Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B | Zendy

Damijan Knez | Zendy; Natalia Colettis | Zendy; L.G. Iacovino | Zendy; Matej Sova | Zendy; Anja Pišlar | Zendy; Janez Konc | Zendy; Samo Lešnik | Zendy; Josefina Higgs | Zendy; Fabiola Kamecki | Zendy; Irene C. Mangialavori | Zendy; Ana Dolšak | Zendy; Simon Žakelj | Zendy; Jurij Trontelj | Zendy; Janko Kos | Zendy; Claudia Binda | Zendy; Mariel Marder | Zendy; Stanislav Gobec | Zendy

Open Access

Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B

Author(s) -

Damijan Knez,

Natalia Colettis,

L.G. Iacovino,

Matej Sova,

Anja Pišlar,

Janez Konc,

Samo Lešnik,

Josefina Higgs,

Fabiola Kamecki,

Irene C. Mangialavori,

Ana Dolšak,

Simon Žakelj,

Jurij Trontelj,

Janko Kos,

Claudia Binda,

Mariel Marder,

Stanislav Gobec

Publication year - 2020

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.9b01886

Subject(s) - chemistry , monoamine oxidase , gene isoform , stereochemistry , monoamine oxidase b , in vivo , enzyme , propargyl , stereoselectivity , monoamine oxidase a , ex vivo , biochemistry , in vitro , gene , catalysis , biology , genetics

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.

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