Parkinson's disease (PD) is the second most common form of neurodegenerative disorders that results from the progressive loss of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc) triggering profound motor perturbation, as well as cognitive, sensory and mood deficits. Although extensive research has been done to elucidate the underlying molecular events leading to neuronal death, yet the cause and individual steps in the pathogenesis of the disease are still not understood well and thus, PD remains a progressive and incurable condition. It is generally believed that oxidative stress, neuroinflammation, compromised natural antioxidant defense, protein aggregation and impaired mitochondrial functions are the mainstream predisposing factors implicated in the pathogenesis of PD. Due to complexity of the pathogenesis of PD, it is increasingly evident that drugs targeting only a single site may not be sufficient to slow the disease progression and alleviate motor dysfunction at the same time. In our overall goal to develop multifunctional drugs as neuroprotective treatment agents for PD, we designed novel dopamine D2/D3 agonist molecules with a capacity to address some underlying pathological factors in PD including chelating iron to reduce oxidative stress. The molecules exhibited high affinity for both D2 and D3 receptors where as in GTP?S functional assay, the lead compound (-)-D-583  showed potent agonist activity at both D2 and D3 receptors (EC50 (GTP?S); D2 = 3.14 nM and D3 = 0.50 nM). Furthermore, the lead molecules demonstrated potent antioxidant activity in DPPH assay and also exhibited iron chelation property. In PD animal model study, both lead molecules (-)-D-583  and (-)-D-607 exhibited potent in vivo activity in reversing hypolocomotion in reserpinized rats. In cell culture study, the selected compounds demonstrated significant reduction of toxicity induced by treatment with 6-hydroxy dopamine, thereby, producing neuroprotection effect. This work is supported by grants from NINDS (NS 047198, AKD).

Design, synthesis, and pharmacological evaluation of novel multifunctional dopamine D<sub>2</sub>/D<sub>3</sub> agonists with iron chelation property: Potential implication in symptomatic and neuroprotective treatment of Parkinson's disease

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Design, synthesis, and pharmacological evaluation of novel multifunctional dopamine D2/D3 agonists with iron chelation property: Potential implication in symptomatic and neuroprotective treatment of Parkinson's disease

Design, synthesis, and pharmacological evaluation of novel multifunctional dopamine D₂/D₃ agonists with iron chelation property: Potential implication in symptomatic and neuroprotective treatment of Parkinson's disease