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.
Keywords: Brain-derived neurotrophic factor, small molecule, Alzheimer’s disease, tropomyosin-receptor-kinase B, mimetics,
CNS disorders, synaptic plasticity, learning and memory, depression.
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