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
{"title":"[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]。","authors":"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","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>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</p>","PeriodicalId":9325,"journal":{"name":"Bioorganicheskaia khimiia","volume":"40 2","pages":"142-56"},"PeriodicalIF":0.0000,"publicationDate":"2014-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"[Study of structure-activity relationship in series of Gsb-106 analogues-dipeptide mimetics of brain-derived neurotrophic factor].\",\"authors\":\"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\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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</p>\",\"PeriodicalId\":9325,\"journal\":{\"name\":\"Bioorganicheskaia khimiia\",\"volume\":\"40 2\",\"pages\":\"142-56\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2014-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganicheskaia khimiia\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganicheskaia khimiia","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
[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