inverse agonists may have therapeutic applications in neurodegenerative disorders, gastrointestinal and inflammatory diseases. This prompted us to design and synthesize azole-based H3 R ligands, i.e. having oxadiazole- or thiazole-based core structures. While ligands of oxadiazole scaffold were almost inactive, thiazole-based ligands were very potent and several exhibited binding affinities in a nanomolar concentration range...
August 7, 2018: Bioorganic & Medicinal Chemistry
Hanyang Cai, Man Zhang, Mengnan Chai, Qing He, Xinyu Huang, Lihua Zhao, Yuan Qin
The accumulation of anthocyanins in response to specific developmental cues or environmental conditions plays a vital role in plant development and protection against stresses. Extensive research has examined the regulation of anthocyanin biosynthetic genes at the transcriptional and post-transcriptional levels, but the role of chromatin in this regulation remains unknown. Chromatin immunoprecipitation and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were performed. Genetic interactions between trimethylation of lysine 4 on histone H3 (H3K4me3) and the chromatin remodeling complex SWR1 in the control of anthocyanin biosynthesis were further studied...
June 30, 2018: New Phytologist
Katsuya Nagai, Yoshiko Misonou, Yosiyuki Fujisaki, Risa Fuyuki, Yuko Horii
We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats...
June 20, 2018: Amino Acids
A Lesniak, A Jonsson, M Aarnio, T Norberg, F Nyberg, T Gordh
Aims In PET studies of patients suffering from chronic pain following whip lash trauma, d-deprenyl was shown to bind to painful sites in the neck [1]. High uptake points towards an existence of an inflammation-specific binding site. Thus, the aim of this study was to identify the binding site for d-deprenyl employing radioligand receptor binding and high-throughput analysis of its activity towards 165 G-protein coupled receptors and 84 enzyme targets commonly used in drug discovery and development. Methods D-Deprenyl activity towards GPCR targets was assessed by DiscoverX in CHO-K1 EDG1 β-arrest in EFC cell line utilizing the PathHunter™ technique...
December 29, 2017: Scandinavian Journal of Pain
Magdalena Kotańska, Kamil J Kuder, Katarzyna Szczepańska, Jacek Sapa, Katarzyna Kieć-Kononowicz
The pharmacological profile of pitolisant, a histamine H3 receptor antagonist/inverse agonist, indicates that this compound might reduce body weight and metabolic disturbances. Therefore, we studied the influence of pitolisant on body weight, water and sucrose intake as well as metabolic disturbances in the high-fat and high-sugar diet-induced obesity model in mice. To induce obesity, male CD-1 mice were fed a high-fat diet consisting of 40% fat blend for 14 weeks, water and 30% sucrose solution available ad libitum...
August 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Ayami Sato, Haruka Ueno, Momoka Fusegi, Saki Kaneko, Kakeru Kohno, Nantiga Virgona, Akira Ando, Yuko Sekine, Tomohiro Yano
BACKGROUND: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of α-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1)...
2018: Pharmacology
Alaa Alachkar, Gniewomir Latacz, Agata Siwek, Annamaria Lubelska, Ewelina Honkisz, Anna Gryboś, Dorota Łażewska, Jadwiga Handzlik, Holger Stark, Katarzyna Kiec-Kononowicz, Bassem Sadek
Novel non-imidazole histamine H3 receptor (H3R) antagonists (2-8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1-H4R. These novel H3R antagonists (2-8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i...
July 2018: Pharmacology, Biochemistry, and Behavior
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