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.
Highlights
Compound 1 is a potent selective human monoamine oxidase B (hMAO-B) inhibitor, with no significant inhibition of Human monoamine oxidase A (hMAO-A) at 100 μM (Figure 1C). This hit inhibitor was resynthesised using an efficient and straightforward synthesis (Scheme 1) that started from readily available isonipecotic acid, which was transformed into Weinreb’s amide 2 and subsequently reduced to obtain aldehyde 3
monoamine oxidases (MAOs)-A and MAO-B are two closely related isoenzymes where numerous selective inhibitors have been described in the literature, with some used in the clinical setting for treatment of neurological disorders
Selective hMAO-B inhibitor 6 was identified in a screening campaign, and chemistry-driven exploration of the chemical space revealed that the trans isomers selectively inhibit hMAO
Summary
Specific interaction patterns and molecular geometry are critical factors that influence ligand binding affinity and ligand selectivity toward a target. Numerous examples of “chiral switching” in drug development have highlighted the effects of spatial geometry on pharmacodynamics and pharmacokinetics and toxicology of drugs. In addition to optical isomers, cis and trans isomers can have different pharmacological activities, as demonstrated by the well-known cases of cisplatin, tamoxifen, and combretastatin A4 (CA-4).6This last includes a stilbene motif in the cis conformation (Figure 1A), which efficiently binds to the colchicine binding site of tubulin and acts as a microtubule-destabilizing agent.6The binding of trans-combretastatin A4 (trans-CA-4, Figure1A) to this site is thermodynamically less stable than that of cis-combretastatin A4 (cis-CA-4), and the trans conformation does not prevent microtubule assembly.6examples of stereoselective activities of cis/trans isomers are rare in comparison with optical isomers. In addition to optical isomers, cis and trans isomers can have different pharmacological activities, as demonstrated by the well-known cases of cisplatin, tamoxifen, and combretastatin A4 (CA-4).. In addition to optical isomers, cis and trans isomers can have different pharmacological activities, as demonstrated by the well-known cases of cisplatin, tamoxifen, and combretastatin A4 (CA-4).6 This last includes a stilbene motif in the cis conformation (Figure 1A), which efficiently binds to the colchicine binding site of tubulin and acts as a microtubule-destabilizing agent.. 1A) to this site is thermodynamically less stable than that of cis-combretastatin A4 (cis-CA-4), and the trans conformation does not prevent microtubule assembly.. Examples of stereoselective activities of cis/trans isomers are rare in comparison with optical isomers
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