Title : Multifunctional, fluorene-based modulator of cholinergic and GABAergic neurotransmission as a novel drug candidate for palliative treatment of Alzheimer's disease - Panek_2024_Angew.Chem.Int.Ed.Engl__e202420510 |
Author(s) : Panek D , Pasieka A , Jonczyk JJ , Gawlinska M , Zareba P , Siwek A , Wolak M , Mordyl B , Gluch-Lutwin M , Latacz G , Brazzolotto X , Chantegreil F , Nachon F , Zdarova Karasova J , Pejchal J , Mzik M , Sestak V , Prchal L , Odvarkova J , Soukup O , Korabecny J , Sorf A , Hamsikova M , Zemanova L , Muckova L , Vanova N , Dryja P , Salat K , Hofner G , Wanner K , Wieckowska A , Malawska B |
Ref : Angew Chem Int Ed Engl , :e202420510 , 2024 |
Abstract :
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 gamma-aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, by using a combination of crystallography and computational methods we developed 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC50 = 0.21 microM) and GABA transporter 1 (IC50 = 10.96 microM) and 3 (IC50 = 7.76 microM), along with a favorable drug-likeness profile. Subsequent in vivo studies revealed 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. |
PubMedSearch : Panek_2024_Angew.Chem.Int.Ed.Engl__e202420510 |
PubMedID: 39523866 |
Gene_locus related to this paper: human-BCHE |
Inhibitor | SCHEMBL24050818 |
Gene_locus | human-BCHE |
Structure | 9EWU |
Panek D, Pasieka A, Jonczyk JJ, Gawlinska M, Zareba P, Siwek A, Wolak M, Mordyl B, Gluch-Lutwin M, Latacz G, Brazzolotto X, Chantegreil F, Nachon F, Zdarova Karasova J, Pejchal J, Mzik M, Sestak V, Prchal L, Odvarkova J, Soukup O, Korabecny J, Sorf A, Hamsikova M, Zemanova L, Muckova L, Vanova N, Dryja P, Salat K, Hofner G, Wanner K, Wieckowska A, Malawska B (2024)
Multifunctional, fluorene-based modulator of cholinergic and GABAergic neurotransmission as a novel drug candidate for palliative treatment of Alzheimer's disease
Angew Chem Int Ed Engl
:e202420510
Panek D, Pasieka A, Jonczyk JJ, Gawlinska M, Zareba P, Siwek A, Wolak M, Mordyl B, Gluch-Lutwin M, Latacz G, Brazzolotto X, Chantegreil F, Nachon F, Zdarova Karasova J, Pejchal J, Mzik M, Sestak V, Prchal L, Odvarkova J, Soukup O, Korabecny J, Sorf A, Hamsikova M, Zemanova L, Muckova L, Vanova N, Dryja P, Salat K, Hofner G, Wanner K, Wieckowska A, Malawska B (2024)
Angew Chem Int Ed Engl
:e202420510