Stereoselective activity of 1-propargyl-4-styrylpiperidine-like analogues that can discriminate between monoamine oxidase isoforms A and B

Knez, Damijan (author), Colettis, Natalia (author), Iacovino, Luca G. (author), Sova, Matej (author), Pišlar, Anja (author), Konc, Janez (author), Lešnik, Samo (author), Higgs, Josefina (author), Kamecki, Fabiola (author), Mangialavori, Irene (author), Dolšak, Ana (author), Žakelj, Simon (author), Trontelj, Jurij (author), Kos, Janko (author), Binda, Claudia (author), Marder Mariel, Nora (author), Gobec, Stanislav (author)

The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.

• Language: English
• Keywords: binding energy, ethyl groups, inhibition, inhibitors, molecular structure
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: Str. 1361-1387
• Numbering: Vol. 63, iss. 3
• PID: 20.500.12556/RUL-141341
• UDC: 615.35:615.015:615.9
• ISSN on article: 0022-2623
• DOI: 10.1021/acs.jmedchem.9b01886
• COBISS.SI-ID: 4872561
• Publication date in RUL: 28.09.2022

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 0022-2623
• COBISS.SI-ID: 25763328

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: English
• Keywords: razvoj zdravil, toksikologija zdravil, monoamin oksidaze