Multifunctional D2/D3 Agonist D-520 with High in Vivo Efficacy: Modulator of Toxicity of Alpha-Synuclein Aggregates

Abstract

We have developed a series of dihydroxy compounds and related analogues based on our hybrid D2/D3 agonist molecular template to develop multifunctional drugs for symptomatic and neuroprotective treatment for Parkinson's disease (PD). The lead compound (-)-24b (D-520) exhibited high agonist potency at D2/D3 receptors and produced efficacious activity in the animal models for PD. The data from thioflavin T (ThT) assay and from transmission electron microscopy (TEM) analysis demonstrate that D-520 is able to modulate aggregation of alpha-synuclein (αSN). Additionally, coincubation of D-520 with αSN is able to reduce toxicity of preformed aggregates of αSN compared to control αSN alone. Finally, in a neuroprotection study with dopaminergic MN9D cells, D-520 clearly demonstrated the effect of neuroprotection from toxicity of 6-hydroxydopamine. Thus, compound D-520 possesses properties characteristic of multifunctionality conducive to symptomatic and neuroprotective treatment of PD.

Inhibition of alpha-synuclein aggregation by multifunctional dopamine agonists assessed by a novel in vitro assay and an in vivo Drosophila synucleinopathy model

“…The multifunctional hybrid compounds D-519 and D-520, were derived from parent precursor molecules Pramipexole and 5-OHDPAT by a fragment based drug development approach4454. The rationale behind testing the parent precursor compounds was to evaluate whether these compounds exhibit an inherent modulation of α-syn aggregation property.…”

“…We have previously shown that D-520, a multifunctional dopamine agonist developed in our laboratory is a potent α-syn aggregation inhibitor44. We therefore tested this compound along with its analog D-519 using the assay developed by us.…”

“…In our approach, along this line, we designed compounds with both symptomatic and neuroprotective disease modifying effects. Thus, we have designed and biologically characterized multifunctional dopamine agonists D-519 and D-520 as modulators of α-syn aggregation44.…”

α-Synuclein Aggregation Modulation: An Emerging Approach for the Treatment of Parkinson'S Disease

“…Furthermore, D520 displayed excellent in vivo activity in PD animal models. Additionally, D520 is able to modulate the toxicity of αSyn aggregates to a significant extent compared with the positive control rifampicin and also provided neuroprotection against 6-OHDA induced toxicity [85]. Recently, D519 ( Figure 5Q), and D520 were tested for their ability to modulate αSyn aggregation in a novel in vitro assay and Drosophila model of synucleinopathy.…”

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

“…As of now, no neuroprotective drugs have been identified or approved by the FDA for the treatment of PD. The overall goal of our research is to develop orally active multifunctional treatment agents to address both symptomatic (relieving motor dysfunction) and disease-modifying neuroprotective effects to slow or stop the progression of the disease (Das et al, 2015; Ghosh et al, 2010; Li et al, 2010; Modi et al, 2014; Santra et al, 2013; Shah et al, 2014). A number of iron chelators have been employed in the preclinical and clinical studies of PD (Devos et al, 2014; Grolez et al, 2015).…”