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  1. Article ; Online: The Novel Pimavanserin Derivative ST-2300 with Histamine H

    Venkatachalam, Karthikkumar / Zhong, Sicheng / Dubiel, Mariam / Satała, Grzegorz / Sadek, Bassem / Stark, Holger

    Biomolecules

    2022  Volume 12, Issue 5

    Abstract: The therapy of depression is challenging and still unsatisfactory despite the presence of many antidepressant drugs on the market. Consequently, there is a continuous need to search for new, safer, and more effective antidepressant therapeutics. Previous ...

    Abstract The therapy of depression is challenging and still unsatisfactory despite the presence of many antidepressant drugs on the market. Consequently, there is a continuous need to search for new, safer, and more effective antidepressant therapeutics. Previous studies have suggested a potential association of brain histaminergic/serotoninergic signaling and antidepressant- and anxiolytic-like effects. Here, we evaluated the in vivo antidepressant- and anxiolytic-like effects of the newly developed multiple-active ligand ST-2300. ST-2300 was developed from 5-HT
    MeSH term(s) Animals ; Anti-Anxiety Agents/pharmacology ; Antidepressive Agents/pharmacology ; Depression/drug therapy ; Histamine ; Histamine Antagonists ; Mice ; Mice, Inbred C57BL ; Piperidines/pharmacology ; Receptors, Histamine ; Serotonin ; Serotonin Antagonists ; Urea/analogs & derivatives ; Urea/pharmacology
    Chemical Substances Anti-Anxiety Agents ; Antidepressive Agents ; Histamine Antagonists ; Piperidines ; Receptors, Histamine ; Serotonin Antagonists ; Serotonin (333DO1RDJY) ; Histamine (820484N8I3) ; Urea (8W8T17847W) ; pimavanserin (JZ963P0DIK)
    Language English
    Publishing date 2022-05-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom12050683
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Book ; Online ; Thesis: Syntheses and evaluation of novel histamine H3 receptor ligands and multi-target-directed ligands as neuroprotective agents

    Zhong, Sicheng [Verfasser] / Stark, Holger [Gutachter] / Kurz, Thomas [Gutachter]

    2021  

    Author's details Sicheng Zhong ; Gutachter: Holger Stark, Thomas Kurz
    Keywords Medizin, Gesundheit ; Medicine, Health
    Subject code sg610
    Language English
    Publisher Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
    Publishing place Düsseldorf
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  3. Article ; Online: Simultaneous Antagonism at H3R/D2R/D3R Reduces Autism-like Self-Grooming and Aggressive Behaviors by Mitigating MAPK Activation in Mice.

    Eissa, Nermin / Awad, Mohamed Al / Thomas, Shilu Deepa / Venkatachalam, Karthikkumar / Jayaprakash, Petrilla / Zhong, Sicheng / Stark, Holger / Sadek, Bassem

    International journal of molecular sciences

    2022  Volume 24, Issue 1

    Abstract: Dysregulation in brain neurotransmitters underlies several neuropsychiatric disorders, e.g., autism spectrum disorder (ASD). Also, abnormalities in the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway pave the ... ...

    Abstract Dysregulation in brain neurotransmitters underlies several neuropsychiatric disorders, e.g., autism spectrum disorder (ASD). Also, abnormalities in the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway pave the way for neuroinflammation, neurodegeneration, and altered learning phenotype in ASD. Therefore, the effects of chronic systemic administration of the multiple-targeting antagonist ST-713 at the histamine H3 receptor (H3R) and dopamine D2/D3 receptors (D2/D3R) on repetitive self-grooming, aggressive behaviors, and abnormalities in the MAPK pathway in BTBR T + Itpr3tf/J (BTBR) mice were assessed. The results showed that ST-713 (2.5, 5, and 10 mg/kg, i.p.) mitigated repetitive self-grooming and aggression in BTBR mice (all p < 0.05), and the ameliorative effects of the most promising dose of ST-713 (5 mg/kg, i.p.) on behaviors were completely abrogated by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. Moreover, the elevated levels of several MAPK pathway proteins and induced proinflammatory markers such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and IL-6 were significantly suppressed following chronic administration of ST-713 (5 mg/kg, i.p.) (all p < 0.01). Furthermore, ST-713 significantly increased the levels of histamine and dopamine in hippocampal tissue of treated BTBR mice (all p < 0.01). The current observations signify the potential role of such multiple-targeting compounds, e.g., ST-713, in multifactorial neurodevelopmental disorders such as ASD.
    MeSH term(s) Mice ; Animals ; Autistic Disorder/genetics ; Autism Spectrum Disorder/drug therapy ; Receptors, Histamine H3/metabolism ; Grooming ; Dopamine/pharmacology ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Extracellular Signal-Regulated MAP Kinases ; Aggression ; Disease Models, Animal
    Chemical Substances Receptors, Histamine H3 ; Dopamine (VTD58H1Z2X) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2022-12-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24010526
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The histamine H3R and dopamine D2R/D3R antagonist ST-713 ameliorates autism-like behavioral features in BTBR T+tf/J mice by multiple actions.

    Venkatachalam, Karthikkumar / Eissa, Nermin / Awad, Mohamed Al / Jayaprakash, Petrilla / Zhong, Sicheng / Stölting, Frauke / Stark, Holger / Sadek, Bassem

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2021  Volume 138, Page(s) 111517

    Abstract: Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are ... ...

