Inhibitory mechanism of influence of thyroid hormones on cognitive function of the brain.

In experiments on young rats there were stu­died changes in the fatty acid spectrum of fraction of  free fatty acids (FFA) of neocortex and hippocampus in con­ditions of thyroid dysfunction. Elevated levels of thyroid hormones caused accumulation of polyunsaturated linoleic and linolenic acids in the neocortex by 2 times, in the hippocampus – by 52%. State of hypo­thyroidism also contributed to the increase of C18: 2,3 in the neocortex by 74.4%. Growth of share of unsaturated fatty acid fraction in the content of fatty acid spectrum of neocortex also was accompanied by decrease in saturated C16:0 and C21:0 by 25% and 36% res­pectively. Increase of the level of unsaturated fatty acids fraction of the cerebral cortex is possibly associated with the decrease in "unsaturation" structure of lipids, which in its turn may enhance serotonergic synaptic activity. Research of concentration of neuromediator amino acids in neocortex showed increase of serotonin content both in conditions of hyperthyroidism and hypothyroidism. In conditions of hyperthyroidism increased content of GABA was observed. Activity of serotonin- and GABA- ergic neurotransmitter systems of the brain in conditions of hyperthyroidism can be considered as increase of inhibitory processes in the  effect of feedback. In conditions of experimental hypothyroidism activation of the inhibitory effects of CNS serotonergic system may be one of the ways to reduce the metabolism

Синтез, анальгетична та протизапальна активність похідних 3-(гет)арил-2-(6,7,8,9-тетрагідро-5Н-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилу

