Damijan Knez (Avtor), Fen Wang (Avtor), Wen-Xiang Duan (Avtor), Martina Hrast (Avtor), Stanislav Gobec (Avtor), Xiao-Yu Cheng (Avtor), Xiao-Bo Wang (Avtor), Cheng-Jie Mao (Avtor), Chun-Feng Liu (Avtor), Rok Frlan (Avtor)

Povzetek

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Inhibitors of monoamine oxidase B (MAO-B) have shown promise in alleviating motor symptoms and reducing oxidative stress associated with PD. In this study, we report the novel use of an azastilbene-based compound library for screening human (h)MAO-B, followed by optimization of initial hits to obtain compounds with low nanomolar inhibitory potencies (compound 9, IC50 = 42 nM) against hMAO-B. To ensure specificity and minimize false positives due to non-specific hydrophobic interactions, we performed comprehensive selectivity profiling against hMAO-A, butyrylcholinesterase (hBChE) and acetylcholinesterase (hAChE) — enzymes with hydrophobic active sites that are structurally distinct from hMAO-B. Docking analysis with Glide provided valuable insights into the binding interactions between the inhibitors and hMAO-B and also explained the selectivity against hMAO-A. In the cell-based model of Parkinson’s disease, one of the compounds significantly reduced rotenone-induced accumulation of reactive oxygen species. In addition, these compounds showed a protective effect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction in PD model mice and reduced MPTP-induced loss of striatal tyrosine hydroxylase-positive neurons in the substantia nigra. These results make azastilbene-based compounds a promising new class of hMAO-B inhibitors with potential therapeutic applications in Parkinson’s disease and related neurodegenerative disorders.

Ključne besede

neurodegenerative diseases;Parkinson’s disease;monoamine oxidase B;inhibitors;azastilbene;library;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 616.831-003.8
COBISS: 211330051 Povezava se bo odprla v novem oknu
ISSN: 0045-2068
Št. ogledov: 19
Št. prenosov: 5
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: zaviralci monoaminooksidaze B;azastilben;Nevrodegenerativne bolezni;Parkinsonova bolezen;
Vrsta dela (COBISS): Članek v reviji
Strani: 22 str.
Letnik: ǂVol. ǂ153
Zvezek: ǂart. ǂ107877
Čas izdaje: 2024
DOI: 10.1016/j.bioorg.2024.107877
ID: 25300997