Eckol as a Potential Therapeutic against Neurodegenerative Diseases Targeting Dopamine D3/D4 Receptors

Abstract

The G protein-coupled receptor (GPCR) family of proteins comprises signaling proteins that mediate cellular responses to various hormones and neurotransmitters, and serves as a prime target for drug discovery. Towards our goal of discovering secondary metabolites from natural sources that can function as neuronal drugs, we evaluated the modulatory effect of eckol on various GPCRs via cell-based functional assays. In addition, we conducted in silico predictions to obtain molecular insights into the functional effects of eckol. Functional assays revealed that eckol had a concentration-dependent agonist effect on dopamine D3 and D4 receptors. The half maximal effective concentration (EC50) of eckol for the dopamine D3 and D4 receptors was 48.62 ± 3.21 and 42.55 ± 2.54 µM, respectively, while the EC50 values of dopamine as a reference agonist for these two receptors were 2.9 and 3.3 nM, respectively. In silico studies revealed that a low binding energy in addition to hydrophilic, hydrophobic, π–alkyl, and π–π T-shaped interactions are potential mechanisms by which eckol binds to the dopamine receptors to exert its agonist effects. Molecular dynamics (MD) simulation revealed that Phe346 of the dopamine receptors is important for binding of eckol, similar to eticlopride and dopamine. Our results collectively suggest that eckol is a potential D3/D4 agonist for the management of neurodegenerative diseases, such as Parkinson’s disease.

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

“…Recently, we demonstrated that the selective h MAO-A inhibitor eckol, which contains phloroglucinol and dibenzo-1,4-dioxin elements, dose-dependently stimulates activity of D 3 R and D 4 R in a GPCR cell-based study with null effects on 5HT 1A , D 1 R, M 5 , NK 1 , and V 1A receptors [23]. Thus, we expected that phloroglucinol plays a role as a modulator of h MAOs and dopamine D 3 and D 4 receptors.…”

“…Strong intermolecular interactions between these phlorotannins and Asp103 and Phe288 residues of D 1 R may contribute to their antagonist effects. In the predicted D 3 R/D 4 R‒dieckol and D 3 R/D 4 R‒PFF-A complexes, phlorotannins strongly interacted with conserved OBP residues Asp110 in TM-3 and Ser192 in TM-5 of D 3 R (Asp115 in TM-3 and Ser197 in TM-5 of D 4 R) and were surrounded by hydrophobic residues of D 3 R/D 4 R. Similar to eckol [23], PFF-A hydrophobically interacted with the Phe346 residue of D 3 R via pi-pi stacked interaction, but dieckol could not interact with that residue due to the binding orientation. Instead of Phe346, dieckol strongly bound the Phe345 residue of D3R via pi-pi stacked interaction (Figure 6F).…”

“…Dieckol, with a number of hydrophilic groups and high molecular weight over 700, has been reported to effectively penetrate the BBB, making it a good candidate for direct neuromodulatory actions [31]. In addition, an in silico prediction study indicated that eckol moderately penetrates the CNS [23]. Studies of PFF-A in BBB permeability are limited, but effects similar to dieckol may be anticipated.…”

“…Recently, we demonstrated that eckol and dieckol, marine phlorotannins isolated from E. stolonifera [22], selectively inhibited h MAO-A in vitro and in silico. We also reported that eckol acts as an agonist of hD 3 R and hD 4 R. Molecular docking and dynamic analyses revealed that the eckol‒D 3 R complex was stabilized by the interaction between orthosteric binding pocket (OBP) residues of D 3 R, including Asp115, Ser192, and Phe346, and eckol [23].…”

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

“…The functional activity of the test compounds (agonist or antagonist) was evaluated by measuring their effects on cAMP modulation or Ca 2+ ion mobilization, depending on the receptor type. All assays were performed at Eurofins Cerep (Le Bois I'Eveque, France) following their in-house protocol, as stated in our previous reports [66][67][68].…”