Aim. To synthesize, prove the structure and study the analgesic and anti-inflammatory activities of 3-(het)-aryl-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile derivatives.Results and discussion. Condensation of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with cyanoacetic acid hydrazide leads to formation of 2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acetonitrile. The latter readily reacts with the corresponding (het)arenecarbaldehydes in refluxing ethanol in the presence of catalytic amount of piperidine yielding a series of new 3-(het)aryl-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile derivatives. Further functionalization of 3-(4-hydroxy-3-R-phenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitriles has been done by modification of the OH group. One of the compounds synthesized, namely 3-(4-hydroxyphenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile, exhibits a high level of the analgesic activity on the “hot plate” model, and a similar level of the activity on the model of “acetic acid-induced writhings” as compared to ketorolac. The results obtained indicate the pronounced antinociceptive activity for the test compound.Experimental part. 1H NMR spectra of the compounds synthesized were recorded on a Bruker VXR-300 spectrometer (Germany) operating at a frequency of 299.945 MHz, in DMSO-d6, using tetramethylsilane (TMS) as an internal standard. Melting points were measured using a RNMK 05 device (VEB Analytik,Dresden). The elemental analysis was performed on a EuroEA 3000 elemental analyzer. The analgesic and anti-inflammatory activities of 3-(4-hydroxyphenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile were determined using models of “carrageenan induced paw edema”, ”hot plate” and “acetic acid-induced writhings”, and compared to the reference drug ketorolac.Conclusions. A series of new 3-(het)aryl-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile derivatives can be easily synthesized by the interaction of 2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acetonitrile with (het)arenecarbaldehydes. The hydroxy group in 3-(4-hydroxy-3-R-phenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitriles can be modified to obtain phenyl esters of aliphatic and aromatic carboxylic acids. The high level of the analgesic activity for 3-(4-hydroxyphenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile has been determined.Received: 30.01.2020Revised: 17.05.2020Accepted: 29.05.2020Цель. Синтезировать, доказать структуру и исследовать анальгетическую и противовоспалительную активность производных 3-(гет)арил-2-(6,7,8,9-тетрагидро-5Н-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрила.Результаты и их обсуждение. Конденсация 2-метокси-3,4,5,6-тетрагидро-7H-азепина с гидразидом циануксусной кислоты приводит к образованию 2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)ацетонитрила. Последний легко реагирует с соответствующими (гет)аренкарбальдегидами в присутствии каталитического количества пиперидина в среде кипящего этанола с образованием серии новых производных 3-(гет)арил-2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрила. Дальнейшая функционализация 3-(4-гидрокси-3-R-фенил)-2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрилов была проведена путем модификации OH-группы. Одно из синтезированных соединений – 3-(4-гидроксифенил)-2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрил проявляет высокий уровень анальгетической активности на модели «горячей пластинки» и сравнимый с кеторолаком уровень анальгетической активности на модели «уксуснокислых корчей». Полученные результаты определенно указывают на выраженную антиноцицептивную активность данного соединения.Экспериментальная часть. 1H ЯМР-спектры синтезированных соединений были записаны на спектрометре Bruker VXR-300 (Германия), рабочая частота – 299,945 MГц, в ДМСО-d6, с использованием тетраметилсилана (TMS) в качестве внутреннего стандарта. Температуры плавления измеряли с помощью устройства RNMK 05 (VEB Analytik, Дрезден). Элементный анализ выполняли на элементном анализаторе EuroEA 3000. Анальгетическую и противовоспалительную активность 3-(4-гидроксифенил)-2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрила исследовали на моделях «карагенин-индуцированного отека», «горячей пластинки» и «уксуснокислых корчей», препарат сравнения – кеторолак.Выводы. Серия новых производных 3-(гет)арил-2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрила может быть легко синтезирована взаимодействием 2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)ацетонитрила с (гет)аренкарбальдегидами. Гидроксигруппа в 3-(4-гидрокси-3-R-фенил)-2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрилах может быть модифицирована с образованием фениловых эфиров алифатических и ароматических карбоновых кислот. Установлен высокий уровень анальгетической активности для 3-(4-гидроксифенил)-2-(6,7,8,9-тетрагидро-5H-[1,2,4]триазоло[4,3-a]азепин-3-ил)акрилонитрила.Received: 30.01.2020Revised: 17.05.2020Accepted: 29.05.2020Мета. Синтезувати, довести структуру і дослідити анальгетичну та протизапальну активність похідних 3-(гет)арил-2-(6,7,8,9-тетрагідро-5Н-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилу.Результати та їх обговорення. Конденсація 2-метокси-3,4,5,6-тетрагідро-7H-азепіну з гідразидом ціанооцтової кислоти приводить до утворення 2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)ацетонітрилу. Останній легко реагує з відповідними (гет)аренкарбальдегідами у присутності каталітичної кількості піперидину у середовищі киплячого етанолу з утворенням серії нових похідних 3-(гет)арил-2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилу. Подальшу функціоналізацію 3-(4-гідрокси-3-R-феніл)-2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилів було проведено шляхом модифікації OH-групи. Одна із синтезованих сполук – 3-(4-гідроксифеніл)-2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрил виявляє високий рівень анальгетичної активності на моделі «гарячої пластинки» та близький до кеторолаку рівень анальгетичної активності на моделі «оцтовокислих корчів». Одержані результати чітко вказують на виражену антиноцицептивну активність цієї сполуки.Експериментальна частина. 1H ЯМР-спектри синтезованих сполук було записано на спектрометрі Bruker VXR-300 (Німеччина), робоча частота – 299,945 MГц, в ДМСО-d6, з використанням тетраметилсилану (TMS) як внутрішнього стандарту. Температури плавлення вимірювали за допомогою пристрою RNMK 05 (VEB Analytik, Дрезден). Елементний аналіз виконували на елементному аналізаторі EuroEA 3000. Анальгетичну та протизапальну активність 3-(4-гідроксифеніл)-2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилу досліджували на моделях «карагенін-індукованого набряку», «гарячої пластинки» та «оцтовокислих корчів», препарат порівняння – кеторолак.Висновки. Серія нових похідних 3-(гет)арил-2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилу може бути легко синтезована взаємодією 2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)ацетонітрилу з (гет)аренкарбальдегідами. Гідроксигрупа у 3-(4-гідрокси-3-R-феніл)-2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилах може бути модифікована з утворенням фенілових естерів аліфатичних та ароматичних карбонових кислот. Встановлено високий рівень анальгетичної активності для 3-(4-гідроксифеніл)-2-(6,7,8,9-тетрагідро-5H-[1,2,4]триазоло[4,3-a]азепін-3-іл)акрилонітрилу.Received: 30.01.2020Revised: 17.05.2020Accepted: 29.05.202

