Isoform Selectivity of Harmine-Conjugated 1,2,3-Triazoles against Human Monoamine Oxidase

Abstract

Compounds 3e and 4c exhibited an IC of 0.83 ± 0.03 and 0.43 ± 0.002 μM against MAO-A and an IC of 0.26 ± 0.04 and 0.36 ± 0.001 μM against MAO-B, respectively. Molecular docking studies revealed π-π interactions between the synthesized molecules and aromatic amino acid residues. Conclusion & future perspective: The current study delineates the structural requirements for MAO-A selectivity and such information may be helpful in designing selective analogs for kinase, DYRK1A and harmine-based cytotoxics without apparent MAO enzyme inhibition.

How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine

“…This change in selectivity was exactly the opposite of what we intended to achieve. For the 7-aminoethyl ether AnnH62 , we confirmed the published moderate MAO-A inhibitory potency [ 18 ] and found, not surprisingly, loss of kinase inhibition due to the known steric constraints at the small binding pocket of DYRK1A [ 19 ]. For this reason, we did not perform further modifications at C-7 with large substituents.…”

“…On the other hand, the co-crystal structure suggested that substituents at the central pyrrole nitrogen, which prevent formation of the hydrogen bond network, might lead to reduced MAO-A inhibition. This evidence was confirmed recently by Haider et al with harmine-based 7-triazolylmethyl ethers [ 19 ]. In contrast, the methoxy group appeared essential for DYRK1A inhibition, while larger ether residues at C-7 should be detrimental due to steric hindrance in the pocket.…”

β-carboline-independent antidepressant-like effect of the standardized extract of the barks of Mimosa tenuiflora (Willd) Poir. occurs via 5-HT2A/2C receptors in mice

“…Nevertheless, in the open-field test, animals treated with harmine showed greater horizontal mobility in comparison to the group treated with the vehicle, which may indicate an increase in psychomotor activity due to a possible stimulant effect promoted by harmine in the dose and pathway used (Prut and Belzung, 2003). As it inhibits the enzyme MAO-A and MAO-B (Haider et al, 2018; Mckenna et al, 1984), harmine causes an increase in the availability of monoamines in synaptic clefts (Yamada and Yasuhara, 2004) ultimately resulting in a decrease in the immobility time of mice submitted to the TST and FST (Peng et al, 2007). Despite this, according to the present data, it is not possible to state that harmine has an antidepressant-like effect in the dose and route used in this study.…”

Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

“…In this study, we have investigated the effect of the isolated constituents ( 1 – 6 ) on human recombinant MAO-A and -B. The kynuramine oxidation deamination assay was performed in 96-well plates as previously reported, with modification [ 18 , 35 ]. A fixed concentration of kynuramine substrate and varying concentrations of test compounds or inhibitor were used to determine the IC 50 values.…”