RÉSUMÉ
The dimeric dipeptide mimetic hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301) was created on the basis of the structure of the exposed region of the neurotrophin-3 4th loop. The new compound, as well as the full-length neurotrophin, activated the TrkC and TrkB receptors. GTS-301 showed neuroprotective activity in experiments on HT-22 mouse hippocampal cells under conditions of oxidative stress and glutamate toxicity at concentrations of 10-12 and 10-8 M, respectively, and antidepressant-like activity in the forced swimming test on mice with 7-day intraperitoneal administration in doses of 10-40 mg/kg.
Sujet(s)
Dipeptides , Récepteur trkB , Animaux , Antidépresseurs/composition chimique , Antidépresseurs/pharmacologie , Matériaux biomimétiques , Dipeptides/composition chimique , Dipeptides/pharmacologie , Hippocampe , Souris , Facteurs de croissance nerveuseRÉSUMÉ
Previously, we synthesized a dimeric dipeptide mimetic of the brain-derived neurotrophic factor (BDNF) loop 4, GSB-106, which, similarly to BDNF, activated TrkB, PI3K/AKT, and MAPK/ERK. When administered systemically, it exhibited neuroprotective, antidepressant, and antidiabetic activities and stimulated neurogenesis and synaptogenesis. In this study, we established that GSB-106 also exhibits the analgesic activity, typical for BDNF, which was revealed in rats in hot plate and tail flick tests 0.5-48 h after intraperitoneal injection at doses of 0.1 and 1 mg/kg.
Sujet(s)
Analgésiques , Facteur neurotrophique dérivé du cerveau , Dipeptides , Peptidomimétiques , Analgésiques/composition chimique , Analgésiques/pharmacologie , Animaux , Facteur neurotrophique dérivé du cerveau/composition chimique , Facteur neurotrophique dérivé du cerveau/pharmacologie , Dipeptides/composition chimique , Dipeptides/pharmacologie , Humains , Mâle , Peptidomimétiques/composition chimique , Peptidomimétiques/pharmacologie , Structure secondaire des protéines , RatsRÉSUMÉ
On the basis of the structure of beta-turn of loop 2 of brain-derived neurotrophic factor (BDNF), its new dimeric dipeptide mimetic bis-(N-hexanoyl-L-seryl-L-lysine) hexamethylenediamide (GTS-201) was created. It activated TrkB and Erk, did not activate Akt, and exhibited neuroprotective activity in vitro at concentrations of 10-5-10-8 M. Unlike the mimetics that activate Erk and Akt, GTS-201 did not exhibit antidepressant properties. For the manifestation of the antidepressant activity of BDNF mimetics, the activation of its both major signaling pathways is required.
Sujet(s)
Facteur neurotrophique dérivé du cerveau/composition chimique , Dimérisation , Dipeptides/composition chimique , Extracellular Signal-Regulated MAP Kinases/métabolisme , MAP Kinase Kinase Kinase 5/effets des médicaments et des substances chimiques , Peptidomimétiques/composition chimique , Peptidomimétiques/pharmacologie , Animaux , Lignée cellulaire , Souris , Neuroprotecteurs/composition chimique , Neuroprotecteurs/pharmacologie , Récepteur trkB/métabolismeRÉSUMÉ
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
Sujet(s)
Facteur neurotrophique dérivé du cerveau/composition chimique , Dipeptides/composition chimique , Neuroprotecteurs/composition chimique , Relation structure-activité , Acides aminés/composition chimique , Animaux , Antidépresseurs/administration et posologie , Antidépresseurs/composition chimique , Antidépresseurs/métabolisme , Biomimétique , Facteur neurotrophique dérivé du cerveau/synthèse chimique , Facteur neurotrophique dérivé du cerveau/métabolisme , Dipeptides/synthèse chimique , Dipeptides/métabolisme , Lysine/composition chimique , Structure moléculaire , Neuroprotecteurs/administration et posologie , Neuroprotecteurs/métabolisme , Rats , StéréoisomérieRÉSUMÉ
Dimeric dipeptide GSB-106, a novel structural analogue of neurotrophin BDNF, in doses from 10(-5) to 10(-8) M protected cultured immortalized mouse hippocampal HT-22 neurons from H2O2 or glutamate damage. The neuroprotective effect of GSB-106 was also shown on cultured SH-SY5Y human neuroblastoma cells after treatment with neurotoxin 6-hydroxidopamine. These data attest to functional similarity of GSB-106 and neurotrophin BDNF.
Sujet(s)
Facteur neurotrophique dérivé du cerveau/composition chimique , Dipeptides/pharmacologie , Hippocampe/cytologie , Neurones/métabolisme , Neuroprotecteurs/pharmacologie , Animaux , Survie cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Dipeptides/composition chimique , Relation dose-effet des médicaments , Acide glutamique/toxicité , Hippocampe/métabolisme , Humains , Peroxyde d'hydrogène/toxicité , Souris , Oxidopamine/toxicité , SpectrophotométrieRÉSUMÉ
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.