title: 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 D2/D3receptors 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, Fe3+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.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Banibrata
authors.initials: B
authors.lastname: Das
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Ashoka
authors.initials: A
authors.lastname: Kandegedara
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Psychiatry, New York University , New York, New York 10016, United States.
authors.forename: Tamara
authors.initials: T
authors.lastname: Antonio
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Stemmler
authors.affiliation: Department of Psychiatry, New York University , New York, New York 10016, United States.
authors.forename: Maarten E A
authors.initials: MEA
authors.lastname: Reith
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
authors.forename: Aloke K
authors.identifier: 0000-0003-3347-0538
authors.initials: AK
authors.lastname: Dutta
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D010300:Parkinson Disease; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D000978:Antiparkinson Agents; C000617983:D-607 compound; D018491:Dopamine Agonists; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D010879:Piperazines; D015082:2,2'-Dipyridyl
keywords: D2/D3 agonist; Parkinson’s disease; iron chelation; multifunctional drug; neuroprotection