Design and synthesis of dipeptide mimetics of the brain-derived neurotrophic factor

Abstract

Low-molecular-weight mimetics of loops 1 and 4 of the brain-derived neurotrophic factor (BDNF) have been designed and synthesized. The compounds represent monomeric and dimeric amides of N-acyldipeptides. Their dipeptide fragments coincide in sequence with the central regions of beta-turns of the corresponding neurotrophin loops, and acyl groups are the bioesosteres of preceding amino acid residues. Hexa- or heptamethylenediamines were used as spacers to link the C-terminal regions of dipeptides in dimeric mimetics of BDNF. These compounds were synthesized by classical methods of peptide synthesis in solution and received the laboratory codes GSB-104 (HO-Suc-Ser-Lys-NH₂), GSB-106 {[HO-Suc-Ser-Lys-NH-(CH₂)₃−]₂}, GSB-207 (HO-Suc-Met-Ser-NH₂), and GSB-214 ([HO-Suc-Met-Ser-NH-(CH₂)_7/2-]₂). It was shown using immortalized hippocampal cells of the HT22 line under conditions of oxidative stress that the dimeric mimetics of both loops at concentrations of 10⁻⁵−10⁻⁸ M possess a neuroprotective activity. The monomeric loop 1 mimetic GSB-207 in the same concentration range is inactive, and the monomeric loop 4 mimetic GSB-104 at a concentration of 10⁻⁷ impairs the survival of neurons. The finding that only dimeric mimetics possess the neuroprotective activity is consistent with the data indicating that BDNF is active in the homodimeric form. As opposed to the dimeric loop 1 mimetic GSB-214, the dimeric loop 4 mimetic GSB-106 exhibits the antidepressant activity typical for BDNF in the Porsolt test on rats at doses of 0.1 and 1 mg/kg injected intraperitoneally. This suggests that the antidepressant activity of BDNF is related to its 4th loop. We believe that the compounds obtained will be useful in studies of the mechanism of action of BDNF and may form the basis for the design of a novel group of drugs with antidepressant and neuroprotective activities.