[Antiamyloid properties of fullerene C60 derivatives].

A comparative estimation of the ability of complexes of fullerene C60 with polyvinylpyrrolidone and fullerene C60 derivatives (the sodium salt of the polycarboxylic derivative of fullerene C60, sodium fullerenolate), has been carried out. The fullerenes destroyed amyloid fibrils of the Abeta(1-42) peptide of the brain and the muscle X-protein. A study of the effect of fullerenes on muscle actin showed that complexes of fullerene C60 with polyvinylpyrrolidone and sodium fullerenolate did not prevent the filament formation of actin, nor did they destroy its filaments in vitro. Conversely, sodium salt of the polycarboxylic derivative of fullerene C60 destroyed actin filaments and prevented their formation. It was concluded that sodium fullerenolate and complexes of fullerene C60 with polyvinylpyrrolidone are the most effective antiamyloid compounds among the fullerenes examined.

[Effect of different water-soluble forms of the fullerene C60 on the metabolic activity and ultra-structure of cells in culture].

In view of contradictory data on the toxicity of fullerenes for live organisms we studied the effect of water-soluble complexes of C60 with N-polyvivyl-pirrolidone (C60/PVP) and gamma-cyclodextrine (C60/gamma-CD) on MA-104 cells in culture. Both complexes proved to be non-toxic for cultured cells in the dark in wide range of concentrations. Both complexes provoke changes of cellular ultra-structure which reflect the enhancement of metabolic activity. At the same time only the exposition with the complex C60/PVP leads to the essential growth of number and size of mitochondria. However, the effect of two studied water-soluble forms of C60 under intensive UV-irradiation of cells proved to be opposite: C60/PVP had a cyto-protective action while C60/gamma-CD caused a significant growth of photo-toxicity. Possible reasons of the differences in the action of different forms of C60 on living organisms are discussed.

[Effect of polymer carrier origin and physical state on fullerene C60 phototoxicity in vitro].

Biological effects of water-soluble inclusion complexes of fullerene C60 with poly(vinyl pyrrolidone) (C60/PVP) and gamma-cyclodextrin (C60/g-CD) as well as solid C60 (C60-coated surface) on cell viability have been studied in vitro. It is established that both inclusion complexes (in a broad range of concentrations) and solid fullerene coatings are nontoxic in the dark for the cell of all lines tested. In contrast, under intense UV illumination, the C60/PVP complex reliably protected test cells from the UV radiation damage, whereas the C60/g-CD and fullerene-coated surface exhibited pronounced phototoxicity. Moreover, solid fullerene caused a photodynamic effect under irradiation with both UV and visible light. The radiation damage could be blocked by some antioxidants (e.g., hypoxen) and singlet-oxygen scavenger (sodium azide). This is evidence for the participation of 1O2 in phototoxicity manifestations. The results indicate that the biological properties of fullerene C60 in vitro depend on its aggregate state, form of solubilization, and, probably, the nature of solubilizing medium.

[Nanomedicine as a part of nanotechnology].

In the general sense, nanomedicine is defined as the application of nanotechnologies including nanobiothechnologies in medicine. Under conditions of current rapid development of nanotechnologies, many terms and definitions lack clarity and precision and boundaries between traditional and nanotechnologies are equally poorly determined. Evidently, dimensional parameters alone are insufficient to refer someone or other work to the field of nanotechnology (e.g., nanomedicine). Fundamental novelty of nanomedicine as a branch of knowledge and technology is exemplified by the developments in pharmacology and design of medicinal products that brought about new nanomedical (nanopharmacological, nanopharmaceutical) drugs. These products are multicomponent supramolecular compounds designed for a specific purpose whose intricate structure is intended not so much to impart new properties as to properly deliver the active ingredient to the biological target. Accordingly, nanomedicine should be regarded as the use of supramolecular complexes with a well differentiated surface manufactured by purposeful assembly of selected components for diagnostic and/or therapeutic application.

[Effect of some imidazole-4,5-dicarboxylic acid derivatives on the activity of N-methyl-D-aspartate (NMDA) receptors].

The results of experiments on mice showed that some imidazole-4,5-dicarboxylic acid derivatives injected into lateral cerebral ventricles produce a dose-dependent convulsant or anticonvulsant effects, that is, possess the properties of partial NMDA receptor agonists. The most promising partial NMDA receptor agonist selected for further investigation is 2-propylimidazole-4,5-dicarboxylic acid.

[The structural and functional analysis of the biological activity of acridine derivatives]. / Strukturno-funktsional'nyi analiz biologicheskoi aktivnosti proizvodnykh akridina.

