Parkinson's Disease (PD) isa progressive, chronic neurodegeneration disorder which is characterized by agradual loss of dopaminergic neurons in the par compacta of the substantianigra. It is primarily a sporadic disorder although a rare subset of population(<10%) acquires this disease due to several genetic defects. The etiology ofPD is not fully understood although both oxidative stress and mitochondrialdysfunction have been strongly implicated in cell death. Due to complexity ofthe pathogenesis of PD, it is increasingly evident that drugs targeting only asingle site may not be adequate to slow the disease progression and alleviatemotor dysfunction at the same time. In our effort to develop bifunctional/multifunctional ligands to provide not only symptomatic relief but also toprovide survival of more dopamine neurons as a part of neuroprotective therapystrategy, we have designed several bifunctional dopamine agonists. Thesebifunctional molecules are hypothesized to provide symptomatic relief viastimulation of post synaptic D2/D3 receptors and also to provide reduction ofoxidative stress via different mechanistic pathways. We used our hybrid 7-{[4-(4-Phenyl-piperazin-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-olmolecular scaffold to design such drugs. One of our lead molecules (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamineexhibited potent selective functionalactivity (EC50,0.52 nM, D2/D3 > 223) for D3 receptorand also exhibited potent antioxidant activity. The lead molecule was evaluatedin PD animal models, unilaterally lesioned 6-OHDA rat and reserpinized ratmodels, to evaluate its efficacy in motor stimulation. Detail structureactivity relationship study along with in vitro and in vivo studies will bepresented. Supported by NS047198 (AKD).

Bifunctional dopamine D3
selective agonist as novel antiparkinsonian agents: Evaluation of selected
compounds in Parkinson's disease animal model

240th National Meeting (2010)

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Bifunctional dopamine D3 selective agonist as novel antiparkinsonian agents: Evaluation of selected compounds in Parkinson's disease animal model