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

Abstract

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.

Keywords

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

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 616.831-003.8
COBISS: 211330051 Link will open in a new window
ISSN: 0045-2068
Views: 19
Downloads: 5
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Other data

Secondary language: Slovenian
Secondary keywords: zaviralci monoaminooksidaze B;azastilben;Nevrodegenerativne bolezni;Parkinsonova bolezen;
Type (COBISS): Article
Pages: 22 str.
Volume: ǂVol. ǂ153
Issue: ǂart. ǂ107877
Chronology: 2024
DOI: 10.1016/j.bioorg.2024.107877
ID: 25300997