Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders.

Su Hui Seong,Dong Hyun Ahn,Pradeep Paudel,Jeong-Wook Choi,Hyun Ah Jung,Taek-Jeong Nam,Jae Sue Choi

doi:10.3390/md17060377

Su Hui Seong, Dong Hyun Ahn + Show 5 more

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https://doi.org/10.3390/md17060377

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Abstract

Modulation of multiple protein targets with a single compound is essential for the effective treatment of central nervous system disorders. In our previous G protein-coupled receptor (GPCR) cell-based study, a selective human monoamine oxidase (hMAO)-A inhibitor, eckol, stimulated activity of dopamine D3 and D4 receptors. This result led to our interest in marine phlorotannin-mediated modulation of hMAO enzymes and related GPCRs in neuronal disorders. Here, we evaluate the multi-target effects of phloroglucinol, phlorofucofuroeckol-A (PFF-A), and dieckol by screening their modulatory activity against hMAO-A and -B and various neuronal GPCRs. Among the tested phlorotannins, PFF-A showed the strongest inhibitory activity against both hMAO isoforms, with higher selectivity toward hMAO-B than hMAO-A. Enzyme kinetics and docking data revealed that PFF-A noncompetitively acts on hMAOs into the alternative binding pocket of enzymes with allosteric functions. In a functional assay for GPCR screening, dieckol and PFF-A exhibited a multi-target combination of D3R/D4R agonism and D1/5HT1A/NK1 antagonism. In particular, they effectively stimulated D3R and D4R, compared to other GPCRs. Docking analysis confirmed that dieckol and PFF-A successfully docked into the conserved active sites of D3R and D4R and interacted with aspartyl and serine residues in the orthosteric binding pockets of the respective receptors. Based on our experimental and computational data, we established the structure-activity relationship between tested phlorotannins and target proteins, including hMAOs and GPCRs. Our current findings suggest that hMAO inhibitors dieckol and PFF-A, major phlorotannins of edible brown algae with multi-action on GPCRs, are potential agents for treatment of psychological disorders and Parkinson’s disease.

Highlights

The mechanisms of anti-depressant and anti-Parkinson’s disease (PD) drugs have been extensively studied in animal models and one of their common characteristics is the enhancement of central serotoninergic or dopaminergic neurotransmission [1,2].Mar
Earlier studies demonstrated that a potent 5-HT1A receptor antagonist, WAY 100635, blocked the inhibition of 5-HT cell firing induced by MAO inhibitors with increasing effects of MAO inhibitors on the concentration of extracellular 5-HT in the forebrain [4]
Three phlorotannins were tested for their human monoamine oxidase (hMAO)-A and -B inhibitory activities using R-(-)-deprenyl

Summary

Introduction

Mar. Drugs 2019, 17, 377; doi:10.3390/md17060377 www.mdpi.com/journal/marinedrugs. There are two isoforms, MAO-A and MAO-B. They share up to 70% identical sequences, but have different affinities for neurotransmitters. Inhibition of MAO-A is a common strategy to increase the concentration of 5-HT in the synaptic cleft, whereas acute systemic injection of a MAO inhibitor induces inhibition of 5-HT cell firing [1]. Earlier studies demonstrated that a potent 5-HT1A receptor antagonist, WAY 100635, blocked the inhibition of 5-HT cell firing induced by MAO inhibitors with increasing effects of MAO inhibitors on the concentration of extracellular 5-HT in the forebrain [4]

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