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Information × Registration Number 0220U000125, 0118U005323 , R & D reports Title Development of prototypes of antiepileptic drugs - modulators of the brainstem of the brain. popup.stage_title Head Maximyuk Oleksandr Petrovych, Registration Date 16-01-2020 Organization Bogomolets Institute of Physiology, National Academy of Sciences of Ukraine popup.description2 A study has been conducted on the optimization of conformationally controlled heterocyclic orthoamino ketones as potential modulators of GABA receptors. Object of study: modulators of GABA channels as potential means of influencing the pathological synchronization of neural networks of the brain, which underlie epileptic seizures of different etiology. Objective: To create and conduct a series of preclinical studies of a series of novel chemical compounds that can be used to develop innovative next-generation antiepileptic pharmacological agents. A set of in silico tools, namely, stacking and molecular dynamics, together with ab initio heterocyclic orthoamino ketones in aqueous solution and during binding to the GABA receptor were used to evaluate the conformational profile. Methods for the synthesis of new organic compounds from the class of heterocyclic orthoamino ketones - potential modulators of GABA receptor - have been developed. Using the electrophysiological method of measurement, 25 compounds were investigated and 15 active chemotypes were identified. The remaining compounds showed no activity at a concentration of 100 µM. All active molecules showed no signs of cytotoxic action on neurons, brain sections of rats at a concentration of 100 µМ, and intracranial injection into the ventricles of the experimental animals (injection of 3 µl of 100 µМ solution of compounds). The anti-epileptic potential of the most active substances was investigated. The results of the solubility test indicate moderate (4 compounds) or very good (4 compounds) solubility. Chemical optimization of the active compounds of heterocyclic orthoamino ketones was performed. The synthesized compounds were characterized by chromatomospectrometry and NMR spectroscopy, partially elemental analysis, and determined to be 98% pure. In total, 70 chemical compounds were synthesized and resynthesized. The anti-epileptic potential of the most active substances in vivo in a kainate epilepsy model has been investigated. The application of kainic acid to the CA1 area of the hippocampus caused electrographic, epileptic activity in rats. The introduction of Z37377-3554 in the hippocampus of the animal did not reduce the amplitude and frequency of the electrographic correlates of epileptic activity. The introduction of substances Z76305-5070, Z5798-5362, Z76305-5064 led to a significant decrease in the amplitude and frequency of the electrographic correlates of epileptic activity. Z76305-5064 exhibited the highest activity in the results of all tests. Laboratory regulations for obtaining and acts on the manufacture of test batches of candidate compounds for medicinal products have been drawn up. The results of preclinical studies of 3 compounds (Z76305-5070, Z5798-5362, Z76305-5064) indicate that this class of chemicals is promising for the development of the latest anti-epileptic drugs. Product Description popup.authors Єгорова Олена Володимирівна Ісаєв Дмитро Сергійович Кришталь Олег Олександрович Хмиз Володимир Васильович Чернінський Андрій Олександрович popup.nrat_date 2020-04-02 Close