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Stereoselective activity of 1-propargyl-4-styrylpiperidine-like analogues that can discriminate between monoamine oxidase isoforms A and B
ID Knez, Damijan (Author), ID Colettis, Natalia (Author), ID Iacovino, Luca G. (Author), ID Sova, Matej (Author), ID Pišlar, Anja (Author), ID Konc, Janez (Author), ID Lešnik, Samo (Author), ID Higgs, Josefina (Author), ID Kamecki, Fabiola (Author), ID Mangialavori, Irene (Author), ID Dolšak, Ana (Author), ID Žakelj, Simon (Author), ID Trontelj, Jurij (Author), ID Kos, Janko (Author), ID Binda, Claudia (Author), ID Marder Mariel, Nora (Author), ID Gobec, Stanislav (Author)

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Abstract
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 This link opens in a new window
UDC:615.35:615.015:615.9
ISSN on article:0022-2623
DOI:10.1021/acs.jmedchem.9b01886 This link opens in a new window
COBISS.SI-ID:4872561 This link opens in a new window
Publication date in RUL:28.09.2022
Views:548
Downloads:100
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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 This link opens in a new window

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

Projects

Funder:ARRS - Slovenian Research Agency
Project number:L1-8157-2017
Name:Razvoj multifunkcionalnih učinkovin za zdravljenje Alzheimerjeve bolezni

Funder:ARRS - Slovenian Research Agency
Project number:L7-8269-2017
Name:Novi pristopi za boljša biološka zdravila

Funder:ARRS - Slovenian Research Agency
Project number:P4-0127-2019
Name:Farmacevtska biotehnologija: znanost za zdravje

Funder:ARRS - Slovenian Research Agency
Project number:P1-0208-2015
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Funder:Other - Other funder or multiple funders
Funding programme:Fondazione Cariplo
Project number:2014-0672

Funder:Other - Other funder or multiple funders
Funding programme:MIUR “Dipartimenti di Eccellenza” Programme (2018−2022), and European Community Seventh Framework Programme
Project number:FP7/2007−2013

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