Synthesis and Biological Properties of a New Dipeptide Mimetic of Brain-Derived Neurotrophic Factor Loop 2**

Low‐molecular mimetics of nerve growth factor and brain‐derived neurotrophic factor: Design and pharmacological properties

“…All BDNF dipeptide mimetics exhibited neuroprotective activity at concentrations of 10 −6 -10 −8 M protecting HT22 hippocampal neurons from H 2 O 2 -induced oxidative stress, with a maximum effect of ∼50% of the one of BDNF (10 −9 M). 126,128,131 The effect of the most active compound, GSB-106, was confirmed on HT22 cells under glutamate toxicity conditions and on SH-SY5Y line human neuroblastoma cells under conditions of 6-OHDA-induced toxicity 131 ; in both cases, at a concentration of 10 −7 M the dipeptide showed the same activity level as BDNF.…”

“…The fundamentally different approach based on the use of central fragments of loop β-turns as the most exposed outward and, therefore, most accessible for interaction with the receptor was used for mimetic design at the V. V. [126][127][128] The central β-turn dipeptide fragment was retained in the structure of mimetics, and the previous amino acid residue was replaced by its bioisostere: Asp was replaced by the residue of succinic acid, Val-by the residue of hexanoic acid (Figure 16).…”

“…By Western blot analysis with antibodies to phosphorylated and nonphosphorylated kinases all the compounds were demonstrated to activate the BDNF-specific tyrosine kinase receptor TrkB, but with different patterns of postreceptor signaling, namely activation of PI3K /AKT and MAPK/ERK pathways. 128,129 Like a full-sized neurotrophin, the loop 4 mimetic, GSB-106, activated both PI3K/AKT and MAPK/ERK, 130 while the loop 1 mimetic, GSB-214, and the loop 2 mimetic, GSB-201, selectively activated PI3K/AKT 129 and MAPK / ERK, 128 respectively.…”

“…GSB-106 showed antidepressant activity at doses of 0.1 and 1.0 mg/kg ip in the forced swimming test on BALB/ c mice, while selective GSB-214 and GTS-201 were inactive. 126,128 The antidepressant activity of nonselective mimetic only suggests that PI3K/AKT and MAPK/ERK should be promoted simultaneously for effect.…”

“…136 The results for dipeptide mimetics of BDNF are consistent with the data on the PI3K/AKT involvement in the diabetes pathogenesis obtained in the experiments in transgenic mice deficient in PI3K/AKT 137 and with overexpression of PI3K/AKT. 138 F I G U R E 1 6 Dimeric dipeptide mimetics of BDNF loop 1 (GSB-214), 126 loop 2 (GTS-201), 128 and loop 4 (GSB-106). 126 Dipeptide sequences corresponding to the central fragments of the BDNF loop's β-turns depicted in bold.…”