The paper contains an analysis of research on designing drugs based on acridine derivatives. The discussed series of compounds is of essential value since acridines belong to the group of natural compounds with the pronounced antibacterial and anti-tumor activity. Improved chemical-synthesis techniques made it possible to synthesize both simple and complex compounds of the acridine series; they displayed a clear pharmacological activity as anti-proliferative, anti-tumor and antiparasitic preparations. The ability to induce interferons (INF), type 1, is an expected property of simple acridine derivatives. A variety of INF inducers, now used clinically, have been designed recently on the basis of the above compounds. The most well-known acridine derivatives, their pharmacological properties, action mechanisms and outlooks for practical application are described in the paper. The unique qualities of acridines are primarily attractive due to the possibility of using them for the purpose-oriented designing of drugs. Thus, acridines were used as a basis to create the specific regulatory HIV-1 elements, proliferation inhibitors of leukemia cells and new anti-tumor drugs. The elaboration of complexes of acridines derivatives combined with peptides intercalating specifically into the DNA big or small grooves is the most outstanding trend of acridines' research--it opens up prospects for using them in the synthesis of compounds regulating the gene expression.

Antidepressant activity of aspartic acid derivatives.

Antidepressant activity of N-phenyl(benzyl)amino derivatives of aspartic acid was studied on various experimental models of depression. IEM-1770 (30 mg/kg) and IEM-1944 (20 mg/kg) exhibited antidepressant activity after single injection in the forced swimming and tail suspension tests. Antidepressant effect of 14-day administration of these compounds and reference drugs maprotiline (10 mg/kg) and citalopram (10 mg/kg) was confirmed on the model of learned helplessness.

[Effect of fullerene C60-polyvinilpyrrolidone complexes on influenza virus reproduction]. / Vliianie kompleksov fullerena C60 s polivinilpirrolidonom na reproduktsiiu virusov grippa.

The capacity of water-soluble complexes of fullerene C60-polyvinylpyrrolidone to inhibit the replication of influenza viruses was studied. In contrast to remantadine, these complexes inhibit the replication of both A and B viruses (including the remantadine-resistant strains). The complexes inhibit influenza virus replication at all stages of replication cycle.

A new class of agonists and antagonists of N-methyl-D-aspartic acid receptors: derivatives of imidazole-4,5- and pyrazole-3,4-dicarboxylic acids.

Studies of imidazole-4,5- and pyrazole-3,4-dicarboxylic acid derivatives revealed a number of new agonists and antagonists of N-methyl-D-aspartic acid (NMDA) receptors. Studies were based on whole-cell patch-clamp methods applied to rat hippocampus pyramidal cells. Increases in the lipophilicity of the environment of the nitrogen atom, keeping the distance between the terminal acid functions constant, led to a weakening of NMDA antagonism and increases in NMDA antagonism. Increases in the lipophilicity around the nitrogen atom could also lead to less of selectivity in the interaction with NMDA receptors and the appearance of non-NMDA antagonist properties.

[A new class of N-methyl-D-aspartic acid receptor agonists and antagonists--derivatives of imidazole-4,5- and pyrazole-3,4-dicarboxylic acids]. / Novyi klass agonistov i antagonistov retseptorov N-metil-D-asparaginovoi kisloty--proizvodnye imidazol-4,5- i pirazol-3,4-dikarbonovykh kislot.

New agonists and antagonists of the N-methyl-D-aspartic acid (NMDA) receptors were found among the derivatives of 1- or 2-alkyl-substituted imidazole-4,5- and pyrazole-3,4-dicarboxylic acids. Lipophilic surrounding of the nitrogen atom in these compounds was found to determine their ability to be either agonists or antagonists, while the distance between the terminal acidic functions was the same. An increase in the lipophilicity can also cause loss of selective action upon the NMDA receptors and occurrence of non- NMDA antagonistic activity.

[N-butylaspartic acid--a partial agonist of NMDA receptors?]. / N-butilasparaginovaia kislota--chastichnyi agonist NMDA retseptorov?

The convulsive and anticonvulsive properties of the N-alkyl-substituted DL-aspartic acids derivatives were studied after intracerebroventricular injections in mice. It was found that N-butyl-DL-aspartic acid shows some properties of the partial agonist of NMDA receptors.

[The effect of N-methyl-D,L-aspartic acid on the nociceptive reaction of mice]. / Vliianie N-metil-D,L-asparaginovoi kisloty na notsitseptivnuiu reaktsiiu u myshei.

Intraperitoneal NMDLA was pharmacologically studied in mice for effects by using the hot-plate test. The agent given in a subconvulsive dose of 50 mg/kg showed a biphasic action: 5 minutes after administration there was hyperalgesia (Phase I) followed by hypoalgesia (Phase II) 15 minutes later. The effects of phencyclidine, ketamine, morphine, naloxone, bromocriptine and isradipine on NMDLA's analgetic action were also examined. Bearing in mind the fact that the action of NMDLA is decreased by isradipine in Phase I and by receptor-acting agents in Phase II it is suggested that there is a great difference in the patterns of the two phases of the analgetic action of NMDLA systemically used.

