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Multifunctional D2/D3 Agonist D-520 with High in Vivo Efficacy: Modulator of Toxicity of Alpha-Synuclein Aggregates.
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ACS Chem Neurosci 2014 Jul;
Authors: Gyan Modi, Chandrashekhar Voshavar, Sanjib Gogoi, Mrudang Shah, Tamara Antonio, Maarten E A Reith, Aloke K Dutta
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 (?SN). Additionally, coincubation of D-520 with ?SN is able to reduce toxicity of preformed aggregates of ?SN compared to control ?SN 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.
PMID: 24960209 [PubMed - as supplied by publisher]