Background. Alcohol remains the most commonly consumed psychoactive substance associated with cognitive impairment, which poses a significant public health concern. By damaging various regions of the brain, particularly the hippocampus, ethanol exposure causes serious neuropsychiatric disorders. In this connection, restoration of its structural integrity plays a key role in treating the consequences of chronic alcohol intoxication.Objective. To study the pathomorphological changes in pyramidal neurons across different subfields of the rat hippocampus following chronic alcohol intoxication and treatment with new derivatives of neuroactive amino acids (glufimet and mefargin).Methods. A preclinical randomized controlled trial was conducted on 28 ten-month-old outbred female Wistar rats weighing 280–320 g. The animals were divided into an intact group (Group I) and three experimental groups (II–IV). In Groups II–IV, chronic alcohol intoxication was induced by replacing drinking water with a 10 % (v/v) ethanol solution sweetened with sucrose (50 g/L) for 24 weeks. After that, they were administered 0.1 mL saline solution per 100 g of body weight (Group II/control), glufimet at a dose of 28.7 mg/kg (Group III), or mefargin at a dose of 25 mg/kg (Group IV). Qualitative signs of neuronal damage in the hippocampal pyramidal layer were assessed via microscopic detection of cytoplasmic chromatolysis, karyolysis, shrunken perikarya and nuclei, and nuclear hyperchromasia. Cellular and nuclear swelling, as well as the presence of hypocellular areas, were also evaluated. Morphometric analysis was performed using cross-sectional micrographs to determine the mean absolute areas of neuronal nuclei and perikarya, the relative area of all perikarya and neuropils per field of view, and the granular layer width. The proportion of shrunken and hyperchromic neurons was also calculated. Statistical analysis was conducted using the Statistica 12 software (StatSoft, USA). Differences were considered statistically significant at p < 0.05.Results. Chronic alcohol intoxication led to a marked increase in the number of hyperchromic and chromatolytic shrunken neurons. This was accompanied by a neuronal loss in the hippocampal CA1–CA3 pyramidal layer, alongside the appearance of hypocellular areas and an increase in the number and size of glial cells and their nuclei. In Group III, glufimet improved cytoarchitecture in the hippocampal CA1–CA3 pyramidal layer relative to untreated female rats. Perikarya were predominantly round in shape and slightly enlarged, with no observable areas of cellular depletion. The absolute areas of perikarya and neuronal nuclei in all studied hippocampal subfields were statistically significantly greater than those in Group II — by an average of 31.3 % (p < 0.05) and 45.2 % (p < 0.05), respectively. The pyramidal layer width was comparable to that of intact animals. The proportion of shrunken neurons with hyperchromic nuclei was 42.1 % lower (p < 0.05), while the relative area of perikarya was 19.8 % (p < 0.05) greater compared to Group II. Mefargin, a γ-aminobutyric acid derivative administered to the female rats in Group IV, produced similar effects, albeit to a slightly lesser extent. Specifically, the pyramidal layer width was 12.9 % (p < 0.05) greater in the subfields CA1 and CA2, and the proportion of shrunken neurons with hyperchromic nuclei in the subfields CA1–CA3 was 11.1 % lower compared to the control group. The mean areas of neuronal perikarya and nuclei were greater by 54.9 % (p < 0.05) and 96.5 % (p < 0.05), respectively, than those in Group II, exceeding the values observed in intact animals.Conclusion. Chronic alcohol intoxication leads to marked morphological changes in the rat hippocampal CA1–CA3 pyramidal neurons. Glufimet, a new glutamic acid derivative administered to animals following prolonged alcohol intoxication, helped to preserve the cytoarchitecture of the hippocampal CA1–CA3 pyramidal layer. These findings, together with data from previous studies, may serve as a basis for the development of a neuroprotective drug that can counteract the negative effects of alcohol on the central nervous system.

Spiroheterocyclic compounds, (3′R*,4′ S*)-3′-(het)aryl-3,5,5′-trioxospiro[pyrazolidine-4,2′-pyrrolidine]-4′-carbohydrazides, were synthesized by the reaction of diastereopure trimethyl (3R*,4S*)-1-acetyl-4-(het)aryl-2-pyrrolidone-3,5,5-tricarboxylates with hydrazine hydrate. The structures of the synthesized compounds were confirmed by spectral methods and X-ray diffraction analysis. Some of the new compounds were found to exhibit anxiolytic and antidepressant activity.

The reaction of methyl 4-aryl(indol-3-yl)-2-pyrrolidone-3(5)-carboxylates with ammonia afforded racemic (3R*,4S*)-4-(indol-3-yl)-2-pyrrolidone-3-carboxamides and (4R*,5R*)-4-aryl-2-pyrrolidone-5-carboxamides. The three-dimensional structures of these compounds were determined by X-ray diffraction analysis.

