Polyfluorinated salicylic acid derivatives as analogs of known drugs: Synthesis, molecular docking and biological evaluation.

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.

[Docosahexaenoyl dopamine in freshwater hydra: effects on regeneration and metabolic changes].

The effects of docosahexaenoyl dopamine and docosahexaenoic acid on the regeneration of hydra gastric and basal fragments are studied. Docosahexaenoyl dopamine induced morphogenetic abnormalities such as single ectopic tentacles in the gastric region and projections in the gastric and basal regions. Docosahexaenoic acid had no effect on the morphogenesis except for a mild slowing of the regeneration rate. Since no hydrolysis of docosahexaenoyl dopamine was detected in hydra extract, it was assumed that the morphogenetic effect could be associated with the dopamine component of this complex.

[N-arachidonoyl dopamine is a possible factor of the rate of tentacle formation in freshwater hydra].

The effect of N-arachidonoyl dopamine, haloperidol, and their mixture on the rate of tentacle formation was studied during regeneration of the gastral and basal fragments of freshwater hydra. Some concentrations of haloperidol inhibited the tentacle formation, which was more pronounced in the basal fragment. N-arachidonoyl dopamine accelerated the tentacle formation in both fragments, particularly, in the basal one (an inversion of the natural difference in the rate of tentacle formation between the gastral and basal fragments). After the exposure to the mixture of these drugs, the effects of each of them were observed. Mass spectrometry assay has demonstrated endogenous N-arachidonoyl dopamine in the intact hydra homogenate. The possible involvement of this acyl-neurotransmitter in the regulation of the rate of tentacle formation in regenerating hydra is discussed.

[Effects of arachidonoyl dopamine, haloperidol, and their mixtures on regeneration of freshwater Hydra attenuata]. / Vliianie arakhidonoildofamina, galoperidola i ikh smesei na regeneratsiiu presnovodnoi gidry Hydra attenuata.

Arachidonoyl dopamine and haloperidol, both separately and in different combinations, inhibit regeneration of the gastral and basal regions of hydra. In addition, both substances induce stable anomalies of morphogenesis in the form of outgrowths and additional tentacles in gastral regenerates. In the presence of both substances at different combinations, anomalies either do not appear altogether, or exist for a short time, thus suggesting the normalization of morphogenesis. Possible mechanisms underlying the effects of these substances are discussed.

The effects of dopamine synthesis inhibitors and dopamine antagonists on regeneration in the hydra Hydra attenuata.

The effects of catecholamine synthesis inhibitors (alpha-methyltyrosine, 3-iodotyrosine, and alpha-methyl-DOPA) and dopamine receptor blockers (haloperidol and spiperone) on the regeneration of apical, gastral, and basal fragments of the hydra Hydra attenuata were studied. These experiments showed that alpha-methyltyrosine and 3-iodotyrosine significantly inhibited regeneration but did not produce morphological anomalies. Alpha-Methyl-DOPA produce less inhibition of regeneration, but induced ectopic tentacles and outgrowths in gastral regenerates. Haloperidol and spiperone had no significant effect on the rate of regeneration but induced significant numbers of morphogenetic anomalies in gastral regenerates. Apical and basal regenerates, which retained their natural organizers (the head and base respectively) never yielded morphogenetic anomalies in the presence of either dopamine receptor blockers or dopamine synthesis inhibitors. The possible role of neurotransmitters. particularly dopamine, in morphogenesis in hydras is discussed.

[The action of catecholamine-synthesis inhibitors and of spiperone on sea urchin and mouse embryos]. / Deistvie ingibitorov sinteza katekholaminov i spiperona na zarodyshi morskikh ezhei i myshei.

We studied the effects of three inhibitors of catecholamine synthesis on the development of sea urchins Sphaerechinus granularis and Paracentrotus lividus. These drugs affected the early embryogenesis, which was expressed in inhibition of the cleavage divisions, appearance of abnormal embryos, and developmental arrest. The addition of arachidonic acid amide and dopamine to the incubation medium weakened the effects of the inhibitors. Spiperone induced developmental defects in preimplantation mouse embryos and sea urchin embryos. Arachidonic acid amide with dopamine exerted a protective effect against spiperone when introduced to sea urchin embryos at the blastula or late gastrula stages, rather than after fertilization. In murine embryos, this amide induced developmental defects and arrest itself and its effect was reversible. Possible mechanisms underlying the effects of these drugs are discussed.

[Effect of inhibitors of synthesis of dopamine and its antagonists on Hydra attenuata regeneration]. / Vliianie ingibitorov sinteza i antagonistov dofamina na regeneratsiiu gidry Hydra attenuata.

