To overcome the limitations of the clinical use of neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), scientists have been trying to create their low-molecular-weight mimetics having improved pharmacokinetic properties and lacking side effects of full-sized proteins since the 90s of the last century. The efforts of various research groups have led

No abstract

The search for new highly-effective, fast-acting antidepressant drugs is extremely relevant. Brain derived neurotrophic factor (BDNF) and signaling through its tropomyosin-related tyrosine kinase B (TrkB) receptor, represents one of the most promising therapeutic targets for treating depression. BDNF is a key regulator of neuroplasticity in the hippocampus and the prefrontal cortex, the dysfunction of which is considered to be the main pathophysiological hallmark of this disorder. BDNF itself has no favorable drug-like properties due to poor pharmacokinetics and possible adverse effects. The design of small, proteolytically stable BDNF mimetics might provide a useful approach for the development of therapeutic agents. Two small molecule BDNF mimetics with antidepressant-like activity have been reported, 7,8-dihydroxyflavone and the dimeric dipeptide mimetic of BDNF loop 4, GSB-106. The article reflects on the current literature on the role of BDNF as a promising therapeutic target in the treatment of depression and on the current advances in the development of small molecules on the base of this neurotrophin as potential antidepressants.

On the basis of the structure of beta-turn of loop 2 of brain-derived neurotrophic factor (BDNF), its new dimeric dipeptide mimetic bis-(N-hexanoyl-L-seryl-L-lysine) hexamethylenediamide (GTS-201) was created. It activated TrkB and Erk, did not activate Akt, and exhibited neuroprotective activity in vitro at concentrations of 10-10 M. Unlike the mimetics that activate Erk and Akt, GTS-201 did not exhibit antidepressant properties. For the manifestation of the antidepressant activity of BDNF mimetics, the activation of its both major signaling pathways is required.

No abstract