A Novel Iron(II) Preferring Dopamine Agonist Chelator as Potential Symptomatic and Neuroprotective Therapeutic Agent for Parkinson’s Disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder, and development of disease-modifying treatment is still an unmet medical need. Considering the implication of free iron(II) in PD, we report here the design and characterization of a novel hybrid iron chelator, (-)-12 (D-607) as a multitarget-directed ligand against PD. Binding and functional assays at dopamine D/D receptors indicate potent agonist activity of (-)-12. The molecule displayed an efficient preferential iron(II) chelation properties along with potent in vivo activity in a reserpinized PD animal model. The compound also rescued PC12 cells from toxicity induced by iron delivered intracellularly in a dose-dependent manner. However, Fe selective dopamine agonist 1 and a well-known antiparkinsonian drug pramipexole produced little to no neuroprotection effect under the same experimental condition. These observations strongly suggest that (-)-12 should be a promising multifunctional lead molecule for a viable symptomatic and disease modifying therapy of PD.

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

“…This was further validated in a cell-based lipid peroxidation assay where pre-treatment with the compound was found to significantly reduce iron (II) induced lipid peroxidation. Our results also demonstrated D-607 to be much more neuroprotective in this experimental model versus pramipexole and a 8-hydroxyquinoline-derived Fe(III) preferring dopamine agonist, thereby, reflecting contribution of the bipyridyl moiety in enhanced neuroprotection (Das et al, 2017). …”

“…Our previous iron binding study revealed far higher specificity for complex formation of D-607 with Fe(II) compared to Fe(III). This study also indicated a neuroprotective effect of D-607 in neuronal PC12 cells against iron (II)-induced cell death (Das et al, 2017). The fact that compound D-607 was able to rescue these cells strongly indicated the ability of selective intracellular complexation of Fe(II) by the compound to reduce oxidative stress.…”

“…1) was synthesized by a multistep synthesis process as described in our recent publication (Das et al, 2017). …”

“…1) based on our hybrid drug design template (Das et al, 2017; Dutta et al, 2004). In this molecule, a D 2 /D 3 agonist moiety is linked to a bipyridyl moiety, a known iron-chelating agent that has preferential affinity for Fe 2+ (Breuer et al, 1995; Cabantchik et al, 1996; Romeo et al, 2001).…”

“…Thus, a Fe 2+ preferring chelator should provide greater beneficial effect against neurodegeneration. The lead molecule, D-607 , not only exhibited potent in vivo activity in a PD animal model but also displayed neuroprotection effect in a cellular model which was attributed to preferential complexing with Fe 2+ (Das et al, 2017). Moreover, the compound was efficacious in significantly reducing lipid peroxidation induced by Fe 2+ in vitro delineating its antioxidant property (Das et al, 2017).…”