Bromophenols from Symphyocladia latiuscula Target Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Abstract

Progressive degeneration of dopaminergic neurons in the substantia nigra is the characteristic feature of Parkinson’s disease (PD) and the severity accelerates with aging. Therefore, improving dopamine level or dopamine receptor signaling is a standard approach for PD treatment. Herein, our results demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) from red alga Symphyocladia latiuscula are moderate-selective human monoamine oxidase-A inhibitors and good dopamine D3/D4 receptor agonists. Bromophenol 3 showed a promising D4R agonist effect with a low micromole 50% effective concentration (EC50) value. All of the test ligands were docked against a three-dimensional (3D) model of hD3R and hD4R, and the result demonstrated strong binding through interaction with prime interacting residuesAsp110, Cys114, and His349 on hD3R and Asp115 and Cys119 on hD4R. Overall, the results demonstrated natural bromophenols, especially 1 and 3, from Symphyocladia latiuscula as multitarget ligands for neuroprotection, especially in PD and schizophrenia.

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

“…Interestingly, fucoxanthin was also identified as a dopamine agonist, where a molecular docking study suggested that it formed H-bonding with Ser196 and Asp115 of the D4 receptor, and Ser196 and Thr115 residues of D3 receptors [ 250 ]. The same group also identified some bromophenols derivatives as D3R and hD4R antagonists and studied the interaction and binding pattern by molecular docking [ 251 ].…”

Progress of Bromophenols in Marine Algae from 2011 to 2020: Structure, Bioactivities, and Applications

“…Moreover, BPs 6.1–6.3 exhibited more than 50% inhibition of self-induced A β 25–35 aggregation [ 9 ], which may be another mechanism for their anti-AD activity. In addition to anti-AD activity, BPs 6.1–6.3 have also been reported as inhibitors of human monoamine oxidase-A (hMAO-A) [ 109 ], which catalyzes the inactivation of multiple neurotransmitters in the treatment of PD. Furthermore, the same research group found that BPs 6.1–6.3 were also good dopamine D 3 /D 4 receptor agonists.…”

“…Furthermore, the same research group found that BPs 6.1–6.3 were also good dopamine D 3 /D 4 receptor agonists. BP 6.3 was the most promising dopamine D 4 receptor agonist exhibiting EC 50 value at very low micromolar levels ( Table 5 ) [ 109 ]. Since AChE, BChE, BACE1, hMAO-A, and dopaminergic receptors are closely related to the neurodegenerative diseases such as AD and PD, these BPs compounds can possibly be developed as new drugs for the treatment of neurodegenerative disorders.…”

“…As can be seen from Figure 6 , phenolic hydroxyl groups in BP 6.1 can form hydrogen bonds with Tyr444, FAD600, Asn181, and Ile207. In addition, methoxyl and phenolic hydroxyl groups in BP 6.2 can form hydrogen bonds with Gln215 and FAD600, while phenolic hydroxyl groups in BP 6.3 can form hydrogen bonds with Lys363, Met300, and Asp359 [ 109 ].…”

“…BP 6.1 (also 2.1 and 7.1.1 ), BP 6.2 (also 2.2 ), and BP 6.3 (also 2.3 , 7.1.2 , and 7.3.5 ) docked to D 3 R ligands indicated that Asp110, Cys114, His349, and Phe345 are the most important residues, and hydrogen bonds are formed between the compound and these amino acid residues ( Figure 7 ). Moreover, BPs 6.1 – 6.3 were also docked to D 4 R, and BP 6.3 showed the strongest combination ability to D 4 R. Phenolic hydroxyl groups in BP 6.3 can form various hydrogen bonds with Ser196, Asp115, Val193, and Ser197 residues ( Figure 8 ) [ 109 ].…”