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

TitleOptimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression
Authors
Issue Date2012
Citation
Journal of Medicinal Chemistry, 2012, v. 55, n. 19, p. 8524-8537 How to Cite?
AbstractStructure-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. © 2012 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/225039
ISSN
2015 Impact Factor: 5.589
2015 SCImago Journal Rankings: 2.529

 

DC FieldValueLanguage
dc.contributor.authorLiu, Xia-
dc.contributor.authorChan, Chi Bun-
dc.contributor.authorQi, Qi-
dc.contributor.authorXiao, Ge-
dc.contributor.authorLuo, Hongbo R.-
dc.contributor.authorHe, Xiaolin-
dc.contributor.authorYe, Keqiang-
dc.date.accessioned2016-04-18T11:16:35Z-
dc.date.available2016-04-18T11:16:35Z-
dc.date.issued2012-
dc.identifier.citationJournal of Medicinal Chemistry, 2012, v. 55, n. 19, p. 8524-8537-
dc.identifier.issn0022-2623-
dc.identifier.urihttp://hdl.handle.net/10722/225039-
dc.description.abstractStructure-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. © 2012 American Chemical Society.-
dc.languageeng-
dc.relation.ispartofJournal of Medicinal Chemistry-
dc.titleOptimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression-
dc.typeArticle-
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1021/jm301099x-
dc.identifier.pmid22984948-
dc.identifier.scopuseid_2-s2.0-84867352628-
dc.identifier.volume55-
dc.identifier.issue19-
dc.identifier.spage8524-
dc.identifier.epage8537-
dc.identifier.eissn1520-4804-

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