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 2024-01-20T01:04:26Z 2024-01-20T01:04:26Z 2021-09-05 2017-06-15 0928-0987 https://pubs.kist.re.kr/handle/201004/122620 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. English ELSEVIER SCIENCE BV PROTEIN 18 KDA CENTRAL-NERVOUS-SYSTEM TRANSLOCATOR PROTEIN NEURODEGENERATIVE DISEASES CLINICAL-SIGNIFICANCE THERAPEUTIC TARGET ALZHEIMERS-DISEASE DRUG DESIGN IN-VIVO BENZODIAZEPINE 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 Article 10.1016/j.ejps.2017.04.015 1 EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, v.104, pp.366 - 381 EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 104 366 381 scie scopus 000405251600036 2-s2.0-85018295921 Pharmacology & Pharmacy Pharmacology & Pharmacy Article PROTEIN 18 KDA CENTRAL-NERVOUS-SYSTEM TRANSLOCATOR PROTEIN NEURODEGENERATIVE DISEASES CLINICAL-SIGNIFICANCE THERAPEUTIC TARGET ALZHEIMERS-DISEASE DRUG DESIGN IN-VIVO BENZODIAZEPINE Mitochondrial permeability transition pore (mPTP) Retrosynthesis Neurodegenerative diseases Translocator protein (TSPO) beta-amyloid peptide (A beta) Molecular modelling