{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T09:39:07Z","timestamp":1768556347428,"version":"3.49.0"},"reference-count":88,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Natural flavone and isoflavone analogs such as 3\u2032,4\u2032,7-trihydroxyflavone (1), 3\u2032,4\u2032,7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer\u2019s and Parkinson\u2019s disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL\/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC50 value: 7.57 \u00b1 0.14 \u03bcM) and 3 as a competitive inhibitor of hMAO-B with an IC50 value of 7.19 \u00b1 0.32 \u03bcM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD4R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL\/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD4R antagonist effect, respectively, for neuroprotection. The route of administration should be considered.<\/jats:p>","DOI":"10.3390\/ijms242115859","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T07:24:04Z","timestamp":1698823444000},"page":"15859","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In Vitro Human Monoamine Oxidase Inhibition and Human Dopamine D4 Receptor Antagonist Effect of Natural Flavonoids for Neuroprotection"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8482-1129","authenticated-orcid":false,"given":"Pradeep","family":"Paudel","sequence":"first","affiliation":[{"name":"Invasive Insect Biocontrol and Behavior Laboratory, Beltsville Agricultural Research Center-West, USDA-ARS, Beltsville, MD 20705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9034-8868","authenticated-orcid":false,"given":"Jae Sue","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6862-1901","authenticated-orcid":false,"given":"Ritu","family":"Prajapati","sequence":"additional","affiliation":[{"name":"Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su Hui","family":"Seong","sequence":"additional","affiliation":[{"name":"Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea"},{"name":"Natural Products Research Division, Honam National Institute of Biological Resource, Mokpo 58762, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Se Eun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woo-Chang","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong-Hoon","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9145-9594","authenticated-orcid":false,"given":"Hyun Ah","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1001\/jamapediatrics.2019.1759","article-title":"Association of screen time and depression in adolescence","volume":"173","author":"Boers","year":"2019","journal-title":"JAMA Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Davidson, M., Rashidi, N., Nurgali, K., and Apostolopoulos, V. (2022). The role of tryptophan metabolites in neuropsychiatric disorders. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179968"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/bs.acc.2019.08.005","article-title":"Tryptophan in health and disease","volume":"95","author":"Comai","year":"2020","journal-title":"Adv. Clin. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"985378","DOI":"10.3389\/fimmu.2022.985378","article-title":"Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Poly\u00e1k, H., Galla, Z., N\u00e1n\u00e1si, N., Cseh, E.K., Rajda, C., Veres, G., Spekker, E., Szab\u00f3, \u00c1., Kliv\u00e9nyi, P., and Tanaka, M. (2023). The tryptophan-kynurenine metabolic system is suppressed in cuprizone-induced model of demyelination simulating progressive multiple sclerosis. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030945"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"158","DOI":"10.3389\/fendo.2019.00158","article-title":"Tryptophan metabolic pathways and brain serotonergic activity: A comparative review","volume":"10","author":"Winberg","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41380-019-0414-4","article-title":"The kynurenine pathway: A finger in every pie","volume":"25","author":"Savitz","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Maffei, M.E. (2020). 5-Hydroxytryptophan (5-HTP): Natural occurrence, analysis, biosynthesis, biotechnology, physiology and toxicology. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010181"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1217090","DOI":"10.3389\/fnmol.2023.1217090","article-title":"Activated tryptophan-kynurenine metabolic system in the human brain is associated with learned fear","volume":"16","author":"Battaglia","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"IJTR.S36464","DOI":"10.4137\/IJTR.S36464","article-title":"Tryptophan metabolism and its relationship with depression and cognitive impairment among HIV-infected individuals","volume":"9","author":"Keegan","year":"2016","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"507","DOI":"10.9758\/cpn.2020.18.4.507","article-title":"Kynurenine pathway of tryptophan metabolism in neuropsychiatric disorders: Pathophysiologic and therapeutic considerations","volume":"18","author":"Muneer","year":"2020","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110770","DOI":"10.1016\/j.exger.2019.110770","article-title":"Kynurenine pathway and human systems","volume":"129","author":"Badawy","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3389\/fpsyt.2020.00071","article-title":"Neuroinflammation in bipolar depression","volume":"11","author":"Benedetti","year":"2020","journal-title":"Front. