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

Bioorganicheskaia khimiia Pub Date : 2014-03-01
A V Tarasiuk, T A Gudasheva, N M Sazonova, P I Antipov, D V Kurilov, P Iu Povarnina, I O Logvinov, T A Antipova, S B Seredenin
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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

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[Gsb-106脑源性神经营养因子双肽模拟物系列的构效关系研究]。
在之前的工作中,我们已经获得了BDNF第4环的二聚二肽模拟物-六亚二胺双-(n -单琥珀酸-l -seryl- l-赖氨酸)(GSB-106),在体外浓度范围为10(-5)-10(-8)M时具有神经保护活性,在体内剂量为0.1和1 mg/kg时具有抗抑郁活性。我们研究了GSB-106类似物之间的结构和功能关系。进行甘氨酸扫描,合成了一些合适的化合物:GT-105(这里赖氨酸被甘氨酸取代),GT-107(这里丝氨酸被甘氨酸取代),GT-106Ac(这里单琥珀基被乙酰基取代)。我们研究了GT-107D (GT-107的d对映体)、GT-106DL (l -丝氨酸被d -丝氨酸取代)、GT-106LD (l -赖氨酸被d -赖氨酸取代)等化合物的氨基酸残基构型对活性的依赖性。在氧化应激条件下使用HT22细胞培养对这些化合物进行的研究已批准只有两种GSB-106类似物具有神经保护作用:在将丝氨酸替换为甘氨酸的情况下,以及将琥珀酸自由基替换为乙酸基的情况下。在GT-105中将赖氨酸残基替换为甘氨酸,将l -赖氨酸残基替换为d -赖氨酸以及将丝氨酸构型转化时,这种效应消失。这些结果表明,赖氨酸残基对GSB-106的神经保护活性至关重要。所需赖氨酸和丝氨酸残基的构型。赖氨酸残基的构型在没有丝氨酸侧基的情况下变得至关重要。因此,以下片段是BDNF 4环β匝最小药效团:HOOC-CH2-CH-CO-NH-(S)- ch (CH2OH)- co - nh -(S)- ch ((CH2)4NHz)- co - nh -(CH2)3-。GSB-106的两种类似物中只有一种(GT-106Ac)具有神经保护活性,也具有抗抑郁活性。这一事实表明,有必要对抗抑郁药物活性暴露进行更严格的结构要求。所得结果可为新型BDNE主动模拟物的设计提供参考
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