Design, synthesis, biological evaluation and molecular modelling of 2-(2-aryloxyphenyl)-1,4-dihydroisoquinolin-3(2H)-ones: A novel class of TSPO ligands modulating amyloid-β-induced mPTP opening

• Published in: European journal of pharmaceutical sciences Vol. 104; pp. 366 - 381
• Main Authors: Elkamhawy, Ahmed, Park, Jung-eun, Hassan, Ahmed H.E., Pae, Ae Nim, Lee, Jiyoun, Park, Beoung-Geon, Paik, Sora, Do, Jimin, Park, Jong-Hyun, Park, Ki Duk, Moon, Bongjin, Park, Woo Kyu, Cho, Heeyeong, Jeong, Dae Young, Roh, Eun Joo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.06.2017
• Subjects: Amyloid beta-Peptides; Animals; Cell Line; Cell Survival - drug effects; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2D6 - metabolism; Isoquinolines - chemistry; Isoquinolines - pharmacology; Ligands; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial permeability transition pore (mPTP); Models, Molecular; Molecular modelling; Neurodegenerative diseases; Retrosynthesis; Translocator protein (TSPO); β-amyloid peptide (Aβ); Retrosynthesis; β-amyloid peptide (Aβ); Molecular modelling; Mitochondrial permeability transition pore (mPTP); Neurodegenerative diseases; Translocator protein (TSPO)
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2017.04.015

Translocator protein (TSPO) is involved in modulating mitochondrial permeability transition pore (mPTP) opening/closure leading to either apoptotic cell death via opening of mPTP or cell protection mediated by mPTP blocking and hence intercepting mPTP induced apoptosis. Herein, 2-(2-aryloxyphenyl)-1,4-dihydroisoquinolin-3(2H)-one derivatives have been designed and synthesized as new modulators for amyloid-β-induced mPTP opening. Among all, compound 7c remarkably enhanced mPTP opening while compound 7e showed the highest mPTP blocking activity. Molecular modelling study revealed different binding modes which might underlie the observed opposing biological activities. Both compounds bound to the translocator protein 18kDa (TSPO) in low micromolar range and elicited good profiles on CYP2D6 and CYP1A2. Taken as a whole, this report presents compound 7e as a hit TSPO ligand for treatment of neurodegenerative diseases and compound 7c as a hit TSPO ligand for promoting cell death of cells over-expressing TSPO. [Display omitted]