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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 D₁R, D_2LR, D₃R, and D₄R, vasopressin V_1AR, and serotonin 5-HT_1AR 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_1AR, 5-HT_1AR, and hMAOs. Radioligand binding assays revealed considerable binding of kurarinone on D₁R, D_2LR, and D₄R. Functional GPCR assays unfolded the compound's antagonist behavior on D₁R (IC₅₀ 42.1 ± 0.35 μM) and agonist effect on D_2LR and D₄R (EC₅₀ 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 D₁R, D_2LR, and D₄R, validating substantial binding affinities to these prime targets. With appreciable D_2LR and D₄R agonism and D₁R antagonism, kurarinone might be a potential compound that can alleviate clinical symptoms of Parkinson's disease and other NDDs.

SUBMITTER: Prajapati R

PROVIDER: S-EPMC8674921 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Adenosine A2A and dopamine D2 receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A2A receptor-mediated modulation of D2 receptor binding in vivo using positron emission tomography (PET) with the D2 antagonist tracer [11C]raclopride. Healthy male Wistar rats (n = 8) were scanned (60 min dynamic scan) with [11C]raclopride at baseline and 7 days later following an acute administration of the A2A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BPND) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [11C]raclopride BPND (p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BPND from the k3/k4 ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [11C]raclopride scans after pretreatment with a vehicle (n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A2A antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group (p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k3/k4 ratio (p < 0.01), but k3 and k4 estimates may be less reliable. The BPND (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 (p = 0.080) or 1.961 ± 0.11 (p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A2A agonist CGS21680, but not the antagonist KW6002, may reduce the D2 receptor availability in the striatum.

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

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In Vitro and In Silico Characterization of Kurarinone as a Dopamine D1A Receptor Antagonist and D2L and D4 Receptor Agonist.

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