A new group of aminoalkyl dibenzofuranone oxime derivatives was designed and synthesized. Several compounds were found to exhibit anticonvulsant activity in the maximum electroshock test. The most active compound was 3,4,6,7,8,9-hexahydrodibenzo[b, d]furan-1(2H)-one O-[2-(diethylamino)ethyl]oxime oxalate (GIZh-347), which at a dose of 60 mg/kg (mice, i.p.) was as effective as valproic acid at a dose of 200 mg/kg.

Установлено, что новое производное оксима дибензофурана ГИЖ-272 (40 мг/кг) обладает отчетливой противосудорожной активностью на хронической модели парциальной (фокальной) эпилепсии, индуцированной кобальтом у крыс, ослабляя первично- и вторично-генерализованные очаги эпилептической активности как на этапе формирования, так и стабилизации эпилептической системы. Структурными мишенями действия ГИЖ-272 на этапе формирования эпилептической системы являются очаги в гиппокампе и гипоталамусе, а на стадии стабилизации — очаги в гиппокампе. ГИЖ-272 (10 мг/кг) обладает выраженным противоишемическим эффектом на модели интрацеребральной посттравматической гематомы, повышая выживание животных и ослабляя неврологический, моторный и когнитивный дефициты.

We studied the influence of intraperitoneal injection of ATP-sensitive potassium channels inhibitor glibenclamide in doses of 0.01, 0.1, 1, and 10 mg/kg on the effects of a new pyrazolo[C]pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1Hpyrazolo[ 4,3-C]pyridine-3-on, chloral hydrate; 20 mg/kg, intraperitoneally) in the marble burying and open-field tests in mice. It was found that glibenclamide produced an anxiolytic effect in the open-field test (in a dose of 0.01 mg/kg) and anticompulsive effect in the marble burying test (in doses of 1 and 10 mg/kg). The observed behavioral effects of glibenclamide did not depend on blood glucose level. At the same time, glibenclamide in subeffective (0.01 and 0.1 mg/kg) and effective (1 and 10 mg/kg) doses potentiated the psychotropic effects of GIZh-72 in these tests. It can be assumed that the psychotropic effects of GIZh-72 depend on functional activity of ATP-sensitive potassium channels.

It was shown that finasteride, a 5α-reductase inhibitor (50 mg/kg, intraperitoneally) produced analgesic and antiexudative effects in experimental peritonitis induced by intraperitoneal injection of 1% acetic acid. These results agree with published data on its anti-inflammatory properties and ability to potentiate the analgesic effect of morphine in rodents. New pyrazolo[C] pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]pyridine-3-on, chloral hydrate) injected intraperitoneally in doses of 20-80 mg/kg produced dose-dependent antiexudative effects, but exhibited no analgesic properties.

New dibenzofuranone-oxime derivatives were designed based on active structures of oxime esters. Compounds of the proposed group were synthesized using 3,4,6,7,8,9-hexahydrodibenzo[ b,d ]furan-1(2 H )-one oxime and aromatic acid chlorides. The anticonvulsant activity of the new compounds was studied. The structure— activity relationship was analyzed. Compound 1a [3,4,6,7,8,9-hexahydrodibenzo[ b,d ]furan-1(2 H )-one O -(3,4-dichlorobenzoyl)oxime] was the most active compound after i.p. injection to mice in the maximal electroshock test over a wide dose range of 20 – 100 mg/kg. Compound 1a at doses of 10 and 30 mg/kg exhibited antihypoxic activity in a hypoxia test with hypercapnia in a hermetic chamber and anti-ischemic activity at a dose of 10 mg/kg in a rat ischemic stroke model.

Ранее показано, что производное оксима дибензофурана ГИЖ-272 обладает выраженным противосудорожным свойством. Установлено, что соединение (10 мг/кг/7 дней введения) на модели глобальной ишемии мозга защищает животных от гибели и уменьшает выраженность неврологического дефицита, нарушений исследовательской активности животных в тесте Y-лабиринта. В дозе 60 мг/кг проявляет противогипоксические свойства на модели гемической гипоксии и вызывает существенное увеличение локального кровотока в коре большого мозга крыс, перенесших глобальную преходящую ишемию. По выраженности цереброваскулярного эффекта ГИЖ-272 не уступает мексидолу. Наличие противоишемической, противогипоксической и цереброваскулярной активности у потенциального противосудорожного препарата следует считать полезным свойством при разработке препарата для лечения эпилепсии, пароксизмальных состояний, а также для лечения неврологических и когнитивных нарушений.

New 4-phenylpyrrolidone derivatives were designed from racetam structures that combine nootropic and anticonvulsant activity. The proposed compounds were synthesized using 4-phenylpyrrolidone and aromatic amines. The anticonvulsant activity of the new compounds was studied. The structure–activity relationship was analyzed. The most active compound was the 2,6-dimethylanilide of (2-oxo-4-phenylpyrrolidin-1-yl)acetic acid at doses of 2.5 – 5.0 mg/kg, which surpassed the reference drug levetiracetam at doses of 2.5 – 600 mg/kg in all tests and possessed distinct nootropic activity that was comparable to that of the reference nootropic drug piracetam at a dose of 400 mg/kg.

