The inhibition of monoamine oxidase by harmine derivatives

Abstract

The monoamine oxidase (MAO) enzymes are established targets for the treatment of neuropsychiatric and neurodegenerative disorders. Inhibitors of MAO-A have been used for many decades in the treatment of depression while MAO-B inhibitors are used in Parkinson’s disease therapy. Harmine is one of many MAO inhibitors described in literature, and is a high potency reversible inhibitor of MAO-A (IC50 = 0.0041 µM). Even though the structures of MAO-A and MAO-B are highly similar, particularly the architectures of their active sites, harmine is not an inhibitor of MAO-B. Based on an academic interest in discovering novel MAO inhibitors, the present study synthesised series of harmine and related carbazole derivatives, and investigated their in vitro human MAO inhibition properties. Among 21 compounds synthesised, 7 compounds inhibited MAO-A with IC50 < 0.1 µM, while 3 compounds inhibited MAO-B with IC50 < 0.1 µM. The most potent MAO-A inhibitor (1f) exhibited an IC50 value of 0.0049 µM, while the most potent MAO-B inhibitor (1c) exhibited an IC50 value of 0.024 µM. An analysis of the structure–activity relationships for MAO inhibition shows that a large substituent (e.g., benzyloxy) is well tolerated on position 7 of harmine, while similar substitution on position 2 of carbazole resulted in no MAO-A inhibition. In contrast, substitution on position 4 of carbazole yielded, in certain instances, active MAO-A inhibitors. Interestingly, substitution on position 7 of harmine yielded good potency MAO-B inhibitors. In certain instances, substitution on positions 2 and 4 of carbazole also yielded active MAO-B inhibitors. Molecular docking suggests that electronic properties rather that steric factors are responsible for the potent MAO inhibition observed for β-carboline compounds compared to the carbazoles. This study concludes that active inhibitors identified in this study may serve as leads for the future development of drugs for the treatment of neuropsychiatric and neurodegenerative disorders.