title: Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Chi-Bun
authors.initials: CB
authors.lastname: Chan
authors.forename: Qi
authors.initials: Q
authors.lastname: Qi
authors.forename: Ge
authors.initials: G
authors.lastname: Xiao
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.forename: Xiaolin
authors.initials: X
authors.lastname: He
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D044950:Flavanones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D020813:Receptor, trkB / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C478869:7,8-dihydroxyflavanone; D000928:Antidepressive Agents; D044950:Flavanones; D007093:Imidazoles; D007211:Indoles; D020813:Receptor, trkB