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"130369","DOI":"10.1016\/j.molstruc.2021.130369","article-title":"Insights into the structure activity relationship of nitrogen-containing heterocyclics for the development of antidepressant compounds: An updated review","volume":"1237","author":"Singh","year":"2021","journal-title":"J. Mol. Struct."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1177\/0141076819899299","article-title":"Antidepressants and sexual dysfunction: A history","volume":"113","author":"Healy","year":"2020","journal-title":"J. R. Soc. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"42","DOI":"10.2174\/1874350100801010042","article-title":"Persistence of sexual dysfunction side effects after discontinuation of antidepressant medications: Emerging evidence","volume":"1","author":"Bahrick","year":"2008","journal-title":"Open Psychol. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1097\/JCP.0b013e31819c76e9","article-title":"Sexual dysfunction, depression, and the impact of antidepressants","volume":"29","author":"Kennedy","year":"2009","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.euroneuro.2017.04.003","article-title":"Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta-analysis of controlled studies in depression","volume":"27","author":"Ricken","year":"2017","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_19","unstructured":"Quevedo, J., Riva-Posse, P., and Bobo, W.V. (2022). Managing Treatment-Resistant Depression, Academic Press."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125124","DOI":"10.1016\/j.foodchem.2019.125124","article-title":"Anti-inflammatory effects of flavonoids","volume":"299","author":"Maleki","year":"2019","journal-title":"Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"457","DOI":"10.3390\/nu12020457","article-title":"Flavonoids as anticancer agents","volume":"12","author":"Kopustinskiene","year":"2020","journal-title":"Nutrients"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3390\/cancers11010028","article-title":"Flavonoids in cancer and apoptosis","volume":"11","author":"Abotaleb","year":"2019","journal-title":"Cancers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ejmech.2017.07.034","article-title":"Recent discoveries of anticancer flavonoids","volume":"142","author":"Raffa","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s11101-018-9591-z","article-title":"Comprehensive review of antimicrobial activities of plant flavonoids","volume":"18","author":"Bartoszewski","year":"2019","journal-title":"Phytochem. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.jff.2019.05.004","article-title":"A comparative analysis of various flavonoids in the regulation of obesity and diabetes: An in vitro and in vivo study","volume":"59","author":"Varshney","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.foodchem.2018.10.008","article-title":"Identifying an isoflavone from the root of Pueraria lobata as a potent tyrosinase inhibitor","volume":"276","author":"Wagle","year":"2019","journal-title":"Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1021\/jf00045a015","article-title":"Quantitation of phytoestrogens in legumes by HPLC","volume":"42","author":"Franke","year":"1994","journal-title":"J. Agric. Food Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.jnutbio.2009.06.010","article-title":"Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells","volume":"21","author":"Sakamoto","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1002\/ddr.21534","article-title":"Glycitein induces reactive oxygen species-dependent apoptosis and G0\/G1 cell cycle arrest through the MAPK\/STAT3\/NF-\u03baB pathway in human gastric cancer cells","volume":"80","author":"Zang","year":"2019","journal-title":"Drug Dev. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kim, J.H., Lee, J.-E., Kim, T., Yeom, M.H., Park, J.S., di Luccio, E., Chen, H., Dong, Z., Lee, K.W., and Kang, N.J. (2020). 7, 3\u2032, 4\u2032-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses \u03b1-Melanocyte-Stimulating Hormone-Induced Melanogenesis by Targeting Melanocortin 1 Receptor. Front. Mol. Biosci., 7.","DOI":"10.3389\/fmolb.2020.577284"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.jep.2016.10.007","article-title":"Protein tyrosine phosphatase 1B and \u03b1-glucosidase inhibitory activities of Pueraria lobata root and its constituents","volume":"194","author":"Seong","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.neuint.2017.06.002","article-title":"Genistein, a dietary soy isoflavone, exerts antidepressant-like effects in mice: Involvement of serotonergic system","volume":"108","author":"Hu","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kim, S.-N., Ahn, S.-Y., Song, H.-D., Kwon, H.-J., Saha, A., Son, Y., Cho, Y.K., Jung, Y.-S., Jeong, H.W., and Lee, Y.