Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. The cardinal clinical features of PD include resting tremor, rigidity, difficulty initiating movement, and postural instability. Currently, no ideal therapies are available for slowing the progression of the degeneration process and at the same time relieving symptomatic abnormalities associated with this disease. Although the pathogenesis of PD is poorly understood both oxidative stress and mitochondrial dysfunction resulting from loss of glutathione with increased concentration of free iron have been strongly implicated in dopamine cell death. It is increasingly evident that for a complex disease such as PD, a drug targeting only one target site will only partially address the therapeutic need of the disease. The overall goal in this proposal is to develop multifunctional therapeutic agents which will be useful not only in symptomatic treatment but also could be used as disease-modifying agents by promoting survival of DA neurons. Dopamine D3 preferring agonists besides providing symptomatic relief in PD with less motor complications, have also been shown to act as neuroprotective agents. A D3 preferring compound D-264 derived from our novel hybrid template was shown to be neuroprotective in two different animal models studies. Our studies demonstrated that interaction of D-264 with the D3 receptor along with its other properties e.g. antioxidant, might be responsible for its neuroprotection property. In another preliminary development, unique multifunctional dopamine D2/D3 agonist compounds with a capacity to chelate iron have been developed. Such molecules are not only expected to relieve motor dysfunction in PD but also will have the potential to reduce oxidative stress in the PD brain by chelating with iron which has been implicated in the pathogenesis of the disease. Initial studies indicate facile blood-brain-barrier crossing ability of these compounds, and in cell culture and in vivo MPTP mouse model experiments one of the lead molecules indicated neuroprotection property. We now propose to expand drug development studies based on hybrid D-264 related analogues to improve pharmacokinetic properties to increase bioavailability and to carry out expanded structure activity relationship studies on multivalent iron binding D2/D3 agonists. Selected molecules from these two series of compounds will be evaluated in PD animal models to determine specificity and efficacy. Promising leads from these studies will next be evaluated in neuroprotection studies which include both acute neurotoxicant MPTP and chronic dox-inducible dopaminergic glutathione depletion transgenic mouse models.

Public Health Relevance

Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. It is estimated that PD affects approximately 1-2 % of people older than 65 years of age. The primary therapeutic agent for PD is L-DOPA which improves the symptoms of the disease by producing dopamine in dopamine depleted neurons. However, long term use of L-dopa gives rise to motor fluctuations with dyskinesias and a decrease in duration of response to a given L-dopa dose. Prolonged use of L-dopa also gives rise to 'on' and 'off' episodes and may lead to toxicity to DA neurons and hence, accelerating the DA neurodegeneration process. It is increasingly evident that for a complex disease such as PD, a drug targeting only one target site will only partially address the therapeutic need of the disease. The overall goal in this proposal is to develop multifunctional therapeutic agents which will be useful not only in symptomatic treatment but also could be used as disease-modifying agents by promoting DA neuron survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047198-10
Application #
8876817
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
2005-05-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2017-06-30
Support Year
10
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Wayne State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Das, Banibrata; Rajagopalan, Subramanian; Joshi, Gnanada S et al. (2017) A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses ?-syn- and MPTP-induced toxicities in vivo. Neuropharmacology 123:88-99
Das, Banibrata; Kandegedara, Ashoka; Xu, Liping et al. (2017) A Novel Iron(II) Preferring Dopamine Agonist Chelator as Potential Symptomatic and Neuroprotective Therapeutic Agent for Parkinson's Disease. ACS Chem Neurosci 8:723-730
Singh, Sushil K; Dutta, Aloke; Modi, Gyan (2017) ?-Synuclein aggregation modulation: an emerging approach for the treatment of Parkinson's disease. Future Med Chem 9:1039-1053
Lindenbach, David; Das, Banibrata; Conti, Melissa M et al. (2017) D-512, a novel dopamine D2/3 receptor agonist, demonstrates greater anti-Parkinsonian efficacy than ropinirole in Parkinsonian rats. Br J Pharmacol 174:3058-3071
Yedlapudi, Deepthi; Joshi, Gnanada S; Luo, Dan et al. (2016) Inhibition of alpha-synuclein aggregation by multifunctional dopamine agonists assessed by a novel in vitro assay and an in vivo Drosophila synucleinopathy model. Sci Rep 6:38510
Zhen, Juan; Antonio, Tamara; Jacob, Joanna C et al. (2016) Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D? and D? Receptors. Neurochem Res 41:328-339
Dholkawala, Fahd; Voshavar, Chandrashekhar; Dutta, Aloke K (2016) Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson's disease. Eur J Pharm Biopharm 103:62-70
Luo, Dan; Sharma, Horrick; Yedlapudi, Deepthi et al. (2016) Novel multifunctional dopamine D2/D3 receptors agonists with potential neuroprotection and anti-alpha synuclein protein aggregation properties. Bioorg Med Chem 24:5088-5102
Rajagopalan, Subramanian; Rane, Anand; Chinta, Shankar J et al. (2016) Regulation of ATP13A2 via PHD2-HIF1? Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease. J Neurosci 36:1086-95
Zhen, Juan; Antonio, Tamara; Ali, Solav et al. (2015) Use of radiolabeled antagonist assays for assessing agonism at D2 and D3 dopamine receptors: comparison with functional GTP?S assays. J Neurosci Methods 248:7-15

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