title: 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.
authors: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors: Gyan
authors: G
authors: Modi
authors: Chandrashekhar
authors: C
authors: Voshavar
authors: Sanjib
authors: S
authors: Gogoi
authors: Mrudang
authors: M
authors: Shah
authors: Tamara
authors: T
authors: Antonio
authors: Maarten E A
authors: ME
authors: Reith
authors: Aloke K
authors: AK
authors: Dutta
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D012110:Reserpine; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D050637:Receptors, Dopamine D3; D051844:alpha-Synuclein; D012110:Reserpine; D016627:Oxidopamine