Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression

Xia Liu, Chi Bun Chan, Qi Qi, Ge Xiao, Hongbo R. Luo, Xiaolin He, Keqiang Ye*

*Corresponding author for this work

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is critical for agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-containing molecules and to elevate the agonistic effect of the lead compound, we initiated the lead optimization campaign by synthesizing various bioisosteric derivatives. Here we show that the optimized 2-methyl-8-(4′- (pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one derivative possesses enhanced TrkB stimulatory activity. Chronic oral administration of this compound significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compound possesses the improved features compared to the previous lead compound. Hence, this optimized compound may act as a promising lead candidate for in-depth drug development for treating various neurological disorders including depression.

Original languageEnglish (US)
Pages (from-to)8524-8537
Number of pages14
JournalJournal of Medicinal Chemistry
Volume55
Issue number19
DOIs
StatePublished - Oct 11 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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