Dokument: Syntheses and evaluation of novel histamine H3 receptor ligands and multi-target-directed ligands as neuroprotective agents
| Titel: | Syntheses and evaluation of novel histamine H3 receptor ligands and multi-target-directed ligands as neuroprotective agents | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=57642 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20211020-101058-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Zhong, Sicheng [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Stark, Holger [Gutachter] Prof. Dr. Kurz, Thomas [Gutachter] | |||||||
| Stichwörter: | Histamine, H3 Rezeptor, Multi-targeting directed Ligand, Neuroprotection | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | In this present work, more than fifty novel histamine H3 receptor (H3R) ligands and multi-target-directed ligands (MTDLs) comprising H3R antagonist scaffolds have been designed, synthesized, and evaluated. H3R screenings were performed for the final compounds P1-P56, whereas histamine H1 and H4 receptors affinities, monoamine oxidase (MAO) inhibitions, serotonin receptors affinities, antioxidative properties, and cytotoxicities were investigated for selected ligands.
The first main pillar aimed to improve the knowledge of the structure-activity-relationship of H3R ligands. Miscellaneous structural modifications were conducted in chosen scaffolds of well-known H3R antagonists/inverse agonists. Functional groups with distinct lipophilicities, molecular weights, electronic effects, and basicities such as the pentafluorosulfanyl (SF5), malononitrile, (thio-)hydantoin and derivatives, and N,N’-disubstituted urea structures were introduced as substituents at the phenyl moiety of the H3R scaffolds. Moreover, the ether function of the N-(3-phenoxypropyl)piperidine scaffold was replaced by different hydrogen bond acceptors such guanidine and carboxamide structures, while the central phenyl moiety of this scaffold was replaced by the heteroaromatic phenyl pyrazole. Notably, compounds P1-P6 were, to my knowledge, the first H3R ligands with the SF5 group. Compounds P17 and P18 with imidazo[2,1-b]thiazinane structures, developed from the thiohydantoin derivatives, were the most affine selective H3R ligands in this work with Ki values in the picomolar concentration ranges. The second main pillar of this work aimed to present H3R ligands with additional functions and MTDLs as pharmacological tools. The spin-labeled ligand P26 with excellent H3R affinity H3R may be a useful tool to study the H3R protein structure via electron paramagnetic resonance spectroscopy. In addition to H3R pharmacophores, the development of MTDLs in this work deployed second pharmacophores with great structural diversities. As second targets serve the calcium channels, γ-aminobutyric acid receptor subtype A, monoamine oxidases, N-methyl-D-aspartate receptors, serotonin 5-HT2A receptor, and the adenosine A2A receptor. Most MTDLs from this work demonstrated decent H3R affinities. Especially compounds P28 and P34 with dihydropyridine, P51 with cycloserine, and P55 with pimavanserin structures, have demonstrated excellent H3R affinities with Ki values in the low digit nanomolar concentration ranges. Notably, P28 and P34 have shown strong antioxidative properties, while P55 demonstrated anti-depressive effects in an in-vivo study. Screenings of many second targets are currently performing, the efforts will provide a comprehensive overview of the potential of these MTDLs. This work helped to gain a deeper understanding of the H3R receptor and the central nervous system. This work also suggested that MTDLs may be attractive therapeutic options for multiple neuronal disorders. However, simultaneously affecting different brain functions requires careful coordination and, therefore, remained a challenging task. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie | |||||||
| Dokument erstellt am: | 20.10.2021 | |||||||
| Dateien geändert am: | 20.10.2021 | |||||||
| Promotionsantrag am: | 29.06.2021 | |||||||
| Datum der Promotion: | 24.08.2021 |
