title: [Study of structure-activity relationship in series of Gsb-106 analogues-dipeptide mimetics of brain-derived neurotrophic factor].
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
authors.forename: A V
authors.initials: AV
authors.lastname: Tarasiuk
authors.forename: T A
authors.initials: TA
authors.lastname: Gudasheva
authors.forename: N M
authors.initials: NM
authors.lastname: Sazonova
authors.forename: P I
authors.initials: PI
authors.lastname: Antipov
authors.forename: D V
authors.initials: DV
authors.lastname: Kurilov
authors.forename: P Iu
authors.initials: PIu
authors.lastname: Povarnina
authors.forename: I O
authors.initials: IO
authors.lastname: Logvinov
authors.forename: T A
authors.initials: TA
authors.lastname: Antipova
authors.forename: S B
authors.initials: SB
authors.lastname: Seredenin
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D032701:Biomimetics; D019208:Brain-Derived Neurotrophic Factor / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004151:Dipeptides; D018696:Neuroprotective Agents; D008239:Lysine