We present here the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant action. The most active compound in the maximum electric shock test was 4-benzoylpyridine O-2-morpholinoethyloxime oxalate (1a), i.p. doses of 60 – 150 mg/kg of which increased the survival of mice to 100%. The best effect in the corasol antagonism test was obtained with 4-benzoylpyridine O-(isonicotinoyl)oxime (2c), i.p. doses of 12.5 mg/kg of which increased the survival of mice to 67% and the latent period of onset of generalized tonic-clonic convulsions to 52 sec. Compound 1a had low toxicity (the i.p. LD50 in mice was 316 mg/kg) and a therapeutic index of 21.

Objective of the research is to evaluate the anticonvulsant effect of the new original compound GIZH-298 (4-benzoylpyridine oxime derivative) versus valproic acid (VPA) in a model of epilepsy in rats with cobalt-induced lesions.Materials and methods. Modeling of epileptic status was performed using the technique of creating a chronic epileptogenic focus caused by the application of cobalt to the sensorimotor zone of the rat cortex, followed by intraperitoneal administration of homolecysteine thiolactone. Compounds GIZH-298 and VPA were introduced against the background of development of electrographic status with behavioral convulsive seizure manifestations.Results. The study revealed that GIZH-298 at a dose of 60 mg/kg (i. p.) in 50 minutes after injection reduces the number of high-amplitude generalized discharges caused by homocysteine thiolactone in the ipsilateral and contralateral cortex (46-fold decrease), in the hippocampus and hypothalamus (28-fold decrease); eliminates (in 100% of the animals) the generalized tonic-clonic seizures that arise in the advanced stage of status epilepticus. VPA at a dose of 100 mg/kg (i. p.) in 3 hours after injection significantly suppresses the EpA in all evaluated structures with the maximum value in the hypothalamus (28-fold decrease), and after 5 hours in the ipsilateral and contralateral (33-fold decrease). At the same time, VPA eliminates generalized motility of status epilepticus only in 71% of the animals and protects from death 86% of the rats.Conclusion. The compound GIZH-298 significantly earlier (for 2 hours) than the VPA (100 mg/kg) and at a lower dose (60 mg/kg) fully eliminates electrographic (in all evaluated brain structures with the greatest efficiency in the contralateral cortex and the hypothalamus) and behavioral manifestations of unfolded status epilepticus and prevents deaths in 100%.

The effects of the putative antiepileptic drug GIZh-298 and the reference standard topiramate on the concentrations of monoamines and their metabolites in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus of Wistar rats was investigated using HPLC. It was shown that topiramate at a dose of 100 mg/kg induces an increase in dopamine concentration and a decrease in its metabolism rate in the frontal cortex, a decrease in the level of its metabolites in the dorsal striatum, and an increase in concentrations of dopamine and its metabolites in the hypothalamus 30 minutes after injection. GIZh-298 at a dose of 60 mg/kg caused an increase in the serotonin and dopamine concentration in the frontal cortex and a decrease in the dopamine metabolism rate in the dorsal striatum 30 minutes after injection, which may be considered as one of the components of the antiepileptic effect of this drug.

На мышах и крысах изучено влияние 5 оригинальных производных 4-фенилпирролидона в тестах оценки противосудорожной и мнемотропной активности в сравнении с леветирацетамом и пирацетамом. В тестах максимального электрошока и антагонизма с коразолом соединение ГИЖ-290 ослабляло судороги и повышало выживаемость мышей, тогда как леветирацетам лишь увеличивал латентное время наступления клонического приступа в тесте антагонизма с коразолом. Противосудорожная активность ГИЖ-290 и леветирацетама отмечена в тесте литий-пилокарпиновых судорог на крысах, когда оба вещества увеличивали выживаемость животных, а также продолжительность латентного периода начала генерализованного приступа. ГИЖ-290 и пирацетам уменьшали время обнаружения платформы в водном лабиринте Морриса, тогда как леветирацетам был неэффективен в начальной стадии обучения. Все вещества способствовали облегчению воспроизведения навыка через 5 сут после обучения, увеличивая время пребывания мышей в секторе с платформой. Таким образом, соединение ГИЖ-290 характеризуется сочетанием противосудорожной и мнемотропной активности, существенно превосходя леветирацетам и пирацетам по уровню эффективных доз.

Novel derivative of benzoylpyridine oximes - GIZH-298 (4-benzoylpyridine 0-(2-morpholinoethyl) oxime oxalate) was designed and synthesized in this work. This compound has a broad spectrum of anticonvulsant effects, eliminating primary generalized seizures in maximal electroshock (MES) and corazol antagonism tests in rodents in the doses of 0,5-100 mg/kg. LD50 for compound GIZH-298 is 316 mg/kg intraperitoneally (mouse). GIZH-298 has a large therapeutic breadth.

