Parkinson's disease (PD) is an age-related and progressive movement disorder that is characterized by dopaminergic neuronal loss in the substantia nigra region of the brain. Dopamine modulates movement, cognition, and emotion through activation of dopamine receptors in the brain. PD is a multifactorial disease caused by oxidative stress and mitochondrial dysfunction in neuronal cells with subsequent reduction of the dopamine level. An interesting development in the use of dopamine receptor agonists for the treatment of PD is that some of them may prove to be neuroprotective such as D3 receptor preferring agonists. Targeting dopamine D3 receptor, a subfamily of dopamine D2-class of receptors, for various CNS disorders is drawing much attention because of its unique location of D3 receptor. It has also been shown that selective D3 receptor agonists can provide neuroprotection in PD by inducing brain derived neurotrophic factors (BDNF). Much of the pharmacological actions mediated by D3 receptor are still unresolved because of the lack of highly potent and selective D3 receptor agonist. In our previous communication, we described the development of a series of hybrid molecules for D2 and D3 receptors that showed high agonist potency by combining pharmacophoric elements of aminothiazole and piperazine molecular fragments derived from known dopamine receptor agonist and antagonist molecules. In our present SAR study, we used N6-(2-(4-(1H-indole)piperazine-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine analogues to design such drugs. In these molecules, we specifically introduced various indole derivatives as accessory binding sites which led to the discovery of highly potent and selective molecules for D3 receptor. Compounds were characterized both in the in vitro binding and functional assays. Synthesis and in vitro binding and functional characterization will be presented. This work is supported by NS047198 (AD).

Further structure activity relationship (SAR) study of novel hybrid N6-(2-(4-(1H-indole)piperazine-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine analogs: Development of highly potent and selective D3 receptor preferring agonist molecules

248th National Meeting (2014)

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