2021 - The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents

  Patchliner Publication in Journal of Enzyme Inhibition and Medicinal Chemistry (2021)

Authors:
Kim T., Morshed M.N., Londhe A.M., Lim J.W., Lee H.E., Cho S., Cho S.J., Hwang H., Lim S.M., Lee J.Y., Lee J., Pae A.N.

Journal:

Journal of Enzyme Inhibition and Medicinal Chemistry (2021) doi: 10.1080/14756366.2021.1900158

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.

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