Obvious inhibition of the hydra regeneration with no subsequent morphological abnormalities, was shown to occur when using alpha-methylthyrosine and 3 Jthyrosine. alpha-Methyldopa induced a slight inhibition but a considerable morphological change: ectopic tentacles, projections, bipolar forms in the gastric fragment. The apical and basal fragments did not suffer. The role of neurotransmitters in the hydra morphogenesis is discussed.

[The positive effect of pretreatment with serotonin and gangliosides on the development of early mouse embryos after cryopreservation]. / Polozhitel'noe vliianie predobrabotki serotoninom i gangliozidami na razvitie rannikh zarodyshei myshei posle kriokonservatsii.

We have demonstrated that viability of preimplantation mouse embryos F1 (C57B1/6 x CBA) after cryoconservation at the stage of four blastomeres improves after pretreatment with serotonin (5 HT, 5 microM) or total gangliosides of bovine brain gangliosides (TG, 3 microM) added to the cultivation medium. After thawing, 64% of embryos preincubated with total brain gangliosides and 49% of embryos preincubated with serotonin developed to the stage of blastocyst during the cultivation in vitro; in the control, no more than 25% of embryos reaches this stage, and all these embryos were abnormal. Possible mechanisms of protective action of these compounds is discussed. We conclude that mouse embryos subjected to freezing-thawing procedure can be used to examine the role of serotonin and gangliosides in the regulatory processes of mammalian preimplantation development.

[The action of tiazofurin on the development of sea urchin embryos and larvae]. / Deistvie tiazofurina na razvitie zarodyshei i lichinok morskikh ezhei.

The effects of the antitumor drug tiazofurin on development of sea urchins Sphaerechinus granularis, Paracentrotus lividus, Strongylocentrotus intermedius, and Arbacia lixula were studied. When 0.01-200 microM tiazofurin (TAF) was introduced in the incubation medium (artificial sea water) just after fertilization or at the midblastula stage, the development proceeded quite normally until the beginning of gastrulation. But later TAF blocked gastrulation and induced formation of mobile ball-shaped larvae with normal pigment cells but devoid of the nervous system, skeletal spicules and digestive tract. The threshold TAF concentrations varied from 0.05 microM (S. granularis) to 2-5 microM (all other species). When TAF was introduced during gastrulation and just after gastrulation, the larvae had defective nervous system and skeleton and suppressed expression of gangliosides. The nonhydrolyzable analog of GTP, GTP-gamma-S (5-20 microM), introduced in artificial sea water no later than at the midblastula stage prevented all above mentioned developmental defects.

[The action of acetylcholine antagonists on preimplantation mouse embryos cultured in vitro]. / Deistvie antagonistov atsetilkholina na doimplantatsionnykh zarodyshei myshei, kul'tiviruemykh in vitro.

The effects of acetylcholine antagonists on development of the two-cell mouse embryos was studied. Etpenal-3 and etpenal-14 were shown to delay cleavage, affect cytokinesis, induce fusion of the blastomeres and arrest development at the stage of two-eight blastomeres with respect to the concentration used. Atropine, an M-cholinolytic, affects the early embryogenesis at a higher concentration than the cholinolytics with mixed effect. Acetylcholine does not prevent cleavage and compactization of the embryos and exerts a protective effect against the cholinolytics with mixed effect at the early developmental stages. The effect of atropine is weaker. The data obtained suggest the presence of structures sensitive to cholinolytics in the early mouse embryos and a possible involvement of acetylcholine in the early development of mammals.

[The effect of cyclic nucleotides on the sensitivity of early mouse embryos to biogenic monoamine antagonists]. / Vliianie tsiklicheskikh nukleotidov na chuvstvitel'nost' rannikh zarodyshei myshei k antagonistam biogennykh monoaminov.

The effect of lipophilic cAMP analogs on the sensitivity of preimplantation mouse embryos of two strains to cytotoxic serotonin and adrenalin antagonists was studied. Dioctanoyl-cAMP significantly decreased the sensitivity of embryos to inmecarb and cyproheptadine: experimental embryos developed to the stage of morula or blastocyst, in contrast to control embryos incubated without this protector. A somewhat weaker effect was observed in experiments with propranolol: embryos incubated in the propranolol-containing medium after the addition of dioctanoyl-cAMP were capable of one to two cleavage divisions. 8-bromomonobutyryl-cAMP partially suppressed the inhibitory effect of cyproheptadine and did not affect the sensitivity of embryos to propranolol. These data suggest cAMP involvement in the regulatory activity of neurotransmitters in the early mouse embryos.

[The effect of biogenic monoamine antagonists on the development of preimplantation mouse embryos cultured in vitro]. / Vliianie antagonistov biogennykh monoaminov na razvitie doimplantatsionnykh zarodyshei myshei, kul'tiviruemykh in vitro.

