Registration Number
0225U000241,
(0120U100179)
, R & D reports
Title
Chiral neurotropic compounds, ligands of CNS receptors. Synthesis, Structure, Structure-Property Relationship
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Пошук можливостей синтезу нових оптично активних похідних 1,4-бенздіазепіну або 1,5-бензодіазоцину та арилпіперазинів. Вивчення афінітету отриманих похідних до відповідних рецепторів та встановлення фармакологічних властивостей. SAR аналіз зв’язку між структурою, афінітетом до відповідних рецепторів і фармакологічними властивостями лігандів рецепторів ЦНС. Встановлення структурних параметрів, які визначають фізіологічну активність потенційних лігандів рецепторів ЦНС.
Head
Krysko Andrii A., Кандидат хімічних наук
Registration Date
07-01-2025
Organization
Physico-Chemical Institute O. Bogatsky National Academy of Sciences of Ukraine
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Synthesis of new chiral benzodiazepine and serotonin ligands of CNS receptors. Establishment of dependence of ligand-receptor interaction, pharmacological properties on the structure and configuration of the optical center.
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The purpose of the research: Synthesis of new chiral ligands of benzodiazepine and serotonin receptors of the CNS. Establishment of the dependence of ligand-receptor interaction, pharmacological properties on the structure and configuration of the optical center.
A method for obtaining optically active 3-alkyl-substituted 1,4-benzdiazepin-2-ones based on the condensation of 2-aminobenzophenones from chloranhydrides of L- or D-α-amino acids is proposed. The advantages of the above method in comparison with the N-carboxyanhydride method are shown. Chiral derivatives of 1,4-benzdiazepine containing a carboxyl, ester or amide group are synthesized. Lower 3-alkyl-3-alkoxy derivatives of 1,4-benzdiazepin-2-one are synthesized. The affinity of S- and R-enantiomers of 3-methyl derivatives of 1,4-benzdiazepin-2-one for CBD was established by radioligand analysis. Starting from Phenibut, a pair of optical isomers of 4-phenylpyrrolidin-2-one were synthesized in three stages, which were used as building blocks for obtaining 5-HT1A-R ligands. L- or D-pyroglutamic acids were also used as other terminal "amide" fragments. Screening studies (anticonvulsant, anxiolytic and muscle relaxant properties) of optically active 3-alkyl-substituted 1,4-benzdiazepin-2-ones were conducted in mice. In the “open field” test, the greatest anxiolytic effect was demonstrated by the compounds R-3-methyl-7-chloro-, S-3-methyl-7-chloro-5-(o-chlorophenyl)-, and R-3-methyl-7-bromo-5-(o-fluorophenyl)-1,4-benzdiazepines. The greatest anticonvulsant activity was demonstrated by (3S)-3-methyl-7-nitro-5-phenyl-1,4-benzdiazepin-2-one and (3R)-5-(2-chlorophenyl)-3-methyl-7-nitro-1,4-benzdiazepin-2-one. The latter compounds showed activity greater than that of clonazepam (19 μmol/kg) and phenazepam (106 μmol/kg). In the "rotating rod" test, (3S)-3-methyl-7-nitro-5-phenyl-1,4-benzdiazepin-2-one exhibited a pronounced muscle relaxant effect; in the studied dose range (4-40 μmol/kg).
Product Description
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Illiushko Nataliia О.
Bachynskyi Serhii Yu.
Burenkova Nataliia O.
Нolovenko Mykola Ya.
Kornilov Oleksandr Yu.
Krysko Andrii А.
Larionov Vitalii B.
Tsapenko Zhanna М.
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2025-01-07
