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

Ahmed Elkamhawy, Jung eun Park, Ahmed H.E. Hassan, Ae Nim Pae, Jiyoun Lee, Beoung Geon Park, Sora Paik, Jimin Do, Jong Hyun Park, Ki Duk Park, Bongjin Moon, Woo Kyu Park, Heeyeong Cho, Dae Young Jeong, Eun Joo Roh

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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-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 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.

Original languageEnglish
Pages (from-to)366-381
Number of pages16
JournalEuropean Journal of Pharmaceutical Sciences
Volume104
DOIs
StatePublished - 15 Jun 2017

Keywords

  • Mitochondrial permeability transition pore (mPTP)
  • Molecular modelling
  • Neurodegenerative diseases
  • Retrosynthesis
  • Translocator protein (TSPO)
  • β-amyloid peptide (Aβ)

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