Целью исследования являлось изучение эндотелиопротективного действия ГАМК и ее нового производного — композиции МФБА, состоящей из гидрохлорида метил-4-амино-3-фенилбутаноата и гидрохлорида L-аргинина в соотношении 1:1, в условиях длительной гипергликемии. В качестве модели использовали крыс Вистар (12 мес) с 6-месячным стрептозотоцин-никотинамид-индуцированным сахарным диабетом. Проводили глюкозотолерантный тест и распределяли животных на группы, которым в течение 4 недель внутрь вводили ГАМК и композицию МФБА. Далее оценивали уровень гликемии, суточную протеинурию, функциональное состояние эндотелия: его вазодилатирующую, антитромботическую функцию, уровень фактора фон Виллибранда (vWF) и количество циркулирующих эндотелиальных клеток в крови. Методом ИФА в плазме крови определяли содержание ряда маркеров, в большей степени влияющих на развитие осложнений сахарного диабета (белок Клото, BDNF, Nrf2, ФНО-α и iNOS). Показано, что длительная гипергликемия приводила к формированию эндотелиальной дисфункции, которая проявлялась снижением эндотелийзависимой вазодилатации и антитромботической функции эндотелия, увеличением в крови циркулирующих эндотелиальных клеток и уровня vWF, а также суточной протеинурии. В плазме наблюдалось снижение содержания белка Клото, BDNF, Nrf2 и повышение содержания провоспалительных факторов ФНО-α и iNOS. Курсовое введение ГАМК и МФБА приводило к снижению гликемии и значительному улучшению вазодилатирующей и антитромботической функции эндотелия, повышению плазменного уровня белка Клото, нейротрофического фактора BDNF и транскрипционного фактора Nrf2, а также снижению ФНО-α и iNOS. По сравнению с ГАМК ее производное — композиция МФБА оказывала более выраженное действие в меньшей дозе (20 мг/кг в сравнении с 1000 мг/кг). Таким образом, производное ГАМК — композиция МФБА при длительной гипергликемии, помимо гипогликемического, оказывает выраженное эндотелиопротективное действие, улучшая вазодилатирующую и антитромботическую функции эндотелия и снижая содержание провоспалительных факторов ФНОα, iNOS и количество циркулирующих эндотелиальных клеток, что указывает на ее возможный высокий потенциал в качестве средства для профилактики сосудистых осложнений сахарного диабета.

Diastereohomogeneous triamides of 4-het(aryl)-2-pyrrolidone-3,5,5-tricarboxylic acids were synthesized by the ammonolysis reactions of the corresponding trimethyl 1-acetyl-4-aryl(hetaryl)-2-pyrrolidone-3,5,5-tricarboxylates. Structure of the synthesized compounds was studied by means of IR, 1H NMR, 13C {1H}, 1H–13C HMQC and 1H–13C HMBC spectroscopy methods.

We studied the effects of GABA derivatives on anxious and compulsive behavior of progeny of rats with experimental preeclampsia provoked by replacement of drinking water for 1.8% NaCl solution from the first day of pregnancy to delivery. In comparison with progeny of health rats, the offspring of dams with complicated pregnancy demonstrated high level of anxiety and the development of obsessive-compulsive disorder both at the early (40 and 70 days) and late (6 and 12 months) stages of ontogeny. GABA derivatives succicard, salifen, and phenibut reduced symptoms of experimental preeclampsia in offspring of various age by decreasing the level of anxiety and reducing compulsive behavior. The efficacy of the examined derivatives was similar to that of the reference drug Pantogam.

An HPLC method for quantitative determination of the new biologically active GABA derivative Solifen was developed. The method sensitivity, compound retention time and UV absorption maximum were determined. The optimum extractant for the compound from biological samples was determined.

2-[4-(Het)aryl-2-oxopyrrolidin-1-yl]acetohydrazides, structural analogs of piracetam, were synthesized by the condensation of 2-[4-(het)aryl-2-oxopyrrolidin-1-yl]acetates with hydrazine hydrate and phenylhydrazine. New [ N′ -alkyl(hetaryl)idene]-4-(het)aryl-2-oxopyrrolidin-1-ylacetohydrazides were synthesized by the reaction of 2-[4-(het)aryl-2-oxopyrrolidin-1-yl]-acetohydrazides with aromatic aldehydes, acetone, and acetophenone.

4-Het(aryl)-2-pyrrolidone-3(5)-carboxylic acid hydrazides react with aromatic aldehydes, acetone, and acetophenone to give new representatives of N´-alkyl(hetaryl)idenecarbohydrazides of (3R*,4S*)-4-het(aryl)-2-pyrrolidone-3- and (4R*,5R*)-4-het(aryl)-2-pyrrolidone-5-carboxylic acids.

