Background. Compounds capable of suppressing inflammation and modulating the antitumor immune response may enhance the effectiveness of cytostatic therapy. In this regard, the strategy of combined use of 2-isobutyl-4,6-dimethyl-5-oxypyrimidine with classical chemotherapy drugs is of particular interest. Aim. Evaluation of 2-isobutyl-4,6-dimethyl-5-oxypyrimidine (base SNK-411 and salt SNK-578) per se or with doxorubicin on tumor growth inhibition and survival in the murine AKATOL colon adenocarcinoma model. Materials and methods. Antitumor activity of 2-isobutyl-4,6-dimethyl-5-oxypyrimidine was studied in tests on BALB / c mice using the AKATOL colon adenocarcinoma model. A standard graft of 1 × 106 AKATOL tumor cells was administered to each mouse. Starting on day 2, mice received treatment with SNK-578 (10 mg / kg, intraperitoneal) or SNK-411 per os (25 mg / kg) or their combinations with doxorubicin daily. A positive control group received doxorubicin (5 mg / kg, intraperitoneal) on days 2 and 4. The endpoints for assessing antitumor activity were the percentage of tumor growth inhibition (TGI) and increase in lifespan. Results. Monotherapy with SNK-411 and SNK-578 showed high efficacy (TGI ~74 % on day 21). Doxorubicin showed similar efficacy (inhibition of tumor growth 82 %), however, in this group, the death of 2 out of 12 animals was recorded. The combination therapy surpassed the monotherapy with doxorubicin in terms of tumor growth suppression and did not cause the death of animals. The increase in lifespan in the SNK-411 and SNK-578 groups was 31 and 33 %, respectively. Conclusion. Base SNK-411 and salt SNK-578 show antitumor activity and synergize with doxorubicin, reducing its toxicity. These results corroborate earlier data from cervical cancer RSHM-5 and Lewis lung carcinoma models.

Introduction: Therapeutic strategies utilizing neurotrophins hold great promise for treating ischemic brain injuries. However, their clinical application is limited due to low bioavailability, which complicates delivery to damaged neural tissues. To address this challenge, the Center for Innovative and Emerging Biomedical and Pharmaceutical Technologies has developed novel systemically active dipeptide mimics of NGF (GK-2) and BDNF (GSB-106). In this study, we aimed to investigate whether the neuroprotective effects of these compounds in the middle cerebral artery occlusion (MCAO) model of ischemia are related to their influence on neurogenesis. Methods: Following MCAO surgery, rats received intraperitoneal injections of GK-2 (0.5 mg/kg) or GSB-106 (0.1 mg/kg) daily for 7 days. Neurogenesis in the hippocampal subgranular zone (SGZ) was evaluated 8 days post-MCAO by immunohistochemistry using BrdU and doublecortin (Dcx) as markers. Results: A Significant increase in the number of BrdU-containing cells in the MCAO, MCAO+GK-2, and MCAO+GSB-106 groups was revealed (by 217, 172, and 179%, respectively). The number of Dcx-positive cells also increased in the MCAO and MCAO+GSB-106 groups (by 56 and 97%, respectively). A notable prevalence of morphologically abnormal Dcx-positive cells with ectopic dendrite orientation was observed in the MCAO group and the MCAO+GK-2 group (by 63 and 27%, respectively), but not in the MCAO+GSB-106 group. A dramatic 200% increase in ectopic Dcx+ cells in the hippocampal hilus was documented in the ischemic hemisphere of MCAO rats. This deleterious effect was mitigated by treatment with GK-2 (100%) or GSB-106 (87%). Discussion: Numerous studies demonstrate the involvement of BDNF/TrkB and NGF/TrkA and p75NTR in neurogenesis within the hippocampus; therefore, it is reasonable to hypothesize that the application of BDNF and NGF mimetics could be crucial for developing novel stroke treatment strategies. Conclusion: The dipeptides GK-2 and GSB-106, mimicking NGF and BDNF, respectively, attenuated or prevented some MCAO-induced abnormalities in neurogenesis in rats. These findings suggest their potential to modulate post-ischemic neurogenesis and offer a promising therapeutic approach for ischemic brain injury.

