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

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

[The efficacy of human NGF dipeptide mimetic on the streptozotocin-induced model of diabetes in rats].

The effect of a new dimeric dipeptide mimetic GK-2 of the loop-4 human NGF (hexamethylendiamide-bis-N-monosuccinyl-glycil-L-lysine) was investigated for the first time on the dynamics of hyperglycemia and body weight loss caused in Wistar rats by streptozotocin (45 mg/kg i.p.) Prophylactic (2 weeks before streptozotocin) daily administration combined with therapeutic (4 weeks after STZ) administration of GK-2 (0.1 mg/kg i.p.) was shown to attenuate significantly the degree of hyperglycemia and to reverse the streptozotocin-induced weight loss.

[Design and synthesis of dipeptide mimetics of brain-derived neurotrophic factor].

Low-molecular mimetics of brain-derived neurotrophic factor (BDNF) loops 1 and 4 representing to monomeric and dimeric amides of N-acyldipeptides were constructed and synthesized. The sequence of these dipeptides coinside with the central regions of beta-turns of corresponding loops of neurotrophine sequence, and acyl groups are bioisosters of preceding amino acid residues. Hexa- and heptamethylenediamine were used as spacers linking C-terminus ofdipeptides in BDNF dimeric mimetics. These substances were synthesized by classic peptide synthesis methods in solution and got 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). By using the culture of immortalized hippocampal cell line HT-22 on the oxidative stress conditions it was shown that dimeric mimetics of both loops demonstrated neuroprotective activity in the concentration rage of 10(-5)-10(-8) M. Monomeric loop 1 mimetic GSB-207 was inactive in the same concentrations and monomeric loop 4 mimetic GSB-104 in a concentration of 10(-7) M decreased survival of neurons. Presence of neuroprotective activity only for dimeric mimetics correlates with the data that BDNF is active only in homodimeric form. As opposed to dimeric mimetic of loop 1 GSB-214, dimeric mimetic of loop 4 GSB-106 demonstrates specific for BDNF antidepressive activity in Porsolt test on rats in doses 0.1 and 1 mg/kg i.p. It is suggested that antidepressive activity of BDNF is associated with its loop 4. We consider that compounds obtained will be useful for investigation of BDNF action mechanism and can lead to creation of a new group of medicinal substances with antidepressive and neuroprotective activities.