Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease
Language English Country Germany Media print-electronic
Document type Journal Article
Grant support
Project No: DZRO-FVZ22-ZHN II
Ministerstvo Obrany České Republiky
project No. 22-24384S
Grantová Agentura České Republiky
Excellence project no. 2201-2024
Univerzita Hradec Králové
SVV 260 666
Univerzita Karlova v Praze
DGA/SSA - NBC-5-C-2316
Ministère des Armées
UHHK 00179906
Ministerstvo Zdravotnictví Ceské Republiky
UMO-2021/41/B/NZ7/02825
Narodowe Centrum Nauki
PubMed
39523866
PubMed Central
PMC11796312
DOI
10.1002/anie.202420510
Knihovny.cz E-resources
- Keywords
- Alzheimer's disease, GABA transporters, butyrylcholinesterase, inhibitors, multitarget drugs,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Alzheimer Disease * drug therapy metabolism MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors * chemistry pharmacology therapeutic use MeSH
- Fluorenes * chemistry pharmacology therapeutic use MeSH
- gamma-Aminobutyric Acid * metabolism MeSH
- Humans MeSH
- Molecular Structure MeSH
- Mice MeSH
- Synaptic Transmission * drug effects MeSH
- GABA Plasma Membrane Transport Proteins metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors * MeSH
- Fluorenes * MeSH
- gamma-Aminobutyric Acid * MeSH
- GABA Plasma Membrane Transport Proteins MeSH
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ-aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC50=0.21 μM) and GABA transporter 1 (IC50=10.96 μM) and 3 (IC50=7.76 μM), along with a favorable drug-likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi-target-directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD.
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