Dokument: Design, Synthesis and Biological Evaluation of Novel Histamine H3 Receptor Ligands
| Titel: | Design, Synthesis and Biological Evaluation of Novel Histamine H3 Receptor Ligands | |||||||
| Weiterer Titel: | Design, Synthese und biologische Evaluation neuartiger Histamin-H3-Rezeptor-Liganden | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=71844 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20260113-095205-2 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Gajic, Mihajlo [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Dr. h. c. Stark, Holger [Gutachter] Kurz, Thomas [Gutachter] | |||||||
| Stichwörter: | histamine, histamine H3 receptor, H3R, G9a, LRRK2, MTDL | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | This doctoral research focuses on the design, synthesis, and biological evaluation of novel H3R ligands using aminopyrimidine scaffolds (pyrimidin-4-amines, pyrimidin-2-amines, and pyrimidine-2,4-diamines), focusing on both single-target and dual-target approaches for complex neurological disorders. Building on the clinical success of pitolisant (H3R Ki = 13.2 nM), a known antagonist/inverse agonist, the research expanded into the development of dual-target ligands aimed at epigenetic regulator G9a and kinase LRRK2, both implicated in neurodegenerative diseases.
Within the pyrimidin-4-amines series consisting of 13 compounds, piperidine-based representatives achieved exceptional H3R affinities (Ki = 1.11 – 1.97 nM), surpassing pitolisant and rivaling the most potent known H3R ligands. Among 10 pyrimidin-2-amines, thio derivatives outperformed their ether counterparts. The most active compound in this group displayed moderate H3R potency, with SAR trends indicating that smaller substituents favored receptor binding, while bulkier groups led to reduced activity due to steric hindrance. The pyrimidine-2,4-diamine scaffold with a 6-methyl group was used to design 16 ligands targeting H3R/G9a, with the most promising compound (H3R Ki = 25.2 nM; G9a IC50 = 63.9 nM) demonstrating balanced activity by aligning with both targets' binding requirements. In parallel, series of 48 5-chloro- and 5-trifluoromethyl-substituted pyrimidine-2,4-diamines was synthesized to explore dual targeting of H3R and LRRK2. The lead compound, bearing a 4-(3-piperidinopropoxy)anilino group and a C-5 trifluoromethyl substitution, achieved high H3R (Ki = 9.05 nM) alongside potent LRRK2 inhibition (IC50 = 3.6 nM). Several analogs in this series exhibited dual nanomolar potency, with H3R Ki values ranging from 4.1 to 104 nM and LRRK2 IC50 values between 1.1 and 9.3 nM. In conclusion, this research establishes aminopyrimidine derivatives as a versatile platform for the development of both high-affinity H3R ligands and first-in-class dual-target agents. Key outcomes include the identification of structural features enabling dual receptor engagement, the expansion of the H3R/G9a ligand space, and the discovery of the first dual H3R/LRRK2 ligands. The integrated application of medicinal chemistry, molecular docking, and pharmacological profiling underscores the potential of polypharmacology in creating multifunctional therapeutics for neurodegenerative and neuropsychiatric disorders. | |||||||
| 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: | 13.01.2026 | |||||||
| Dateien geändert am: | 13.01.2026 | |||||||
| Promotionsantrag am: | 18.06.2025 | |||||||
| Datum der Promotion: | 08.12.2025 |
