Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 4, Pages 1557-1572Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm401883v
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- National Institute of Neurological Disorders and Stroke/National Institute of Health [NS047198]
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In our overall goal to develop multifunctional dopamine D-2/D-3 agonist drugs for the treatment of Parkinson's disease (PD), we previously synthesized potent D-3 preferring agonist D-264 (1a), which exhibited neuroprotective properties in two animal models of PD. To enhance the in vivo efficacy of la, a structure activity relationship study was carried out. Competitive binding and [S-35]GTP gamma S functional assays identified compound (-)-96 as one of the lead molecules with preferential D3 agonist activity (EC50(GTP gamma S); D-3 = 0.10 nM; D-2/D-3 (EC50): 159). Compounds (-)-9b and (-)-8b exhibited high in vivo activity in two PD animal models, reserpinized and 6-hydroxydopamine (OHDA)-induced unilateral lesioned rats. On the other hand, la failed to show any in vivo activity in these models unless the compound was dissolved in 5-10% beta-hydroxy propyl cyclodextrin solution. Lead compounds exhibited appreciable radical scavenging activity. In vitro experiments with dopaminergic MN9D cells indicated neuroprotection by both la and (-)-9b from toxicity of MPP+.
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