title: Novel multifunctional dopamine D2/D3receptors agonists with potential neuroprotection and anti-alpha synuclein protein aggregation properties.
abstract: Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson's disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of α-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths. Structural optimization led to development of several potent agonists among which (-)-8a, (-)-14 and (-)-20 exhibited potent neuroprotective properties in a cellular PD model involving neurotoxin 6-OHDA. The lead compounds (-)-8a and (-)-14 were able to modulate aggregation of α-synuclein protein efficiently. Finally, in an in vivo PD animal model, compound (-)-8a exhibited efficacious anti-parkinsonian effect.
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48202, United States.
authors: Dan
authors: D
authors: Luo
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48202, United States.
authors: Horrick
authors: H
authors: Sharma
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48202, United States.
authors: Deepthi
authors: D
authors: Yedlapudi
authors: Department of Psychiatry, New York University, New York, NY 10016, United States.
authors: Tamara
authors: T
authors: Antonio
authors: Department of Psychiatry, New York University, New York, NY 10016, United States.
authors: Maarten E A
authors: MEA
authors: Reith
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48202, United States. Electronic address: adutta@wayne.edu.
authors: Aloke K
authors: AK
authors: Dutta
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D066329:Protein Aggregates / Q000187:drug effects; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D051844:alpha-Synuclein; D016627:Oxidopamine
keywords: Alpha synuclein; Dopamine agonist; Multifunctional drug; Neuroprotection; Parkinson’s disease; Structure activity relationship study