Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články
Grantová podpora
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-zdroje
- Klíčová slova
- Alzheimer's disease, GABA transporters, butyrylcholinesterase, inhibitors, multitarget drugs,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory * chemie farmakologie terapeutické užití MeSH
- fluoreny * chemie farmakologie terapeutické užití MeSH
- GABA * metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši MeSH
- nervový přenos * účinky léků MeSH
- proteiny přenášející GABA přes plazmatickou membránu metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory * MeSH
- fluoreny * MeSH
- GABA * MeSH
- proteiny přenášející GABA přes plazmatickou membránu 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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