[Study of structure-activity relationship in series of Gsb-106 analogues-dipeptide mimetics of brain-derived neurotrophic factor]

Bioorg Khim. 2014 Mar-Apr;40(2):142-56.
[Article in Russian]

Abstract

In previous work we have obtained a dimeric dipeptide mimetic of 4th loop of BDNF - hexamethylenediamide bis-(N-monosuccinil-L-seryl-L-lysine) (GSB-106), having a neuroprotective activity in vitro in a concentration range 10(-5)-10(-8) M and an antidepressant activity in vivo at doses 0.1 and 1 mg/kg i.p. in rats. We have investigated the structural and functional relationships among analogues of GSB-106. Glycine scan was performed and a number of appropriate compounds were synthesized: GT-105 (here lysine is replaced by glycine), GT-107 (here serine is replaced by glycine), GT-106Ac (here monosuccinic radical is replaced by acetyl group). We have studied the dependence of activity of following compounds from the configuration of amino acid residues: GT-107D (D-enantiomer of the GT-107), GT-106DL (L-serine was replaced by D-serine), GT-106LD (L-lysine was replaced by D-lysine). The investigation of these compounds using the HT22 cell culture in conditions of oxidative stress has approved only two analogues of GSB-106 to have a neuroprotective effect: in the case of replacement of serine to glycine and of replacment of succinic radical to acetic group. A disappearance of this effect was observed in event of the replacement of lysine residue to glycine in GT-105, L-lysine residue to D-lysine and also by conversion of serine configuration. These results show that lysine residue is crucial for the neuroprotective activity of GSB-106. L-Configuration of the lysine and serine residues required. Configuration of lysine residue becomes critical in absence of serine side group. Thus, the the following fragment is a minimum pharmacophore of beta-turn of 4 loop of BDNF: HOOC-CH2-CH-CO-NH-(S)-CH(CH2OH)-CO-NH-(S)-CH((CH2)4NHz)-CO-NH-(CH2)3-. Only one (GT-106Ac) out of two analogues of GSB-106 with neuroprotective activity possesses antidepressant activity too. This fact indicates about a necessity of more stringent structural requirements for exposure of antidepressant activity. The results obtained can be useful for designing of new active mimetics of BDNE

Publication types

  • English Abstract

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / metabolism
  • Biomimetics
  • Brain-Derived Neurotrophic Factor / chemical synthesis
  • Brain-Derived Neurotrophic Factor / chemistry*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / metabolism
  • Lysine / chemistry
  • Molecular Structure
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / chemistry*
  • Neuroprotective Agents / metabolism
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship*

Substances

  • Amino Acids
  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Dipeptides
  • Neuroprotective Agents
  • Lysine