D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Abstract

In this Article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA-and MPP+-induced toxicity in a dosedependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinson's disease.

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

“…In this regard, we have recently characterized the neuroprotective effects of two lead compounds, D-512 and D-440, via assessment of their effects on neurotoxicity associated with 6-OHDA and MPP + administration in DAergic MN9D cells (Santra et al 2013). We have now begun to further explore the possible mechanisms underlying D-512’s neuroprotective effects in several additional studies.…”

“…Recently, we have shown that D-512 significantly attenuates 6-OHDA- and MPP + -induced neurotoxicity in dopaminergic MN9D cells in a dose-dependent manner. Inhibition of caspase 3/7 activity and reductions in lipid peroxidation along with restoration of tyrosine hydroxylase levels in 6-OHDA-treated cells may partially explain D-512’s mechanism of action (Santra et al 2013). In this current study, we further explore the neuroprotective effect of D-512 in an alternative cellular model, rat adrenal phaeochromocytoma PC12 cells (a rat pheochromocytoma line), against 6-OHDA-induced cytotoxicity, as well as possible mechanisms involved.…”

Development of a Highly Potent D2/D3 Agonist and a Partial Agonist from Structure–Activity Relationship Study of N6-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine Analogues: Implication in the Treatment of Parkinson’s Disease

“…26–36 Some of our lead multifunctional D 2 /D 3 agonist molecules, such as ( S )- N 6 -(2-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)ethyl)- N 6 -propyl-4,5,6,7-tetrahydrobenzo[ d ]thiazole-2,6-diamine (D-264) and 1 (D-512) (Figure 1), exhibited neuroprotection in in vitro and in vivo experiments. 30,33,34 Additionally, we have reported development of multifunctional brain penetrant iron chelators with agonist activity at D 2 /D 3 receptors. 29,31 …”

“…32 As the compound turned out to be a promising candidate for PD through a number of experiments, 33,34 we further wanted to delve into a comprehensive structure−activity relationship (SAR) study and accordingly introduce, in the current work, several indole derivatives on the piperazine ring with varying chain length and position of attachment in the indole aromatic ring. We have also introduced a propargyl group in our core hybrid structure to shed light on its role in interacting with DA D 2 /D 3 receptors.…”

A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo

“…As of now, no neuroprotective drugs have been identified or approved by the FDA for the treatment of PD. The overall goal of our research is to develop orally active multifunctional treatment agents to address both symptomatic (relieving motor dysfunction) and disease-modifying neuroprotective effects to slow or stop the progression of the disease (Das et al, 2015; Ghosh et al, 2010; Li et al, 2010; Modi et al, 2014; Santra et al, 2013; Shah et al, 2014). A number of iron chelators have been employed in the preclinical and clinical studies of PD (Devos et al, 2014; Grolez et al, 2015).…”