The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents. (1st January 2021)

• Record Type: Journal Article
• Authors: Kim, TaeHun; Morshed, Mohammad N.; Londhe, Ashwini M.; Lim, Ji W.; Lee, Ha E.; Cho, Suengmok; Cho, Sung J.; Hwang, Hayoung; Lim, Sang M.; Lee, Jae Y.; Lee, Jiyoun; Pae, Ae N.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 831
• Page End: 846
• Publication Date: 2021-01-01
• Subjects: Alzheimer's disease -- function modulators -- translocator protein ligand; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1900158
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34 ) as a TSPO ligand. After validating its biological activity against amyloid-β (Aβ) induced mitochondrial dysfunction and in acute and transgenic Alzheimer's disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aβ-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.