Dokument: Design and Synthesis of Multifunctional Dopamine D2/D3 and Histamine H3 Receptor Ligands

Titel:	Design and Synthesis of Multifunctional Dopamine D2/D3 and Histamine H3 Receptor Ligands
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=58562
URN (NBN):	urn:nbn:de:hbz:061-20220126-110118-0
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Elek, Milica [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 9,11 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 17.01.2022 / geändert 17.01.2022
Beitragende:	Prof. Dr. Stark, Holger [Gutachter] Prof. Dr. Gohlke Holger [Gutachter]
Stichwörter:	Dopamine, Histamine, D3, Multitargeting
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 540 Chemie
Beschreibung:	Dopamine is one of the crucial neurotransmitters in the human brain. Altered dopamine concentration can lead to serious neurological diseases as schizophrenia, Parkinson’s disease (PD), restless legs syndrome, or addictive behavior. Dopamine acts through: D1-like (D1 and D5), and D2-like (D2, D3 and D4) receptors. D3 receptor (D3R) represents an interesting target due to its local focalization, limited to the limbic region. Due to high homology level between dopamine receptor subtypes, especially D2-like (78% homology in transmembrane domain, and structurally conserved orthosteric binding site (OBS) in D2R and D3R), no selective D3R drug has been marketed. Bitopic ligands present new approach to improve receptor affinity and/or selectivity by coupling pharmacophores that can target both OBS and second (allosteric) binding pocket. Therefore, selective D3R ligands were designed, modifying general pharmacophore, and introducing novel chemical entities (e.g., SF5 moiety), resulting in highly affine compound 9 (pKi (D3R) = 8.45) with highest preference over D2R (SI = 20.5). Molecular docking simulations predicted the binding mode of 9 and identified prerequisites for the interaction with receptors. Further modifications enabled design of potent bitopic D2R/D3R ligands, based on pramipexole (D3R preferring agonist used in PD therapy) and D3R privileged scaffold 4-phenylpiperazine. Compound 15 showed affinities in low nanomolar concentration ranges (pKi (D2R) = 8.25; pKi (D3R) = 8.22) and excellent antioxidant properties, that can impact neuroinflammation caused by reactive oxygen species. Dopamine receptors can form homo- and heterodimers (e.g., with histamine H3 receptor, H3R). Synergistic effects were observed in PD models in vivo when H3R antagonist was applied together with D2R agonists. Multifunctional D2/3R/H3R ligands were designed, by combining, and modifying D3R, H3R pharmacophores (incorporated in Wakix®, only currently approved H3R antagonist/inverse agonist) and linker that couples these two entities. Compound 42 stood out as the most promising multitargeting ligand showing nanomolar affinities (pKi (D2R) = 7.57; pKi (D3R) = 7.30; pKi (H3R) = 8.02) and good, predicted drug like score. Finally, fluorescent dopamine and histamine receptor ligands were developed, to enable receptor visualization and consequent localization and distribution. Novel, thermally and chemically stable fluorophore BOPPY was for the first time coupled with G-protein coupled receptor ligands, to obtain compounds with beneficial optical properties (e.g., quantum yield up to 0.69). In this PhD project 50 potent novel ligands were designed. Optimized synthetic approaches and observed structure-activity relationships shed light on favoring substitution patterns and prerequisites to obtain novel multifunctional ligands with high affinity to the receptor of interest.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie
Dokument erstellt am:	26.01.2022
Dateien geändert am:	26.01.2022
Promotionsantrag am:	12.08.2021
Datum der Promotion:	20.12.2021