Biological Characterization of the Anti-ferroptotic Properties of a Novel Anti-Parkinsonian Iron (II) Selective Dopamine Agonist, D-583

Here, we report the in vitro and in vivo characterization of a novel hybrid D2/D3 agonist and iron (II)-specific chelator, D-583, as a multi-target-directed ligand for Parkinson’s disease (PD). In our previously published work, we demonstrated that D-583 is a potent agonist of dopamine (DA) D2/D3 receptors. In this study, we show that D-583 is an efficacious brain-penetrant compound, exhibiting efficacy in a PD symptomatic animal model. As further evidence of its potential as a neuroprotective agent in PD, the current study reveals that D-583 protects neuronal PC12 cells from 6-OHDA toxicity. Moreover, the compound was found to exhibit anti-ferroptotic activity against RSL3-induced cell death in PANC-1 cell lines. Potent antioxidant activity and mitochondrial membrane potential stabilization were also observed under ferroptotic conditions induced by RSL3. Finally, mechanistic evaluation of its anti-ferroptotic properties revealed the restoration of key ferroptosis-related proteins, including GPX4, SLC7A11, and NRF2, following RSL3 treatment. Our findings establish the potent anti-ferroptotic properties of the brain-penetrant iron (II) chelator and dopamine agonist, D-583. Given that ferroptosis is implicated in PD, compounds like D-583 could serve as potential neuroprotective and symptomatic therapeutic agents for PD.