In Vitro and In Silico Characterization of Kurarinone as a Dopamine D 1A Receptor Antagonist and D 2L and D 4 Receptor Agonist.

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.