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)
Type
Research Project (R01)
Project #
5R01NS047198-09
Application #
8687751
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wayne State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Pharmacy
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Rajagopalan, Subramanian; Rane, Anand; Chinta, Shankar J et al. (2016) Regulation of ATP13A2 via PHD2-HIF1α Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease. J Neurosci 36:1086-95
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 D₂ and D₃ Receptors. Neurochem Res 41:328-39
Voshavar, Chandrashekhar; Shah, Mrudang; Xu, Liping et al. (2015) Assessment of Protective Role of Multifunctional Dopamine Agonist D-512 Against Oxidative Stress Produced by Depletion of Glutathione in PC12 Cells: Implication in Neuroprotective Therapy for Parkinson's Disease. Neurotox Res 28:302-18
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 GTPγS assays. J Neurosci Methods 248:7-15
Das, Banibrata; Modi, Gyan; Dutta, Aloke (2015) Dopamine D3 agonists in the treatment of Parkinson's disease. Curr Top Med Chem 15:908-26
Das, Banibrata; Vedachalam, Seenuvasan; Luo, Dan et al. (2015) Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure-Activity Relationship Study of N(6)-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Implication in the Treat J Med Chem 58:9179-95
Modi, Gyan; Sharma, Horrick; Kharkar, Prashant S et al. (2014) Understanding the Structural Requirements of Hybrid (S)-6-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol and its Analogs as D2/D3 Receptor Ligands: A Three-Dimensional Quantitative Structure-Activity Relationship (3D QS Medchemcomm 5:1384-1399
Shah, Mrudang; Rajagopalan, Subramanian; Xu, Liping et al. (2014) The high-affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease. J Neurochem 131:74-85
Modi, Gyan; Voshavar, Chandrashekhar; Gogoi, Sanjib et al. (2014) Multifunctional D2/D3 agonist D-520 with high in vivo efficacy: modulator of toxicity of alpha-synuclein aggregates. ACS Chem Neurosci 5:700-17
Modi, Gyan; Antonio, Tamara; Reith, Maarten et al. (2014) Structural modifications of neuroprotective anti-Parkinsonian (-)-N6-(2-(4-(biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): an effort toward the improvement of in vivo efficacy of the parent molecule. J Med Chem 57:1557-72

Showing the most recent 10 out of 27 publications