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1.
Behav Brain Res ; 373: 112109, 2019 11 05.
Article in English | MEDLINE | ID: mdl-31340175

ABSTRACT

The neurodegenerative diseases have a complex pathogenetic mechanism comprising oxidative stress and receptor system dysfunction caused by various damaging factors such as, for example, brain hypoxia. The purpose of this study was to elucidate the influence of hexahydropyrimidine derivatives on learning, memory, and orientation and locomotor activities in the passive avoidance (PA) and open field (OF) tests and to evaluate these compounds for their potential antihypoxic and antioxidant action on normobaric hypercapnic hypoxia and toxic hypoxia models. We demonstrated that compounds 1a and 1e administered as a single 100 mg/kg dose (p.o.) one hour before the tests increased the latency time to enter the dark compartment for the first time and reduced the time spent in the dark compartment on the 2nd, 7th, and 14th days of PAT and increased the number of squares crossed and hole-pokings in the OF test. It was also shown that single administration of compounds 1a and 1e (in 100 mg/kg dose, p.o.) one hour before generation of hypoxia increased the life span of mice under normobaric hypoxia by 30% (P < 0.05) and, after injection of sodium nitroprusside, they decreased the malondialdehyde (MDA) level and increased the catalase level in the brain of mice. According to molecular docking results, compounds 1а and 1е are bound in the orthosteric active site of M1 muscarinic receptor via supramolecular interactions with a number of functional amino acids. The results indicate that hexahydropyrimidine derivatives have a beneficial effect on the memory, learning processes, and orientation and locomotor activities of rats in an unfamiliar environment and exhibit antihypoxic and antioxidant activities under hypoxia in mice. The cognitive enhancement can be mediated by the effect of lead compounds on the M1 muscarinic acetylcholine receptor.


Subject(s)
Cognition/drug effects , Pyridazines/pharmacology , Receptor, Muscarinic M1/drug effects , Animals , Avoidance Learning/drug effects , Cognition/physiology , Female , Hypoxia/metabolism , Hypoxia, Brain/metabolism , Hypoxia, Brain/physiopathology , Ligands , Memory/drug effects , Molecular Docking Simulation/methods , Oxidative Stress/drug effects , Pyridazines/chemistry , Rats , Rats, Wistar , Receptor, Muscarinic M1/metabolism
2.
Bioorg Med Chem ; 26(15): 4402-4409, 2018 08 15.
Article in English | MEDLINE | ID: mdl-30056037

ABSTRACT

In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27-15.78 µM). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Hypoglycemic Agents/therapeutic use , Pyrrolidines/chemistry , Alkaloids/chemistry , Animals , Azocines/chemistry , Binding Sites , Camphor/chemistry , Catalytic Domain , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemical synthesis , Male , Mice , Molecular Docking Simulation , Pyrrolidines/therapeutic use , Quinolizines/chemistry , Structure-Activity Relationship
3.
Bull Exp Biol Med ; 164(4): 434-438, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29500804

ABSTRACT

We performed screening of nootropic properties of 10 new derivatives of quinolizidine alkaloid (-)-cytisine. Compounds with ß-endo stereochemistry were more active than α-endo-isomers. Under stress conditions (3aR,4S,8S,12R,12aS,12bR)-10-methyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3',4':3,4]pyrido[1,2-a] [1,5]diazocine-1,3,5(4H)-trione enhanced memory and had a positive effect on cognitive functions of rats. According to molecular docking data, the nootropic activity of the compound can be associated with its affinity for the glutamate-binding subunits GluK1 and GluR2 of the kainate and AMPA receptor, respectively.


Subject(s)
Alkaloids/pharmacology , Nootropic Agents/pharmacology , Receptors, AMPA/chemistry , Receptors, Kainic Acid/chemistry , Alkaloids/chemical synthesis , Animals , Avoidance Learning/drug effects , Azocines/chemical synthesis , Azocines/pharmacology , Binding Sites , Female , Gene Expression , Male , Mice , Molecular Docking Simulation , Nootropic Agents/chemical synthesis , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Quinolizines/chemical synthesis , Quinolizines/pharmacology , Rats , Rats, Wistar , Receptors, AMPA/agonists , Receptors, AMPA/antagonists & inhibitors , Receptors, AMPA/metabolism , Receptors, Kainic Acid/agonists , Receptors, Kainic Acid/antagonists & inhibitors , Receptors, Kainic Acid/metabolism , Structure-Activity Relationship , Toxicity Tests, Acute
4.
Bioorg Med Chem ; 25(1): 91-99, 2017 01 01.
Article in English | MEDLINE | ID: mdl-27776888

ABSTRACT

We have developed the convenient methods for synthesis of polyfluorosalicylic acids and their derivatives. For the first time the biological properties of polyfluorosalicylates were investigated in vitro (permeability through the biological membranes, COX-1 inhibitory action) and in vivo (anti-inflammatory, analgesic activities, acute toxicity). Molecular docking of polyfluorinated salicylates confirmed in vitro and in vivo experiments.


Subject(s)
Analgesics/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cyclooxygenase Inhibitors/therapeutic use , Edema/drug therapy , Salicylates/therapeutic use , Analgesics/chemistry , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 1/metabolism , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacokinetics , Cyclooxygenase Inhibitors/pharmacology , Female , Halogenation , Male , Molecular Docking Simulation , Rats, Sprague-Dawley , Rats, Wistar , Salicylates/chemistry , Salicylates/pharmacokinetics , Salicylates/pharmacology , Sheep
5.
Acta Naturae ; 8(1): 82-9, 2016.
Article in English | MEDLINE | ID: mdl-27099787

ABSTRACT

This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 µM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

6.
Phys Chem Chem Phys ; 18(18): 12733-41, 2016 05 14.
Article in English | MEDLINE | ID: mdl-27098151

ABSTRACT

The model reaction of photoinduced donor-acceptor interaction in linked systems (dyads) has been used to study the comparative reactivity of a well-known anti-inflammatory drug, (S)-naproxen (NPX) and its (R)-isomer. (R)- or (S)-NPX in these dyads is linked to (S)-N-methylpyrrolidine (Pyr) using a linear or cyclic amino acid bridge (AA or CyAA), to give (R)-/(S)-NPX-AA-(S)-Pyr flexible and (R)-/(S)-NPX-CyAA-(S)-Pyr rigid dyads. The donor-acceptor interaction is reminiscent of the binding (partial charge transfer, CT) and electron transfer (ET) processes involved in the extensively studied inhibition of the cyclooxygenase enzymes (COXs) by the NPX enantiomers. Besides that, both optical isomers undergo oxidative metabolism by enzymes from the P450 family, which also includes ET. The scheme proposed for the excitation quenching of the (R)- and (S)-NPX excited state in these dyads is based on the joint analysis of the chemically induced dynamic nuclear polarization (CIDNP) and fluorescence data. The (1)H CIDNP effects in this system appear in the back electron transfer in the biradical-zwitterion (BZ), which is formed via dyad photoirradiation. The rate constants of individual steps in the proposed scheme and the fluorescence quantum yields of the local excited (LE) states and exciplexes show stereoselectivity. It depends on the bridge's length, structure and solvent polarity. The CIDNP effects (experimental and calculated) also demonstrate stereodifferentiation. The exciplex quantum yields and the rates of formation are larger for the dyads containing (R)-NPX, which let us suggest a higher contribution from the CT processes with the (R)-optical isomer.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Naproxen/chemistry , Amino Acids/chemistry , Electron Transport , Light , Models, Molecular , Photochemical Processes , Pyrrolidines/chemistry , Spectrometry, Fluorescence , Stereoisomerism
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