BACKGROUND: The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with the deficit of neurotrophin-3 determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-size neurotrophin-3 is limited by unsatisfactory pharmacokinetic properties, it is relevant to create low-molecular-weight mimetics of neurotrophin-3 that are active when administered systemically. A dimeric dipeptide mimetic of the 4th loop of neurotrophin-3, hexamethylenediamide bis(N--oxibutyryl-L-glutamyl-L-asparagine) GTS-302, which activates TrkC and TrkB receptors, has been developed at the V.V. Zakusov Research Institute of Pharmacology. AIM: The aim of this study was to investigate the spectrum of pharmacological activity of GTS-302. MATERIALS AND МETHODS: The pharmacological effects of GTS-302 were investigated following its intraperitoneal administration. The antidepressant-like activity of GTS-302 was studied in the forced swim test in mice after acute and 7-day administration. The anxiolytic and cognitive activity of the dipeptide were studied in the elevated plus maze test in mice and the novel object recognition test in rats after acute administration, respectively. The effect of GTS-302 on pain sensitivity was studied in the hot plate test in mice after acute administration. RESULTS: It was found that GTS-302 exhibits antidepressant-like activity after acute administration at doses of 0.5, 1.0, 5.0 and 10 mg/kg. After 7-day administration, the antidepressant-like activity of GTS-302 was more pronounced in terms of effect size and statistical significance. The dipeptide GTS-302 at doses of 1.0, 5.0 and 10.0 mg/kg showed anxiolytic and cognitive activity and did not affect pain sensitivity. CONCLUSIONS: The pharmacological spectrum of the low-molecular-weight mimetic of neurotrophin-3, dipeptide GTS-302, revealed upon systemic administration includes a number of neuropsychotropic effects characteristic of the full-sized neurotrophin. This allows us to consider GTS-302 as a potential neuropsychotropic drug.

The accumulated evidence suggests that varying levels of tyrosine kinase receptor signaling pathway activity may regulate opiate-associated neuroadaptation of noradrenergic system. Neurotrophin-3 (NT-3) interacts with tropomyosin receptor kinases (TRKs), binding mainly to TRKC receptors, which are expressed within noradrenergic neurons in the blue spot (locus coeruleus, LC). Considering the difficulties in delivering full-length neurotrophins to the CNS after systemic administration, low-molecular mimetics of loop 4 in NT-3, hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), and hexamethylenediamide bis-(N-γ-oxybutyryl-L-glutamyl-L-asparagine) (GTS-302), activating TRKC and TRKB receptors, were synthesized. The aim of the study is comparative examination of the effects of NT-3 dipeptide mimetics on the signs of morphine withdrawal in outbred white rats with opiate dependence, as well as investigation of activation of postreceptor signaling pathways by the mimetics. Dipeptides GTS-301 and GTS-302 after acute administration at doses of 0.1, 1.0, and 10.0 mg/kg (i.p., intraperitoneal) had a dose-dependent effect on the specific morphine withdrawal symptoms with the most effective dose being 1.0 mg/kg. Maximum decrease in the total index of morphine withdrawal syndrome for GTS-301 was 31.3

Background. The neuropeptide cycloprolylglycine (CPG) is an endogenous dipeptide analogue of the nootropic piracetam. It has been experimentally shown that CPG (designed and synthesized at the Federal State Budgetary Scientific Institution «Federal Research Center of Original and Promising Biomedical and Pharmaceutical Technologies») has a spectrum of pharmacological effects characteristic of piracetam. In studies aimed at studying the mechanisms of action of CPG, it was found that glutamate AMPA receptors and neutrophin Trk receptors are involved in the anxiolytic, neuroprotective and antihypoxic effects of CPG. However, the mechanism of nootropic action of CPG has not been studied.Objective. To test the hypothesis about the involvement of Trk receptors in the nootropic effect of CPG in a model of amnesia in mice induced by the administration of scopolamine.Material and methods. The nootropic activity of CPG (1 mg/kg, i.p.) was studied in a model of amnesia in mice induced by scopolamine (0.75 mg/kg, subcutaneously). A pharmacological inhibitory assay was used with the Trk receptor blocker K252a (5 μg/kg, i.p.). The severity of amnesia was assessed using the Novel Object Recognition (NOR) test.Results. Scopolamine was found to impair novel object recognition in mice in the NOR test. CPG prevents the development of amnesia induced by scopolamine, and Trk receptor blocker K252a blocks this effect.Conclusion. Trk receptors are involved in the nootropic effect of the neuropeptide CPG.

