title: Small molecules activating TrkB receptor for treating a variety of CNS disorders.
abstract: The brain-derived neurotrophic factor (BDNF) and its high affinity receptor tropomyosin-receptor-kinase B (TrkB) play a critical role in neuronal differentiation and survival, synapse plasticity, and memory. Indeed, both have been implicated in the pathophysiology of numerous diseases. Although the remarkable therapeutic potential of BDNF has generated much research over the past decade, the poor pharmacokinetics and adverse side effect profile have limited its clinical usefulness of BDNF. Small compounds that mimic BDNF's neurotrophic signaling and overcome the pharmacokinetic and side effect barriers may have greater therapeutic potential. The purpose of this review is to provide a survey of the various strategies taken towards the development of small molecule mimetics for BDNF and the selective TrkB agonist. A particular focus was placed on TrkB agonist 7, 8-dihydroxyflavone, which modulates multiple functions and has demonstrated remarkable therapeutic efficacy in a variety of central nervous system disease models. Two other small molecules included in this review are adenosine A2A receptor agonists that indirectly activate TrkB, and TrkB binding domains of BDNF, loop II-LM22A compounds that directly activate TrkB. These alternative molecules have shown promise in preclinical studies and may be included in prospective clinical investigations.
authors.affiliation: Department of Pathophysiology, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China. yanzeng11@yahoo.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Shumin
authors.initials: S
authors.lastname: Liu
authors.forename: Xiamin
authors.initials: X
authors.lastname: Hu
authors.forename: Shawn M
authors.initials: SM
authors.lastname: McClintock
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D047309:Flavones / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D058990:Molecular Targeted Therapy; D057786:Peptidomimetics / Q000494:pharmacology / Q000627:therapeutic use*; D020813:Receptor, trkB / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C485383:6,7-dihydroxyflavone; D058908:Adenosine A2 Receptor Agonists; D047309:Flavones; D057786:Peptidomimetics; D020813:Receptor, trkB