Parkinson's Disease (PD) is a progressive neurodegenerative disease which is characterized by degeneration of the nigrostriatal dopaminergic pathway resulting in production of bradykinesia in combination with rigidity and tremor. Although the etiology of PD is not clearly understood, factors such as oxidative stress are now strongly implicated in the selective loss of dopaminergic neurons. 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. Interest in dopamine agonists in PD therapy is growing recently. Dopamine agonists, besides providing symptomatic relief in PD with less motor complications, have also been shown to act as neuroprotective agents. In this regard, the relatively recently discovered dopamine receptor subtype D3 has become an interesting target for drug development for PD for several reasons. DS-preferring agonists e.g. pramipexole, has been shown to provide additional beneficial neuroprotective effects over that seen with D2-selective agonists. In this proposal, we plan to develop novel DS-selective compounds to explore and understand the role of this receptor subtype in producing antiparkinsonian effect in an animal model of PD. In our preliminary study, we have developed a novel molecular template exhibiting preferential affinity for the D3- compared to the D2-receptor and we have generated molecules more potent and selective than the reference 7-OH-DPAT. In in vivo experiment with 6- OHDA-induced unilaterally lesioned rats, one of our lead analogs produced potent contralateral rotations with a long duration of action. We now propose to expand on our initial findings through comprehensive SAR studies with various pharmacological characterizations to develop potent D3-preferring compounds. Furthermore, in our effort to understand molecular interaction of our novel hybrid molecules with the D3 receptor, we will carry out site-directed mutagenesis studies with the selected D3 mutants and will perform molecular modeling studies using a comprehensive training set of agonist molecules. Results from these experiments will help us to build a pharmacophore model for interaction of novel hybrid molecules with the D2/D3 receptors. Finally, we will test whether the two most active compounds developed in the above experiments can provide neuroprotection to dopaminergic neurons in vivo experiments with mice treated with MPTP and whether such an effect is mediated by the DS-receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS047198-01A2
Application #
6915939
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Murphy, Diane
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$294,217
Indirect Cost
Name
Wayne State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Pharmacy
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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
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
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
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
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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