It was previously shown that the original dipeptide mimetic of the 4th loop of neurotrophin-3 (NT-3) hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), like the full-length neurotrophin, predominantly activates the tyrosine kinase receptor TrkC and has a neuroprotective effect in vitro at concentrations of 10-5-10-12 M, as well as antidiabetic (0.1 and 0.5 mg/kg) and antidepressant (5 and 10 mg/kg) effects after systemic administration in rodents. In this work, the analgesic properties of GTS-301 were identified, which were manifested in the dose range of 0.01-10 mg/kg after acute intraperitoneal injection to rats in the "tail flick" test. Dipeptide GTS-301 increased the threshold of pain response by 20-30%; this effect persisted for at least 24 h after administration.

This review covers original research focused on the design, synthesis, and pharmacological evaluation of an innovative dimeric dipeptide mimetic of brain-derived neurotrophic factor (BDNF) loop 4 bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106). Developed using a proprietary approach for creating low-molecular-weight neurotrophin mimetics, GSB-106 displayed marked antidepressant-like activity following systemic and oral administration. The article details its pharmacological properties in vitro and in vivo, mechanism of action, development of a tablet form of the dipeptide, and findings from toxicological and pharmacokinetic studies.

Results from studies of the antidiabetic and antihyperglycemic activity of a low-molecular-weight NGF mimetic, compound GR-2 [bis-(N-monosuccinyl-L-glutamyl-L-lysine)hexamethylenediamide], on a streptozotocin-induced diabetes model in Wistar rats are presented. GK-2 administered perorally at a dose of 5 mg/kg for 28 d significantly reduced the glycemia level in diabetic rats and increased the overall plasma antioxidant capacity. The glycemia level and plasma antioxidant capacity were in an inverse exponential relationship and were closely correlated to each other (correlation coefficient 0.899).

Relevance. The nerve growth factor (NGF), possessing neuroprotective and neuroregenerative properties, holds promise for the development of medications for the treatment of post-stroke conditions. At the Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, a dimeric dipeptide mimic of NGF with the laboratory code GK-2 was designed and synthesized. Under conditions of experimental cerebral ischemia, it significantly reduced the volume of brain infarction and stimulated neuro- and synaptogenesis. Objective. The aim of this study was to investigate the effects of GK-2 on experimental post-stroke dementia and depression. Methods. Ischemic stroke was induced by occlusion of the middle cerebral artery (MCAO) in Wistar rats. GK-2 was administered intraperitoneally at a dose of 0.5 mg/kg for 21 days post MCAO. Short-term and long-term memory of the animals were assessed 30–40 days post MCAO using the novel object recognition test. Depressive-like state was evaluated through the forced swimming test and sucrose preference test. Results. In animals subjected to MCAO, both short-term and long-term memory exhibited a statistically significant decline of 80 %, along with a depressive-like state characterized by a 50 % increase in total immobility time and a 30 % reduction in sucrose preference, when compared to the sham-lesioned group. Dipeptide GK-2 completely averted the onset of these impairments. Conclusion. The dipeptide mimic of NGF, GK-2, mitigates the development of cognitive and psychomotional impairments in the setting of experimental stroke.

Previously, based on the β-turn of the fourth loop of the brain-derived neurotrophic factor, we obtained GSB-106 (bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide), that has pronounced neuroprotective and antidepressant activities in doses of 0.1–10 mg/kg with intraperitoneal and oral administration. For identifying the stereospecificity of the antidepressant-like effect of GSB-106, in this work its enantiomer (GSB-106DD) was synthesized and its antidepressant-like properties were studied. It was shown that GSB-106DD has no antidepressant-like effect when administered intraperitoneally in doses of 0.1 and 1.0 mg/kg. It can be assumed that the stereospecificity of the antidepressant-like activity of GSB-106 dependence on the configuration of amino acid moieties.