-H. (2020). Antiobesity effects of coumestrol through expansion and activation of brown adipose tissue metabolism. J. Nutr. Biochem., 76.","DOI":"10.1016\/j.jnutbio.2019.108300"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1039\/C7FO01094J","article-title":"Anti-obesity molecular mechanism of soy isoflavones: Weaving the way to new therapeutic routes","volume":"8","author":"Wang","year":"2017","journal-title":"Food Funct."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s12272-012-0508-x","article-title":"Anti-inflammatory and antioxidant activities of constituents isolated from Pueraria lobata roots","volume":"35","author":"Jin","year":"2012","journal-title":"Arch. Pharmacal. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ijdevneu.2010.03.003","article-title":"Genistein as a neuroprotective antioxidant attenuates redox imbalance induced by \u03b2-amyloid peptides 25\u201335 in PC12 cells","volume":"28","author":"Ma","year":"2010","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lu, C., Wang, Y., Wang, D., Zhang, L., Lv, J., Jiang, N., Fan, B., Liu, X., and Wang, F. (2018). Neuroprotective effects of soy isoflavones on scopolamine-induced amnesia in mice. Nutrients, 10.","DOI":"10.3390\/nu10070853"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1021\/acsfoodscitech.0c00152","article-title":"Identification of a Potent and Selective Human Monoamine Oxidase\u2014A Inhibitor, Glycitein, an Isoflavone Isolated from Pueraria lobata Flowers","volume":"1","author":"Prajapati","year":"2021","journal-title":"ACS Food Sci. Technol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.phrs.2018.01.017","article-title":"Novel targets in Alzheimer\u2019s disease: A special focus on microglia","volume":"130","author":"Balducci","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"424","DOI":"10.2174\/1389200218666170710190249","article-title":"Natural or plant products for the treatment of neurological disorders: Current knowledge","volume":"19","author":"Parvez","year":"2018","journal-title":"Curr. Drug Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"23399","DOI":"10.1021\/acsomega.1c03250","article-title":"Navigating into the Chemical Space of Monoamine Oxidase Inhibitors by Artificial Intelligence and Cheminformatics Approach","volume":"6","author":"Kumar","year":"2021","journal-title":"ACS Omega"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1080\/17425255.2017.1273901","article-title":"Use of monoamine oxidase inhibitors in chronic neurodegeneration","volume":"13","author":"Riederer","year":"2017","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.jad.2021.01.021","article-title":"Revisiting monoamine oxidase inhibitors for the treatment of depressive disorders: A systematic review and network meta-analysis","volume":"282","author":"Suchting","year":"2021","journal-title":"J. Affect. Disord."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Elkamhawy, A., Paik, S., Park, J.-H., Kim, H.J., Hassan, A.H., Lee, K., Park, K.D., and Roh, E.J. (2021). Discovery of novel and potent safinamide-based derivatives as highly selective hMAO-B inhibitors for treatment of Parkinson\u2019s disease (PD): Design, synthesis, in vitro, in vivo and in silico biological studies. Bioorg. Chem., 115.","DOI":"10.1016\/j.bioorg.2021.105233"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1021\/acscentsci.6b00309","article-title":"Close correlation of monoamine oxidase activity with progress of Alzheimer\u2019s disease in mice, observed by in vivo two-photon imaging","volume":"2","author":"Kim","year":"2016","journal-title":"ACS Cent. Sci."},{"key":"ref_46","first-page":"1","article-title":"Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with \u03b3-secretase and regulates neuronal amyloid \u03b2-peptide levels","volume":"9","author":"Inoue","year":"2017","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"112787","DOI":"10.1016\/j.ejmech.2020.112787","article-title":"A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer\u2019s disease agents: A review","volume":"206","author":"Manzoor","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.ejmech.2018.05.004","article-title":"A review on flavonoid-based scaffolds as multi-target-directed ligands (MTDLs) for Alzheimer\u2019s disease","volume":"152","author":"Babaei","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10719","DOI":"10.1021\/acs.jafc.0c04502","article-title":"Luteolin, a Potent Human Monoamine Oxidase-A Inhibitor and Dopamine D4 and Vasopressin V1A Receptor Antagonist","volume":"68","author":"Park","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"33443","DOI":"10.1021\/acsomega.1c04109","article-title":"In Vitro and In Silico Characterization of Kurarinone as a Dopamine D1A Receptor Antagonist and D2L and D4 Receptor Agonist","volume":"6","author":"Prajapati","year":"2021","journal-title":"ACS Omega"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1248\/bpb.b21-00841","article-title":"3\u2032, 4\u2032, 7-Trihydroxyflavone Downregulates NO Production in LPS-or IFN-\u03b3-Activated MG6 Microglial Cells by Attenuating the JNK\u2013STAT1 Pathway","volume":"45","author":"Akaishi","year":"2022","journal-title":"Biol. Pharm. Bull."