Novel derivative of benzoylpyridine oximes - GIZH-298 (4-benzoylpyridine 0-(2-morpholinoethyl) oxime oxalate) was designed and synthesized in this work. This compound has a broad spectrum of anticonvulsant effects, eliminating primary generalized seizures in maximal electroshock (MES) and corazol antagonism tests in rodents in the doses of 0,5-100 mg/kg. LD 50 for compound GIZH-298 is 316 mg/kg intraperitoneally (mouse). GIZH-298 has a large therapeutic breadth.

Anticompulsive activity of a novel compound GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]Pyridine-3-on, chloral hydrate) in a dose of 20 mg/kg (single, subchronic, and chronic administration) in comparison with fluvoxamine (25 mg/kg) was studied in the marble burying test in the model of unpredictable chronic mild stress on BALB/c mice. GIZh-72 produced an anticompulsive effect that increased with increasing treatment duration under stress conditions in contrast to fluvoxamine that induced inversion of this effect after long-term administration. Neuroleptic activity of GIZh-72 in doses of 20 and 40 mg/kg was studied on the model of apomorphine-induced climbing in C57Bl/6 mice. In contrast to haloperidol (0.5 mg/kg), GIZh-72 exhibited no neuroleptic properties. Our results indicate that GIZh-72 holds much promise for pharmacotherapy of obsessive-compulsive disorder.

The aim of this study was to investigate the electrophysiological and neurochemical mechanisms of the anticonvulsant effect of a new original compound GIZH-298 and to define the leading structure as the target for influence compound. Materials and Methods. The partial (focal) and secondary generalized seizures were modeled by methods of creation a chronic epileptic focus that was caused by cobalt applique on the brain of rats. The liquid chromatography (HPLC) analysis used for neurochemical study of the effect GIZH-298. There was studied the effect on metabolism and quantity of biogenic amines in the brain structures of rats. Results. It was found that GIZH-298 at a dose of 60 mg / kg (i.p.) has a pronounced effect on the primary and especially secondary generalized epileptic foci in various brain structures with a primary influence on the cortex. GIZH-298 at a dose of 60 mg / kg caused a statistically significant increase in the content of serotonin and dopamine in the frontal cortex after 30 minutes after the administration and reduced the rate of metabolism of dopamine in the dorsal striatum. Conclusion. The anticonvulsant effect GIZH-298 is enhanced with increased of epileptic system, may be due to increased synthesis of serotonin and dopamine in the cortex, and decreased metabolism of the latter in the striatum.

It was studied the anxiolytic properties of 4,6-dimethyl-2-(4-chlorophenyl)-2,3-dihydro-1Í-pyrazolo[4,3-c]pyridin-3-one chloralhydrate (GIZh-72, 20 mg/kg, i.p.) and afobazole (1 mg/kg, i.p.) in comparison to fluoxetine (20 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) in open-field and marble burying tests on male mice of inbred strains BALB/C and C57BL/6. It is established that GIZh-72 administered both 30 min and 24 h before testing produces anxiolytic effect in the open-field test. The open field anxiety response patterns following GIZh-72 administration differed from these in diazepam or afobazole treated BALB/C mice. This drug also decreased the number of buried marbles in both BALB/C and C57BL/6 mice, the effect being comparable to that of afobazole and fluoxetine. In operant drug discrimination liquid-reinforcement paradigm in male Wistar rats, GIZh-72 failed to antagonize or substitute for the interoceptive stimulus cues of pentylenetetrazole evoking the saline-like responses in the latter case, which was evidence for the absence of properties of a ligand bearing positive modulator sites of GABA-A receptor.

A new potential neuroleptic drug dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) has been created. This paper describes a 4-step scalable method of dilept synthesis, which provides a nonracemized product with 52% yield. The process includes caproic acid synthesis using thionyl chloride, acylation of proline by the obtained chloroanhydride under Schotten – Baumann reaction conditions, etherification of L-tyrosine in methyl alcohol in the presence of thionyl chloride, and synthesis of N-caproyl-L-prolyl-L-tyrosine methyl ester by the method of mixed anhydrides using isobutyl chloroformate in DMF. The active metabolite of dilept (N-caproyl-L-prolyl-L-tyrosine) has been also synthesized and characterized by physicochemical methods.

The new potential neuroleptic drug dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) was created. A four-step scalable synthetic method for dilept that enabled the product to be obtained in 52% yield without racemization was presented. The process included preparation of caproic acid chloride using thionylchloride, Schotten–Baumann acylation of L-proline by the obtained acid chloride, esterification of L-tyrosine in MeOH in the presence of thionylchloride, and synthesis of the methyl ester of N-caproyl-L-prolyl-L-tyrosine by the mixed anhydride method using isobutylchloroformate in DMF. The active metabolite of dilept (N-caproyl-L-prolyl-L-tyrosine) was synthesized and characterized by physicochemical methods.