Stereoselective Activity of 1-Propargyl-4-Styrylpiperidine-Like Analogues that can Discriminate between Monoamine Oxidase Isoforms A and B

KNEZ, DAMIJAN; COLETTIS, NATALIA; IACOVINO, LUCA GIACINTO; SOVA, MATEJ; PI?LAR, ANJA; KONC, JANEZ; LE?NIK, SAMO; HIGGS, JOSEFINA; KAMECKI, FABIOLA; MANGIALAVORI, IRENE C.; DOL?AK, ANA; ?AKELJ, SIMON; TRONTELJ, JURIJ; KOS, JANKO; BINDA, CLAUDIA; MARDER, MARIEL; GOBEC, STANISLAV

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2020 vol. Feb p. 1361 - 1387

0022-2623

The resurgence of interest in monoamine oxidases (MAOs) has been fuelled 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-propargylpiperidines 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.