Synthesis and anticancer properties of 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene derivatives

In recent years, attention to itself is attracted to the problem of treatment of cancer that is caused by increase in patients, especially of working age. Therefore, the enlargement of the arsenal of anticancer medicines of a wide spectrum of action is actual. The purpose of the study was to synthesize substances with potentially antitumor properties in a series 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene derivatives and to study the effect of synthesized compounds on inhibition of growth (or their destruction) of a wide range of cancer. The objects of the study were derivatives of 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene, which were synthesized by refluxing 3-(2-isopropyl-5-methylphenoxymethyl)-6,7,8,9-tetrahydro-5Н-[1,2,4]triazolo[4,3-a]azepine with с appropriate α-halogenketones in ethyl acetate and further cyclization in an alkaline medium. Использовали данные NMR 1Н spectroscopy data were used. The primary evaluation of anticancer activity was carried out National Cancer Institute of Health, USA within the Development Therapeutic Program. A series of new of 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene derivatives was synthesized, their structure and purity were confirmed by NMR 1Н spectroscopy. The anticancer activity of the synthesized compounds was studied both at a concentration of 10-5 mol/l and in a concentration gradient of 10-4‒10-8 mol/l in experiments in vivo on cancer cell lines. It is shown that insertion of methyl group into position 3 of heterocyclic system of the basic structure of 4-aryl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulene leads to an increase in the anticancer effect. It is found that the tested compounds showed high anticancer effect on all types of cancer cell lines investigated – leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer

The antiinflammatory and analgesic activity of polimetilenimidazol derivatives

The search for new analgesic and anti-inflammatory drugs, exceeding by efficacy and/or safety the existing analogues is very important and relevant. The nitrogenous heterocycles are promising in this respect, in particular, the compounds containing an imidazol moiety. The conducted PASS-prognosis of seven new derivatives of 4.5-polimetilenimidazol has showed a significant probability of their having anti-exudative and anti-nociceptive effects. These effects can be connected both with the influence on the certain links of inflammatory process and with the lack of analgesic effect without an inflammatory component. The toxicity and the specific activity studies have been carried out on the white nonlinear mice. The studied compounds used in a single intragastric administration by the level of toxicity are referred to low or moderate ones. The experimental verification has been carried out on the models of carrageenan edema (anti-exudative action) and “hot plate” (anti-nociceptive action). The substance has been used in a single intragastric administration in a dose of 1/10 LD50. Diclofenac has been used as a reference product in the doses of 3.2 mg/kg (hot plate) and 8 mg/kg (carrageenan edema). The experimental verification has shown a significant validity of the PASS-prognosis and the anti-nociceptive and anti-exudative effects of the derivatives. The most promising compound D-32 has showed a significant anti-exudative activity (-50.0%) and analgesic effect (+110.3%) in the experiment, which is comparable to an active comparator diclofenac: -45.57% and +109.0% respectively

Effect of Particle-Hole Asymmetry on the Mott-Hubbard Metal-Insulator Transition

The Mott-Hubbard metal-insulator transition is one of the most important problems in correlated electron systems. In the past decade, much progress has been made on examining a particle-hole symmetric form of the transition in the Hubbard model with dynamical mean field theory where it was found that the electronic self energy develops a pole at the transition. We examine the particle-hole asymmetric metal-insulator transition in the Falicov-Kimball model, and find that a number of features change when the noninteracting density of states has a finite bandwidth. Since, generically particle-hole symmetry is broken in real materials, our results have an impact on understanding the metal-insulator transition in real materials.Comment: 5 pages, 3 figure

Влияние психотропных лекарственных средств на спонтанную поведенческую активность белых крыс