BACKGROUND:Epilepsy continues to be a significant global health problem and the search for new drugs for its treatment remains an urgent task. 5-HT2 and GABAA-receptors are among promising biotargets for the search for new anticonvulsants.METHODS:New potential 5-HT2 and GABAA ligands in the series of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime were designed using pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out from 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and substituted cinnamoyl chlorides. The anticonvulsant activity of new substances has been established using the maximal electroshock seizure test.RESULTS:Several synthesized substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo [b,d]furan-1-(2H)-one oxime significantly reduced the severity of convulsive manifestations and completely prevented the death of animals after MES. The structure-activity relationship was investigated. The most effective compound was found to be GIZH-348 (1g) (3,4,6,7,8,9-hexahydrodibenzo[ b,d]furan-1(2Н)-one О-(4-chlorophenyl)acryloyl)oxime) at the doses of 10-20 mg/kg.CONCLUSION:Molecular and pharmacophore modelling methods allowed us to create a new group of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime with anticonvulsant activity.

A new group of unsymmetrical ALM-802 analogs, N1-benzyl-N2-2-[(2,3,4-trimethoxybenzyl)amino]-ethylethane-1,2-diamines of general formula 1, in which one of the aromatic groups was changed, was studied. The anti-ischemic and antiarrhythmic activities of the new compounds were studied. Their ADME characteristics were analyzed. The 2,3,4-trimethoxyphenyl group used as one of the aromatic pharmacophores was shown to play a key role in the activity of compounds of this type. The presence of a second aromatic group was also important since its removal led to the disappearance of cardiotropic activity. However, its structure had significantly less impact on the activity of the corresponding compounds because a rather wide variation of substituents in this group did not change the activity in most arrhythmia and ischemia models.

The putative endogenous tripeptide ligand of the translocator protein (TSPO) l-phenylalanyl- l-tryptophanyl- l-leucine amide was obtained using the drug-based peptide design strategy and molecular modeling. This tripeptide demonstrated anxiolytic activity in the elevated plus-maze test and antidepressant-like activity in the forced swimming test in BALB/c mice at the doses of 10 mg kg-1(i.p.) -1 ( i.p .) and also showed neuroprotective activity in the concentration range of 10-5-10-7 -5 -10 -7 M in vitro under conditions of oxidative stress using HT-22 neuronal cell line. Cl

A dimeric dipeptide mimetic based on the β-turn of the 4th loop of neurotrophin-3, bis-(N-monosuccinyl-L-asparaginyl-L-asparagine)hexamethylenediamide (GTS-301LL), was recently designed and synthesized by us. GTS-301, like the full-length neurotrophin, activated TrkC and TrkB receptors and exhibited neuroprotective activity on HT22 cells under oxidative stress conditions in the concentration range 10–5 – 10–12 M and antidepressant-like activity in the forced swimming test in mice (10 – 40 mg/kg, intraperitoneally). The stereospecificity of the pharmacological effects of GTS-301LL was revealed by synthesizing the LD, DL, and DD stereoisomers of GTS-301LL and studying their neuroprotective and antidepressant-like properties under the same conditions as for GTS-301LL. Both activities were found to disappear on going from the LL to the DL and DD stereoisomers and were retained on going to the LD stereoisomer. Thus, the stereospecificity of the neuroprotective and antidepressant-like activities of the dipeptide mimetic of neurotrophin-3 GTS-301LL at the N-terminal asparagine residue was proven, which indicated the key role of that amino-acid residue in the interaction with the receptor.

We studied the anti-anxiety effect of a low-molecular-weight mimetic of the BDNF loop 2, hexamethylenediamide bis-(-N-hexanoyl-L-seryl-L-lysine) (GTS-201) in adult animals. GTS-201 at a dose of 5 mg/kg after acute intraperitoneal administration to outbred male and female rats increased the time spent in the open arms and the number of entries into the open arms in the elevated plus maze (EPM). In "highly emotional" male BALB/c mice, GTS-201 exhibited a dose-dependent anxiolytic effect in the EPM in a dose range of 0.5-2.0 mg/kg with a maximum effective dose of 1 mg/kg. These data confirm the previously revealed anti-anxiety properties of GTS-201 in inbred male and female BALB/c mice and rats and indicate the dependence of the pharmacological activity of the BDNF mimetic on animal age.