The effect of serotonin and adrenaline antagonists was tested on the early embryos of mice of three lines. All the substances tested produced an arrest or inhibition of cleavage division and the appearance of anomalies. Serotonin introduced in the incubation medium was effective against some serotoninolytics. We were unable to test the protective effect of adrenaline, as in the concentrations used it has its own effect on the development. From the data obtained, a conclusion is made of the existence in early mouse embryos of the structures sensitive to serotonin and adrenaline antagonists. The assumptions is made from the previously obtained data on the presence of biogenic monoamines in early mouse embryos, of functional activity of prospective mediators of the nervous system at the earliest stages of embryonic development of mammals.

[Biogenic monoamines in ovum cells and preimplantation embryos of mice]. / Biogennye monoaminy v iaitsekletkakh i doimplantsionnykh zarodyshakh myshei.

Histofluorescence technique using glyoxylic acid revealed a specific fluorescence suggesting the presence of biogenic monoamines in early developmental stages of CBA x C57 Black mice. A yellow fluorescence observed in the blastomere surface from the stage of zygote up to that of four blastomere points to the presence of indole derivates. As development proceeds, the fluorescence increases and its colour becomes more and more green, which is characteristic of catecholamines. From the stage of eight blastomeres up to stage of blastocyst specific fluorescence is revealed in the cytoplasm. The inhibitors of monoamine oxidase, introduced into pregnant mice, markedly increased the specific fluorescence. An assumption is made of functional activity of biogenic monoamines in early mouse embryos.

Histochemical study of biogenic monoamines in early ("Prenervous") and late embryos of sea urchins.

Treatment of the embryos of sea urchins with glyoxylic acid results in the appearance of luminescence which is indicative of the presence of biogenic monoamines. At the early stages of development (cleavage divisions, blastula, gastrula) the histochemical method reveals a tryptamine-like substance which is first found in all embryonic cells and later is concentrated mainly in the cells of the primary gut and ciliary bands. At the stages of prism and pluteus there appear neuron-like cells containing dopamine. The inhibitors of monoamine oxidase and neurotoxins reliably increase the histochemical reaction to monoamines only in late embryos which suggests a change in the properties of monoaminergic systems in the course of embryogenesis.

Sensitivity of starfish oocytes and whole, half and enucleated embryos to cytotoxic neuropharmacological drugs.

In early embryos of eight starfish species both usual sensitivity and supersensitivity to cytotoxic neurochemicals have been found. This sensitivity is unaffected by the removal of the cell nucleus. In the starfish Aphelasterias japonica the supersensitivity in the embryos' red halves is higher and in embryos' white halves lower than in the whole embryos.

[Effect of various pharmacologic preparations on the viability of Chinese hamster fibroblasts in vitro]. / Vliianie nekotorykh farmakologicheskikh preparatov na vyzhivaemost' fibroblastov kitaiskogo khomiachka in vitro.

The effect of the physiologically active substances (histamine, serotonin) and their antagonists (bicarfene, cyproheptadine and preparation 407) on the growth of Chinese hamster fibroblasts in vitro has been studied. The cell survival evaluated from the number of colonies grown by the 7th day of cultivation served as criterion for the action of the substances under study. Determination of amines in fibroblast extracts was made by spectrofluorometry. It has been discovered that Chinese hamster fibroblasts are susceptible to a number of pharmacological preparations, antagonists of serotonin and histamine, and that histamine abolishes the inhibitory action of the respective antagonist on the colony growth. Biochemical analysis has shown that these fibroblasts contain tryptamine and serotonin and, tentatively, histamine. It is assumed that these endogenous physiologically active substances participate in the fibroblast growth control.

Biogenic monoamines in early embryos of sea urchins.

Indolylalkylamine determination was performed on the eggs and embryos of six species of sea urchins, using several fluorometric techniques, including the fluorescence of a substance itself and the fluorescence of its condensation products after treatment with orthophthaldialdehyde and ninhydrin. The serotonin-like substance of sea urchin embryos as well as of adults was shown to consist of at least two components, of which the major one is tryptamine or its derivative with a substituting group at aminonitrogen. Further, serotonin was found to be present at all developmental stages investigated. although at much lower concentrations. The results of this study suggest a regulatory role of 'prenervous' tryptamine in the early embryogenesis of the sea urchin.

[New date on biogenic amines of developming sea urchin embryos]. / Novye dannye o biogennykh monoaminakh razvivaiushchikhsia émbrionov morskikh ezhei.

Using two fluorimetric techniques, identification and assay of indolylalkylamines have been made in sea urchin eggs and embryos. It was shown that serotonin-like substance of embryonic and adult specimens is not usually homogeneous and consists at least of two components, the main of them being presented by tryptamine or one of its derivatives with the replaced group at amino nitrogen. Serotonin is also present at all the developmental stages investigated although its concentrations are significantly lower. It is suggested that these substances are involved into regulatory processes during early embryogenesis.