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.fct.2015.02.014","article-title":"3\u2032, 4\u2032, 7-Trihydroxyflavone prevents apoptotic cell death in neuronal cells from hydrogen peroxide-induced oxidative stress","volume":"80","author":"Kwon","year":"2015","journal-title":"Food Chem. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.jep.2012.09.056","article-title":"Neuroprotective effect of calycosin on cerebral ischemia and reperfusion injury in rats","volume":"144","author":"Guo","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ijbiomac.2021.03.186","article-title":"Antioxidant activity of calycosin against \u03b1-synuclein amyloid fibrils-induced oxidative stress in neural-like cells as a model of preventive care studies in Parkinson\u2019s disease","volume":"182","author":"Pan","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/ptr.6221","article-title":"Calycosin attenuates MPTP-induced Parkinson\u2019s disease by suppressing the activation of TLR\/NF-\u03baB and MAPK pathways","volume":"33","author":"Yang","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ijbiomac.2020.02.144","article-title":"Calycosin and 8-O-methylretusin isolated from Maackia amurensis as potent and selective reversible inhibitors of human monoamine oxidase-B","volume":"151","author":"Oh","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ijdevneu.2019.10.009","article-title":"Phytoestrogen coumestrol attenuates brain mitochondrial dysfunction and long-term cognitive deficits following neonatal hypoxia\u2013ischemia","volume":"79","author":"Anastacio","year":"2019","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/hipo.23418","article-title":"Coumestrol pre-treatment improves spatial learning and memory deficits following transient cerebral ischemia recruiting hippocampal GluR2 AMPA receptors","volume":"32","author":"Castro","year":"2022","journal-title":"Hippocampus"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1179\/1743132810Y.0000000029","article-title":"The protective effects of coumestrol against amyloid-beta peptide-and lipopolysaccharide-induced toxicity on mice astrocytes","volume":"33","author":"Liu","year":"2011","journal-title":"Neurol. Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Koirala, P., Seong, S.H., Jung, H.A., and Choi, J.S. (2018). Comparative evaluation of the antioxidant and anti-Alzheimer\u2019s disease potential of coumestrol and puerarol isolated from Pueraria lobata using molecular modeling studies. Molecules, 23.","DOI":"10.3390\/molecules23040785"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Seong, S.H., Kim, B.R., Cho, M.L., Kim, T.S., Im, S., Han, S., Jeong, J.W., Jung, H.A., and Choi, J.S. (2022). Phytoestrogen Coumestrol Selectively Inhibits Monoamine Oxidase-A and Amyloid \u03b2 Self-Aggregation. Nutrients, 14.","DOI":"10.3390\/nu14183822"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"115604","DOI":"10.1016\/j.jep.2022.115604","article-title":"Phytochemical screening and effect of Viscum album L. on monoamine oxidase A and B activity and serotonin, dopamine and serotonin receptor 5-HTR1A levels in Galleria mellonealla (Lepidoptera)","volume":"298","author":"Szurpnicka","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9004","DOI":"10.1021\/acs.jafc.6b03529","article-title":"Inhibition of human monoamine oxidase: Biological and molecular modeling studies on selected natural flavonoids","volume":"64","author":"Carradori","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"12684","DOI":"10.1073\/pnas.0505975102","article-title":"Three-dimensional structure of human monoamine oxidase A (MAO A): Relation to the structures of rat MAO A and human MAO B","volume":"102","author":"Li","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5739","DOI":"10.1073\/pnas.0710626105","article-title":"Structure of human monoamine oxidase A at 2.2-\u00c5 resolution: The control of opening the entry for substrates\/inhibitors","volume":"105","author":"Son","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","first-page":"327","article-title":"Evaluation of antidepressant like property of amisulpride per se and its comparison with fluoxetine and olanzapine using forced swimming test in albino mice","volume":"66","author":"Pawar","year":"2009","journal-title":"Acta Pol. Pharm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.1248\/bpb.29.2304","article-title":"Antidepressant-like effects of sarsasapogenin from Anemarrhena asphodeloides BUNGE (Liliaceae)","volume":"29","author":"Ren","year":"2006","journal-title":"Biol. Pharm. Bull."