Dual-acting molecular hybrid strategy: A dopamine D2 receptor agonist with synergistic anti-ferroptosis activity for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Accumulating evidence suggests iron homeostasis in the substantia nigra pars compacta and the subsequent induction of ferroptosis play pivotal roles in PD pathogenesis. In this study, we proposed a dual-acting molecular hybrid strategy and identified a promising lead compound 27e. 27e exhibited potent agonistic activity on dopamine D2 receptor (EC50 = 0.0325 nM), demonstrating 10-fold superior to clinical dopamine D2 agonist rotigotine (EC50 = 0.301 nM). Moreover, 27e showed selective iron-chelating ability (Kb = 3.3 × 1022 M-1), which enabled it to decrease intracellular ferrous iron levels and exert potent cytoprotective effects against iron-dependent ferroptosis in vitro. Additionally, 27e displayed weak cytotoxicity and acceptable blood-brain barrier permeability. In a mouse model of PD, treatment with 27e significantly ameliorated motor dysfunction compared to the vehicle group and showed better neuroprotective effects than rotigotine. Collectively, as a dual-acting molecule possessing dopamine D2 receptor agonism and ferroptosis inhibition, 27e offers a promising therapeutic strategy for PD that goes beyond symptomatic relief.