    Abstract Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with Autism spectrum disorder (ASD). Therefore, the ameliorative effects of the novel multiple-active compound ST-713 with high binding affinities at histamine H3 receptor (H3R), dopamine D2sR and D3R on ASD-like behaviors in male BTBR T+tf/J mice model were assessed. ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine; 2.5, 5, and 10 mg/kg, i.p.) ameliorated dose-dependently social deficits, and significantly alleviated the repetitive/compulsive behaviors of BTBR mice (all P < 0.05). Moreover, ST-713 modulated disturbed anxiety levels, but failed to obliterate increased hyperactivity of tested mice. Furthermore, ST-713 (5 mg/kg) attenuated the increased levels of hippocampal and cerebellar protein expressions of NF-κB p65, COX-2, and iNOS in BTBR mice (all P < 0.05). The ameliorative effects of ST-713 on social parameters were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. The obtained results demonstrate the potential of multiple-active compounds for the therapeutic management of neuropsychiatric disorders, e.g. ASD.
    MeSH term(s) Animals ; Autistic Disorder/drug therapy ; Autistic Disorder/genetics ; Autistic Disorder/metabolism ; Cerebellum/drug effects ; Cerebellum/metabolism ; Dopamine Antagonists/pharmacology ; Dopamine Antagonists/therapeutic use ; Dopamine D2 Receptor Antagonists/pharmacology ; Dopamine D2 Receptor Antagonists/therapeutic use ; Dose-Response Relationship, Drug ; Hippocampus/drug effects ; Hippocampus/metabolism ; Histamine Antagonists/pharmacology ; Histamine Antagonists/therapeutic use ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Receptors, Dopamine D2/metabolism ; Receptors, Dopamine D3/antagonists & inhibitors ; Receptors, Dopamine D3/metabolism ; Receptors, Histamine H3/metabolism
    Chemical Substances Dopamine Antagonists ; Dopamine D2 Receptor Antagonists ; Histamine Antagonists ; Receptors, Dopamine D2 ; Receptors, Dopamine D3 ; Receptors, Histamine H3
    Language English
    Publishing date 2021-03-24
    Publishing country France
    Document type Journal Article
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/j.biopha.2021.111517
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ud II Zs.198: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Book ; Online: Constrained Model-based Reinforcement Learning with Robust Cross-Entropy Method

    Liu, Zuxin / Zhou, Hongyi / Chen, Baiming / Zhong, Sicheng / Hebert, Martial / Zhao, Ding

    2020  

    Abstract: This paper studies the constrained/safe reinforcement learning (RL) problem with sparse indicator signals for constraint violations. We propose a model-based approach to enable RL agents to effectively explore the environment with unknown system dynamics ...

    Abstract This paper studies the constrained/safe reinforcement learning (RL) problem with sparse indicator signals for constraint violations. We propose a model-based approach to enable RL agents to effectively explore the environment with unknown system dynamics and environment constraints given a significantly small number of violation budgets. We employ the neural network ensemble model to estimate the prediction uncertainty and use model predictive control as the basic control framework. We propose the robust cross-entropy method to optimize the control sequence considering the model uncertainty and constraints. We evaluate our methods in the Safety Gym environment. The results show that our approach learns to complete the tasks with a much smaller number of constraint violations than state-of-the-art baselines. Additionally, we are able to achieve several orders of magnitude better sample efficiency when compared with constrained model-free RL approaches. The code is available at \url{https://github.com/liuzuxin/safe-mbrl}.

    Comment: 8 pages, 5 figures
    Keywords Computer Science - Artificial Intelligence ; Computer Science - Machine Learning ; Computer Science - Robotics
    Subject code 006
    Publishing date 2020-10-15
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Fishing for accessory binding sites at GPCRs with 'loop-hooks' - an approach towards selectivity? Part I.

    Tröger, Thomas / Langenberg, Maximilian / Zhong, Sicheng / Ambrosini, Dario / Enzensperger, Christoph

    Chemistry & biodiversity

    2014  Volume 11, Issue 2, Page(s) 197–208

    Abstract: Receptor-subtype selectivity is an important issue in medicinal chemistry and can become very difficult to achieve if the actual binding pockets of the respective receptors are highly conserved. For such cases, known unselective ligands could be equipped ...

    Abstract Receptor-subtype selectivity is an important issue in medicinal chemistry and can become very difficult to achieve if the actual binding pockets of the respective receptors are highly conserved. For such cases, known unselective ligands could be equipped with a spacer that sticks outside the actual orthosteric binding pocket towards the extracellular loops. The end of the spacer bears certain functional groups to enable specific or unspecific interactions with the receptor residues outside the binding cavity. Our experiments indicated that it is possible to achieve selectivity within the dopamine D1 family with such 'loop-hooks'.
    MeSH term(s) Binding Sites/drug effects ; Dose-Response Relationship, Drug ; Humans ; Isoquinolines/chemical synthesis ; Isoquinolines/chemistry ; Isoquinolines/pharmacology ; Ligands ; Molecular Structure ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/metabolism ; Structure-Activity Relationship
    Chemical Substances Isoquinolines ; Ligands ; Receptors, G-Protein-Coupled
    Language English
    Publishing date 2014-02
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2139001-0
    ISSN 1612-1880 ; 1612-1872
    ISSN (online) 1612-1880
    ISSN 1612-1872
    DOI 10.1002/cbdv.201300292
    Database MEDical Literature Analysis and Retrieval System OnLINE

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