Objectives The objective of this study was to investigate the effects of a new derivative of GABA, RGPU-207 compound, on the mitochondrial functions of stressed animals. Methods RGPU-207 and the comparator drugs (phenibut and piracetam) were administered intraperitoneally to unstressed and stressed male rats at a dose of 9.4, 25 and 400 mg/kg, respectively. The oxygen consumption by cardiac and cerebral mitochondria in state 3 and 4 and Chance's respiratory control ratio (RCR) was investigated. The concentration of lipid peroxidation products (LPO) such as malondialdehyde (MDA), conjugated dienes (CD) and diketones was evaluated in the isolated mitochondria, as well as the activity of the antioxidant system (AOS) enzymes (superoxide dismutase (SOD), glutathione peroxidase (GP) and catalase). Key findings A new cyclic GABA derivative, RGPU-207 compound, at the dose of 9.4 mg/kg promotes a decline in MDA, diketone and CD concentrations in mitochondria and increases the levels of SOD, GP and catalase activity. Mitochondrial functional activity increases: oxygen consumption by cerebral mitochondria in state 4 decreases when complex I of the respiratory chain is activated, while malate-dependent state 3 respiration of cardiac mitochondria tends to increase. RCR of cardiac mitochondria increases when complexes I and II are involved. In cerebral mitochondria, malate-dependent and succinate-dependent RCR rise. Conclusions Twenty-four-hour immobilization and pain stress activate LPO processes inhibit the activity of the aos enzymes and decrease the functional activity of cardiac and cerebral mitochondria. RGPU-207 restricts LPO, enhances the antioxidant enzyme activity and improves the mitochondrial respiration. The efficacy of RGPU-207 is comparable with phenibut and piracetam.

1-Alkoxycarbonylmethyl-4-heteryl-2-pyrrolidones were synthesized by alkylation of 4-heteryl-2-pyrrolidones. 2-(4-Heteryl-2-pyrrolidon-1-yl)acetamides were prepared through the reaction of N-esters with ammonia. The resulting acetamides of 2-pyrrolidones exhibit nootropic properties, antiarrhythmic and antiischemic activity.

OBJECTIVES: Both NO-ergic and GABA-ergic systems are known to modulate the nociceptive system. However, there is no data available describing the physiological role of slow sodium channels (Na(V)1.8) in antinociceptive response evoked by NO- and GABA-ergic system modulators. Our goal was to examine the central and peripheral analgesic effects possibly resulting from activation of NO-ergic and GABA-ergic signaling cascades in neurons. METHODS: Effects of two-component agent RSPU-260 comprised of methyl-4-amino-3-phenylbutanoate hydrochloride and L-arginine hydrochloride was investigated by patch-clamp, organotypic nerve tissue culture and behavioral (hot plate, tail flick, Randall-Selitto) techniques. RESULTS: Patch-clamp data indicate that only GABA-ergic system modulator, methyl-4amino-3-phenylbutanoate hydrochloride, can control the effective charge transfer in the activation gating system of Na(V)1.8 channels, inducing a weak effect at the spinal level. In vivo experiments demonstrate that both modulators (L-arginine and methyl-4-amino-3-phenylbutanoate hydrochloride) applied simultaneously at relatively low concentrations produce an effective analgesia at the spinal and supraspinal levels. CONCLUSIONS: It is demonstrated that RSPU-260 evokes significant analgesic effects at both spinal and supraspinal levels. GABA-ergic modulator, methyl-4-amino-3-phenylbutanoate hydrochloride, controls the effective charge transfer in the activation gating system of Na(V)1.8 channels responsible for nociceptive information coding. The second component of RSPU-260, L-arginine, is totally ineffective in respect to this target. A pronounced synergic effect at the spinal level can be achieved on the secondary sensory neuron in the dorsal horn whose synaptic membrane may be under NO-ergic system control. It is the unit where the nociceptive system can be additionally effectively regulated by NO- and GABA-ergic systems. At the supraspinal level, both NO- and GABA-ergic modulators activate their corresponding intracellular signaling cascades, thus resulting in a strong RSPU-260 analgesic effect.

Щелочным гидролизом 4-(индол-3-ил)-2-пирролидонов синтезирована серия индолсодержащих производных γ-аминомасляной кислоты (ГАМК). Их строение подтверждено методами ИК, ЯМР 1Н, 13С спектроскопии. Изучение фармакологических свойств 4-амино-3-индолилбутановых производных ГАМК показало, что они обладают нейропсихотропным эффектом, спектр которого зависит от структуры молекулы изучаемой кислоты. У 4-амино-3-(индол-3-ил)бутановой кислоты превалируют ноотропные свойства, а у 4-амино-3-(1-бензилиндол-3-ил)бутановой кислоты более выражена анксиолитическая активность.

A series of indole-containing γ-aminobutyric acids (GABA) were synthesized via alkaline hydrolysis of 4-(indol-3-yl)-2-pyrrolidones. Their structures were confirmed by IR, PMR, and 13C NMR spectroscopy. Studies of the pharmacological properties of 4-amino-3-indolylbutanoic acids (GABA derivatives) showed that they possessed neuropsychotropic activity, the spectrum of which depended on the acid molecular structure. Nootropic properties prevailed for 4-amino-3-(indol-3-yl)butanoic acid; anxiolytic activity, for 4-amino-3-(1-benzylindol-3-yl)butanoic acid.

Hydrolysis of 4-heteryl-3-methoxycarbonyl-2-pyrrolidones in an alkaline medium and subsequent decarboxylation of the resulting 2-pyrrolidine-3-carboxylic acids afforded 4-(pyrid-3-yl)- and 4-(1-methylbenzimidazol-2-yl)-2-pyrrolidones.