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1017\/neu.2017.33","article-title":"Failure to detect the action of antidepressants in the forced swim test in Swiss mice","volume":"30","author":"Suman","year":"2018","journal-title":"Acta Neuropsychiatr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.pbb.2017.04.010","article-title":"Neurochemical arguments for the use of dopamine D4 receptor stimulation to improve cognitive impairment associated with schizophrenia","volume":"157","author":"Huang","year":"2017","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1177\/0269881117693746","article-title":"Dopamine D4 receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia","volume":"31","author":"Miyauchi","year":"2017","journal-title":"J. Psychopharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"13118","DOI":"10.1073\/pnas.1201011109","article-title":"Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors","volume":"109","author":"Andersson","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1007\/s00018-010-0293-y","article-title":"The dopamine D4 receptor: Biochemical and signalling properties","volume":"67","author":"Rondou","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.euroneuro.2014.11.016","article-title":"Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model","volume":"25","author":"Tomlinson","year":"2015","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"707","DOI":"10.2174\/1871527314666150529132723","article-title":"Dopamine D4 receptor antagonists for the treatment of cocaine use disorders","volume":"14","author":"Bergman","year":"2015","journal-title":"CNS Neurol. Disord.-Drug Targets"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.nbd.2016.09.001","article-title":"Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists","volume":"96","author":"Sebastianutto","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/ana.65","article-title":"Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson\u2019s disease: PET evidence of increased dopamine turnover","volume":"49","author":"Lu","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1038\/srep03730","article-title":"L-dopa-induced dyskinesia: Beyond an excessive dopamine tone in the striatum","volume":"4","author":"Porras","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1126\/science.2147780","article-title":"D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons","volume":"250","author":"Gerfen","year":"1990","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7233","DOI":"10.1021\/acs.jmedchem.7b00151","article-title":"Return of D4 Dopamine receptor antagonists in drug discovery: Miniperspective","volume":"60","author":"Lindsley","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.ccell.2016.05.002","article-title":"Inhibition of dopamine receptor D4 impedes autophagic flux, proliferation, and survival of glioblastoma stem cells","volume":"29","author":"Dolma","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"11621","DOI":"10.1021\/acsomega.9b01433","article-title":"Rubrofusarin as a dual protein tyrosine phosphate 1B and human monoamine oxidase-A inhibitor: An in vitro and in silico study","volume":"4","author":"Paudel","year":"2019","journal-title":"ACS Omega"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"16139","DOI":"10.1021\/acsomega.9b02328","article-title":"In vitro and in silico human monoamine oxidase inhibitory potential of anthraquinones, naphthopyrones, and naphthalenic lactones from Cassia obtusifolia Linn seeds","volume":"4","author":"Paudel","year":"2019","journal-title":"ACS Omega"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Paudel, P., Seong, S.H., Wu, S., Park, S., Jung, H.A., and Choi, J.S. (2019). Eckol as a potential therapeutic against neurodegenerative diseases targeting dopamine D3\/D4 receptors. Mar. Drugs, 17.","DOI":"10.3390\/md17020108"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Paudel, P., Seong, S.H., Jung, H.A., and Choi, J.S. (2019). Characterizing fucoxanthin as a selective dopamine D3\/D4 receptor agonist: Relevance to Parkinson\u2019s disease. Chem. Biol. Interact., 310.","DOI":"10.1016\/j.cbi.2019.108757"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Seong, S.H., Paudel, P., Choi, J.-W., Ahn, D.H., Nam, T.-J., Jung, H.A., and Choi, J.S. (2019). Probing multi-target action of phlorotannins as new monoamine oxidase inhibitors and dopaminergic receptor modulators with the potential for treatment of neuronal disorders. Mar. Drugs, 17.","DOI":"10.3390\/md17060377"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6","article-title":"Automated docking of flexible ligands: Applications of AutoDock","volume":"9","author":"Goodsell","year":"1996","journal-title":"J. Mol. Recognit."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1126\/science.aan5468","article-title":"D4 dopamine receptor high-resolution structures enable the discovery of selective agonists","volume":"358","author":"Wang","year":"2017","journal-title":"Science"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"103202","DOI":"10.1016\/j.etap.2019.103202","article-title":"Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model","volume":"70","author":"Xu","year":"2019","journal-title":"Environ. Toxicol. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15859\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:15:28Z","timestamp":1760130928000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15859"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,1]]},"references-count":88,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115859"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115859","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,1]]}}}