The aim of this study was to evaluate the effect of original tyrosine kinase TrkA antagonist GK-1 on tumor growth, median lifespan and hematological parameters in experiment on female mice C57Bl/6 with mammary gland adenocarcinoma Ca755. 14-day intraperitoneal administration of GK-1 at a dose of 10 mg/kg resulted in a significant tumor growth inhibition (TGI) on the 9th, 15th, and 21st day of adenocarcinoma Ca755 development. TGI on the 21st day was 60 %. Administration of GK-1 at doses of 1 mg/kg and 10 mg/kg significantly increased median lifespan of experimental animals by 53 % and 47% respectively. Median lifespan was calculated using the Kaplan-Meier survival analysis. Median lifespan of active control group was 18 days, in groups that received GK-1 at doses of 1 mg/kg and 10 mg/kg median lifespan was 30 days. Hematological parameters of experimental animals were not altered by administration of GK-1. Double injection of the doxorubicin on the 2nd and the 4th day of tumor development at dose of 4 mg/kg resulted in TGI by 73% on the 21st day of experiment, increase in lifespan was 58% and median lifespan was 31 days. Our data show that further investigation of the antitumor activity of GK-1 may bring promising results.

The putative endogenous tripeptide ligand of the translocator protein (TSPO) l-phenylalanyl-l-tryptophanyl-l-leucine amide was obtained using the drug-based peptide design strategy and molecular modeling. This tripeptide demonstrated anxiolytic activity in the elevated plus-maze test and antidepressant-like activity in the forced swimming test in BALB/c mice at the doses of 10 mg kg−1 (i.p.) and also showed neuroprotective activity in the concentration range of 10−5–10−7 m in vitro under conditions of oxidative stress using HT-22 neuronal cell line.

A new group of unsymmetrical ALM-802 analogs, N-1-benzyl-N-2-{2-[(2,3,4-trimethoxybenzyl)amino]-ethyl}ethane-1,2-diamines of general formula 1, in which one of the aromatic groups was changed, was studied. The anti-ischemic and antiarrhythmic activities of the new compounds were studied. Their ADME characteristics were analyzed. The 2,3,4-trimethoxyphenyl group used as one of the aromatic pharmacophores was shown to play a key role in the activity of compounds of this type. The presence of a second aromatic group was also important since its removal led to the disappearance of cardiotropic activity. However, its structure had significantly less impact on the activity of the corresponding compounds because a rather wide variation of substituents in this group did not change the activity in most arrhythmia and ischemia models.

A novel neurotrophin-3 loop 4 dipeptide mimetic, bis(N-γ-hydroxybutyryl-L-glutamyl-L-asparagine) hexamethylenedi-amide (GTS-302), was designed and synthesized. Compound GTS-302 activated the tyrosine kinase receptors TrkC and TrkB, exhibited cytoprotective activity (10-8–10-5 M) in oxidative stress model in HT-22 cells and in 6-hydroxy-dopamine-induced SH-SY5Y cell damage. It also demon- strated an antidepressant-like activity in the forced swim test in mice (0.5–10.0 mg kg–1, intraperitoneally).

A new group of 1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamides, with alkyl, benzyl or alkoxyphenylalkyl groups, amino acid residues or their derivatives as substituents at the amide nitrogen atom, was obtained. The synthesized compounds have high theoretical affinity values to the 18-kDa translocator protein (TSPO) and a favorable profile of ADMET characteristics, which determines their prospects for development as medicines. An anxiolytic activity was detected in eight compounds at doses of 0.1–5.0 mg/kg with intraperitoneal administration under conditions of emotional stress in the “open field” test in Balb/c line mice and in the “elevated plus maze” test in ICR mice. A leader compound N-benzhydryl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxyamide, which demonstrated the presence of antianxiety activity in a wide range of doses in both tests, was selected as a potential anxiolytic agent for subsequent development.