The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 36; no. 1; pp. 831 - 846
• Main 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.
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2021; Taylor & Francis Group
• Subjects: Alzheimer's disease; Biochemistry & Molecular Biology; Chemistry, Medicinal; function modulators; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Research Paper; Science & Technology; translocator protein ligand; function modulators; 160; translocator protein ligand; s disease; Alzheimer’ Alzheimer’s disease
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.1900158

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.