Kim, TaeHun Son, Woo Seung Morshed, Mohammad Neaz Londhe, Ashwini M. Jung, Seo Yun Park, Jong-Hyun Park, Woo-Kyu Lim, Sang Min Park, Ki Duk Cho, Sung Jin Jeong, Kyu-Sung Lee, Jiyoun Pae, Ae Nim 2024-01-20T00:01:02Z 2024-01-20T00:01:02Z 2021-09-03 2017-12-01 0223-5234 https://pubs.kist.re.kr/handle/201004/121940 Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[2',3':4,5]pyrrolo[1,2-d] [1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under A beta-induced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD. (C) 2017 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER 18 KDA TSPO BENZODIAZEPINE-RECEPTOR-LIGAND ALZHEIMERS-DISEASE TRANSLOCATOR PROTEIN NEURODEGENERATIVE DISEASES THERAPEUTIC TARGET MOUSE MODEL DYSFUNCTION IDENTIFICATION STEROIDOGENESIS Discovery of thienopyrrolotriazine derivatives to protect mitochondrial function against A beta-induced neurotoxicity Article 10.1016/j.ejmech.2017.09.033 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.141, pp.240 - 256 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 141 240 256 scie scopus 000417962900022 2-s2.0-85030866140 Chemistry, Medicinal Pharmacology & Pharmacy Article 18 KDA TSPO BENZODIAZEPINE-RECEPTOR-LIGAND ALZHEIMERS-DISEASE TRANSLOCATOR PROTEIN NEURODEGENERATIVE DISEASES THERAPEUTIC TARGET MOUSE MODEL DYSFUNCTION IDENTIFICATION STEROIDOGENESIS Thieno[2 &apos ,3 &apos :4,51pyrrolo[1,2-d][1,2,4]triazine Translocator protein Mitochondria] function Amyloid beta Alzheimer&apos s disease Ro5-4864