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

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.

Seaweed Phenolics: From Extraction to Applications

“…The study of Seong et al [238] focused on the action of phlorotannins in the mechanisms of anti-depressant and anti-Parkinson's disease. Dieckol and phlorofucofuroeckol-A (isolated from Ecklonia stolonifera) demonstrated high inhibition against the monoamine oxidases and demonstrated full agonists with high potency at the dopamine 3 and 4 receptors, proving that these compounds can have a multi-role intervention in the potential treatment of psychological disorders and Parkinson's disease.…”

Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances

“…Enzyme kinetics and computational findings indicated that PFF-A noncompetitively interacted with h MAOs and acted allosterically. In a functional assay for GPCR screening, dieckol and PFF-A showed a multi-target combination of D 3 R/D 4 R agonism and D 1 /5HT 1A /NK 1 antagonism [ 140 ].…”

Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β25-35 Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action

“…Phlorotannins, a natural polyphenol found abundantly in brown seaweeds (especially in the Ecklonia species), are known to have a diverse range of pharmacological activity. As neuroscience research progresses, the many neuroprotective effects of various phlorotannins are being reported, including inhibitory activity against enzymes linked to the pathogenesis of AD and PD [22,24,25,32], modulatory activity against G-protein coupled receptors related to neuronal diseases such as PD and psychological diseases [22,23], and free-radical scavenging activity [15]. Although some reports have indicated that phlorotannins have protective effects against the neurotoxicity of the Aβ 1-42 oligomer [32] or Aβ 25-35 peptides [33,34] in neuronal cell-lines, phlorotannins have not previously been studied as an inhibitor of Aβ self-aggregation.…”

“…Recently, we demonstrated that the molecular mechanism of the neuroprotective effects of eckol depended on monoamine oxidase-A inhibition and dopamine D 3 /D 4 receptor agonism [21,22]. Similarly, dieckol and phlorofucofuroeckol-A (PFFA) showed MAOs-A/B inhibition, D 3 R/D 4 R receptor agonism, and D 1 /5HT 1A /NK 1 receptor antagonism [23]. In addition, we discovered that the anti-AD activity of phlorotannins, including eckol, dioxinodehydroeckol, dieckol, and PFFA, occurred via inhibition of β-secretase and acetylcholinesterase [24,25].…”