A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo

• A novel Fe (II) preferring multifunctional brain penetrant dopamine D2/D3 agonist D-607 has been developed.
• D-607 exhibits neuroprotection in multiple cellular Parkinson's disease models.
• D-607 significantly suppresses α-synuclein induced toxicity in in vivo Drosophila melanogaster fly model.
• D-607 rescues DAergic neurons from MPTP toxicity in mice following both subchronicand chronic MPTP administration.
• Mitochondrial stabilization, inhibition of prolyl hydroxylase domain by D-607 mightexplain mechanism of neuroprotection.

Here, we report the characterization of a novel hybrid D2/D3 agonist and iron (II) specific chelator, D-607, as a multi-target-directed ligand against Parkinson's disease (PD). In our previously published report, we showed that D-607 is a potent agonist of dopamine (DA) D2/D3 receptors, exhibits efficacy in a reserpinized PD animal model and preferentially chelates to iron (II). As further evidence of its potential as a neuroprotective agent in PD, the present study reveals D-607 to be protective in neuronal PC12 cells against 6-OHDA toxicity. In an in vivo Drosophila melanogaster model expressing a disease-causing variant of α-synuclein (α-Syn) protein in fly eyes, the compound was found to significantly suppress toxicity compared to controls, concomitant with reduced levels of aggregated α-Syn. Furthermore, D-607 was able to rescue DAergic neurons from MPTP toxicity in mice, a well-known PD neurotoxicity model, following both sub-chronic and chronic MPTP administration. Mechanistic studies indicated that possible protection of mitochondria, up-regulation of hypoxia-inducible factor, reduction in formation of α-Syn aggregates and antioxidant activity may underlie the observed neuroprotection effects. These observations strongly suggest that D-607 has potential as a promising multifunctional lead molecule for viable symptomatic and disease-modifying therapy for PD.

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