Установлено, что использование нейролептиков в условиях экспериментального психоза сопровождалось более выраженным, чем у интактных животных, понижением подвижности, опытнического поведения, эмоциональности. В отличие от этого, действие атипичного нейролептика сульпирида характеризовалось угнетением тревожности при повышении подвижности. Ноотропные препараты приводили к усилению подвижности и эмоциональной активности. Установлены фармакологические эффекты нейролептиков, антидепрессантов и ноотропных препаратов, которые могут применяться в клинической практике для оптимизации лечения больных с психическими расстройствами, в частности шизофренией

Electronic Structure of Transition-Metal Dicyanamides Me[N(CN)2_2]2_2 (Me = Mn, Fe, Co, Ni, Cu)

The electronic structure of Me[N(CN)$_2$]$_2$ (Me=Mn, Fe, Co, Ni, Cu) molecular magnets has been investigated using x-ray emission spectroscopy (XES) and x-ray photoelectron spectroscopy (XPS) as well as theoretical density-functional-based methods. Both theory and experiments show that the top of the valence band is dominated by Me 3d bands, while a strong hybridization between C 2p and N 2p states determines the valence band electronic structure away from the top. The 2p contributions from non-equivalent nitrogen sites have been identified using resonant inelastic x-ray scattering spectroscopy with the excitation energy tuned near the N 1s threshold. The binding energy of the Me 3d bands and the hybridization between N 2p and Me 3d states both increase in going across the row from Me = Mn to Me = Cu. Localization of the Cu 3d states also leads to weak screening of Cu 2p and 3s states, which accounts for shifts in the core 2p and 3s spectra of the transition metal atoms. Calculations indicate that the ground-state magnetic ordering, which varies across the series is largely dependent on the occupation of the metal 3d shell and that structural differences in the superexchange pathways for different compounds play a secondary role.Comment: 20 pages, 11 figures, 2 table

Russia and the Arab Spring: supporting the counter-revolution

Russia’s response to the Arab Spring ranged from apprehension to deep anxiety and diverged significantly from the US and the EU responses. While initially welcoming the popular demands for political reform in North Africa, the Russian reaction rapidly became more critical as a result of Western military intervention into Libya and the threat of the spread of Islamist extremism. It was these twin fears which prompted the Russian leadership to adopt an uncompromizing stance towards Syria. While geopolitical factors certainly played a role in driving Russian strategy, domestic political factors were also more significant. As the Russian leadership felt internally threatened by the growing opposition within the country, conflict in the Middle East highlighted the perceived flaws of the imposition of Western liberal democracy and the virtues of Russia’s own model of state-managed political order. There was, as such, a significant ideational and ideological dimension to the Russian response to the Arab Spring

Studying galaxy troughs and ridges using weak gravitational lensing with the Kilo-Degree Survey

We study projected underdensities in the cosmic galaxy density field known as ‘troughs’, and their overdense counterparts, which we call ‘ridges’. We identify these regions using a bright sample of foreground galaxies from the photometric Kilo-Degree Survey (KiDS), specifically selected to mimic the spectroscopic Galaxy And Mass Assembly survey. Using background galaxies from KiDS, we measure the weak gravitational lensing profiles of the troughs/ridges. We quantify the amplitude of their lensing strength A as a function of galaxy density percentile rank P and galaxy overdensity δ, and find that the skewness in the galaxy density distribution is reflected in the total mass distribution measured by weak lensing. We interpret our results using the mock galaxy catalogue from the Marenostrum Institut de Ciències de l’Espai (MICE) simulation, and find a good agreement with our observations. Using signal-to-noise weights derived from the Scinet LIghtCone Simulations (SLICS) mock catalogue we optimally stack the lensing signal of KiDS troughs with an angular radius θA={5,10,15,20}arcmin⁠, resulting in {16.8,14.9,10.13,7.55}σ detections. Finally, we select troughs using a volume-limited sample of galaxies, split into two redshift bins between 0.1 < z < 0.3. For troughs/ridges with transverse comoving radius RA=1.9h−170Mpc⁠, we find no significant difference in the comoving excess surface density as a function of P and δ between the low- and high-redshift sample. Using the MICE and SLICS mocks we predict that trough and ridge evolution could be detected with gravitational lensing using deeper and wider lensing surveys, such as those from the Large Synoptic Survey Telescope and Euclid