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

Title
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
Authors
조희영정대영배애님노은주박기덕박종현백소라아흐메드 엘캄하위박정은아흐메드 하산이지연박병건도지민문봉진박우규
Keywords
Mitochondrial permeability transition pore (mPTP); Retrosynthesis; Neurodegenerative diseases; Translocator protein (TSPO); β-amyloid peptide (Aβ); Molecular modelling
Issue Date
2017-06
Publisher
European journal of pharmaceutical sciences
Citation
VOL 104-381
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/66586
ISSN
0928-0987
Appears in Collections:
KIST Publication > Article
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