In Vitro and In Silico Characterization of Kurarinone as a Dopamine D_1A Receptor Antagonist and D_2L and D₄ Receptor Agonist

Abstract

Alterations in the expression and/or activity of brain G-protein-coupled receptors (GPCRs) such as dopamine D 1 R, D 2L R, D 3 R, and D 4 R, vasopressin V 1A R, and serotonin 5-HT 1A R are noted in various neurodegenerative diseases (NDDs). Since studies have indicated that flavonoids can target brain GPCRs and provide neuroprotection via inhibition of monoamine oxidases (hMAOs), our study explored the functional role of kurarinone, an abundant lavandulated flavonoid in Sophora flavescens , on dopamine receptor subtypes, V 1A R, 5-HT 1A R, and hMAOs. Radioligand binding assays revealed considerable binding of kurarinone on D 1 R, D 2L R, and D 4 R. Functional GPCR assays unfolded the compound’s antagonist behavior on D 1 R (IC 50 42.1 ± 0.35 μM) and agonist effect on D 2L R and D 4 R (EC 50 22.4 ± 3.46 and 71.3 ± 4.94 μM, respectively). Kurarinone was found to inhibit hMAO isoenzymes in a modest and nonspecific manner. Molecular docking displayed low binding energies during the intermolecular interactions of kurarinone with the key residues of the deep orthosteric binding pocket and the extracellular loops of D 1 R, D 2L R, and D 4 R, validating substantial binding affinities to these prime targets. With appreciable D 2L R and D 4 R agonism and D 1 R antagonism, kurarinone might be a potential compound that can alleviate clinical symptoms of Parkinson’s disease and other NDDs.

In Vitro Human Monoamine Oxidase Inhibition and Human Dopamine D4 Receptor Antagonist Effect of Natural Flavonoids for Neuroprotection

“…Additionally, they found that it is an MAO-A inhibitor with an IC 50 value of 8.57 ± 0.47 µM [49]. Likewise, a prenylated flavanone, kurarinone, was also found to be a D 1A R antagonist and a D 2L and D 4 agonist [50]. 3 ,4 ,7-Trihydroxyflavone (1) decreases NO production and exerts an anti-neuroinflammatory effect through the inhibition of the JNK-STAT1 pathway in microglia [51].…”

“…a,b % stimulation and % inhibition of control agonist response at 100 µM of compounds, respectively, were calculated from a log dose inhibition curve and expressed as mean ± SD of triplicate experiments. c EC50 (nM) values of standard agonists (D 1 , D 2L , D 3 , and D 4.4 : dopamine, 5-HT 1A : serotonin). d IC 50 (nM) values of standard antagonists (D 1 : SCH-23390, D 2L : butaclamol, D 3 : (+)-butaclamol, D 4.4 : clozapine, and 5-HT 1A : (S)-WAY-100635).…”

Natural Product-Inspired Dopamine Receptor Ligands

“…Kurarinone ( 94 ) is an abundant lavandulylated flavonoid isolated from the perennial shrub Sophora flavescens (Fabaceae) . Known as Kushen, the dried roots of S. flavescens are used in traditional Chinese medicine for the treatment of cancer and inflammatory diseases .…”

Phytochemistry and pharmacology of natural prenylated flavonoids

“…522 could bind well to dopamine receptor subtypes, unfolding antagonist behavior on D 1 R (IC 50 : 42.1 µ M) and agonist effects on D2LR and D4R (EC 50 22.4 and 71.3 µ M, respectively). 522 suppressed hMAO isoenzymes in a modest and nonspecific manner (Prajapati et al 2021 ). 579 acted at GABA A receptors in the hippocampal nerve terminals to downregulate the Ca 2+ influx by N- and P/Q-type Ca 2+ channels, which subsequently suppressed the Ca 2+ -calmodulin/PKA cascade to reduce the evoked glutamate release.…”