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

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.