Dokument: Aminergic Ligands for Multitargeting in Central Nervous System Disorders
| Titel: | Aminergic Ligands for Multitargeting in Central Nervous System Disorders | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=73896 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20260720-132334-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dubiel, Mariam [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Dr. h.c. Stark, Holger [Gutachter] Prof. Dr. Smits, Sander [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Central nervous system (CNS) disorders, such as depression, Alzheimer’s disease (AD), and schizophrenia, continue to present major clinical challenges due to their complex nature. Despite intensive research, drug development has progressed slowly, and current pharmacotherapies often fail to adequately address core symptoms or are limited by side effects. Multitargeting ligands (MTDLs), designed to simultaneously and synergistically modulate multiple biological targets, represent a promising strategy to enhance treatment efficacy. This cumulative dissertation describes the pharmacological characterisation of novel aminergic ligands that, within the multitargeting framework, target dopamine D2 (D2R), dopamine D3 (D3R) and/or histamine H3 receptor (H3R), in combination with serotonin receptors or enzymes such as acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Radioligand binding assays, enzyme assays, and in vivo mouse models were employed to assess affinity, selectivity, and physiological effects. Additionally, fluorescent D2R/D3R ligands were developed as potential tools for bioimaging applications and fluorescence assays.
Several novel MTDLs were characterised within the scope of this work. The pimavanserin derivative ST-2300 combines H3R and serotonin receptor subtype 5-HT2A antagonism and demonstrated antidepressant- and anxiolytic-like effects (Publication 1). In a series of benzothiazole derivatives, promising H3R ligands were identified that also inhibit AChE and MAO-B, making them potential drug candidates for AD (Publication 2). Publication 3 showed that the H3R/D2R/D3R-targeting ligand ST-2223 reduces autism-like repetitive behaviours in a mouse model of autism spectrum disorder (ASD). Publications 4 – 6 focus on the pharmacology of dopamine receptors. An extensive library of bitopic ligands was designed based on the antipsychotic drug cariprazine and pharmacologically characterised. Insights were gained regarding D2R/D3R/5-HT2A selectivity, affinity, and the influence of orthosteric and secondary receptor-ligand interactions (Publication 4). In Publication 5, arylpiperazine derivatives were synthesised and tested pharmacologically, combining dopaminergic and serotonergic activity with antioxidant properties. While these compounds showed promising affinities for potential use in psychoses and ASD, they exhibited limited metabolic stability. Finally, in Publication 6, BOPPY-based fluorescent ligands were developed as fluorescent probes for D2R/D3R. Overall, these results demonstrate that MTDLs targeting histaminergic and dopaminergic systems can make substantial advances in the treatment of CNS disorders. This work highlights the therapeutic and translational potential of the described aminergic ligands and provides a significant contribution to future drug development in neuropsychiatric and neurodegenerative diseases. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie | |||||||
| Dokument erstellt am: | 20.07.2026 | |||||||
| Dateien geändert am: | 20.07.2026 | |||||||
| Promotionsantrag am: | 25.11.2025 | |||||||
| Datum der Promotion: | 31.03.2026 |