[Effects of N-phthalamoyl-L-glutaminic acid, a selective agonist of NMDA receptor, on binding of 3H-L-glutamate with synaptic membranes of the hippocampus]. / Vliianie N-ftalamoil-L-glutaminovoi kisloty, selektivnogo agonista retseptorov NMDA, na sviazyvanie 3H-L-glutamata s sinapticheskimi membranami gippokampa.

In the present investigation the interaction of a novel selective NMDA receptors agonist, N-phthalamoyl-L-glutamic acid (PhGA), with the synaptic membranes preparation of human hippocampus was examined against NMDA. It was established that there are two binding sites of 3H-L-Glu, Kd1 = 0.35 +/- 0.11 nM, Bmax1 = 6.5 +/- 2.3 pmol/mg and Kd2 = 51 +/- 12 nM, Bmax2 = 98 +/- 17 pmol/mg. The inhibition constants (Ki) were calculated for NMDA and PhGA and were equal: Ki(NMDA) = 19 microM, Ki (PhGA) = 13 microM, respectively. It was concluded that PhGA is the partial agonist of the NMDA receptors.

[Search for the substances selectively acting on the mediatory transmission of stimulatory amino acids]. / Poisk veshchestv, izbiratel'no vliiaiushchikh na mediatornuiu peredachu vozbuzhdaiushchikh aminokislot.

The design of new compounds selectively acting on excitatory amino acid neurotransmission is discussed on the basis of structure-activity relationships. Some new compounds, derivatives of aspartic, glutamic, 2,3-diaminopropionic and some other acids, are cited as examples.

[Mnemonic effects of substituted amides of imidazole-4(5)-carboxylic acid in rats]. / Izuchenie mnesticheskikh éffektov zameshchennykh amidov imidazol-4(5)-karbonovoi kisloty u krys.

The effects of four derivatives of imidazole-4(5)-carboxylic acid on the formation and extinction of the conditioned drinking reflex and the preservation of the conditioned response of passive avoidance after electroconvulsive shock or mechanic craniocerebral injury were studied during experiments on rats. N-methylamide of imidazole-4(5)-carboxylic acid exhibited the greatest psychostimulant and antiamnestic activity. Addition of beta-phenylisopropyl radical to NH2-group resulted in the appearance of depressant properties.

[Prodrugs: goals, principles and outlook]. / Prolekarstva: tseli, printsipy i perspektivy.

The review covers the principles of creation of prodrugs as a chemical system for delivering drugs to targets. It presents the strategy of prodrug design and describes the main approaches to creation of prodrugs for drugs of different classes: antibiotics, anti-inflammatory and antitumour agents, corticosteroids, agents of the central action, etc.

[Selective anticonvulsive action of N-substituted imidazole-4,5-dicarboxylic acids against quinolinic acid]. / Izbiratel'noe protivosudorozhnoe deistvie N-zameshchennykh imidazol-4,5-dikarbonovykh kislot protiv khinolinovoi kisloty.

Selective antagonists of quinolinic acid (2,3-pyridine dicarboxylic acid, QUIN)--an endogenous convulsant tryptophan metabolite, administered intracerebroventricular to mice, were identified during comparison with the following intracerebroventricular convulsants: l-kynurenine, aspartic, glutamic, N-methyl-DL-aspartic and kainic acids. It is suggested that the antagonism arises due to a common fragment of the structure which consists of two carboxylic groups at two nearest carbon atoms of the ring and of one nitrogen atom in the alpha-position. The selective action of the compounds found against QUIN supports the suggestion that QUIN produces seizures via N-methyl-D-aspartate binding sites.

[Experimental research on the action of isoptin and alkylenediamine derivatives on the aggregation capacity and the membrane-bound calcium level of thrombocytes]. / Eksperimental'noe issledovanie deistviia izoptina i proizvodnykh alkilendiaminov na agregatsionnuiu sposobnost' i uroven' membranosviazannogo kal'tsiia trombotstiov.

It was found in experiments on rabbit platelets that isoptin and derivatives of N,N'-di(beta-phenylisopropyl)polymethylene diamines produce a dose-dependent decrease of the platelet aggregation activity. The effect correlates with a lowering of membrane-bound calcium level in platelets as shown by the fluorescent technique with the use of chlortetracycline probe. The results obtained demonstrate that the derivatives of alkylenediamines significantly suppress platelet aggregation and block membrane-bound calcium at the lower concentrations than those of isoptin.