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.

• 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