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-beta-induced mPTP opening
- 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-beta-induced mPTP opening
- 조희영; 정대영; 배애님; 노은주; 박기덕; 박종현; 백소라; 아흐메드 엘캄하위; 박정은; 아흐메드 하산; 이지연; 박병건; 도지민; 문봉진; 박우규
- Mitochondrial permeability transition pore
(mPTP); Retrosynthesis; Neurodegenerative diseases; Translocator protein (TSPO); β-amyloid peptide (Aβ); Molecular modelling
- Issue Date
- European journal of pharmaceutical sciences
- VOL 104-381
- 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-beta-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 18 kDa (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.
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