Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their role in Parkinson’s disease (PD) and depression, focusing on their ability to modulate dopaminergic receptors (D(1)R, D(2L)R, D(3)R, and D(4)R). In hMAO-A inhibition, 1–3 showed mild effects (50% inhibitory concentration (IC(50)): 54‒114 μM). However, 1 displayed moderate inhibition of the hMAO-B isozyme (IC(50): 18.14 ± 1.06 μM) followed by mild inhibition by 2 (IC(50): 57.71 ± 2.12 μM) and 3 (IC(50): 90.59 ± 1.72 μM). Our kinetic study characterized the inhibition mode, and the in silico docking predicted that the moderate inhibitor 1 would have the lowest binding energy. Similarly, cell-based G protein-coupled receptors (GPCR) functional assays in vector-transfected cells expressing dopamine (DA) receptors characterized 1–3 as D(1)R/D(2L)R antagonists and D(3)R/D(4)R agonists. The half-maximum effective concentration (EC(50)) of 1–3 on DA D(3)R/D(4)R was 15.13/17.19, 20.18/21.05, and 12.63/‒ µM, respectively. Similarly, 1–3 inhibited 50% of the DA response on D(1)R/D(2L)R by 6.13/2.41, 16.48/31.22, and 7.16/18.42 µM, respectively. A computational study revealed low binding energy for the test ligands. Interactions with residues Asp110, Val111, Tyr365, and Phe345 at the D(3)R receptor and Asp115 and His414 at the D(4)R receptor explain the high agonist effect. Likewise, Asp187 at D(1)R and Asp114 at D(2L)R play a crucial role in the antagonist effects of the ligand binding. Our overall results depict 1–3 from M. alba root bark as good inhibitors of hMAO and potent modulators of DA function as D(1)R/D(2L)R antagonists and D(3)R/D(4)R agonists. These active constituents in M. alba deserve in-depth study for their potential to manage neurodegenerative disorders (NDs), particularly PD and psychosis.