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Registration Number

0224U002872, 0120U100179 , R & D reports

Title

Chiral neurotropic compounds, ligands of CNS receptors. Synthesis, Structure, Structure-Property Relationship

Head

Krysko Andrii A., Кандидат хімічних наук

Registration Date

07-03-2024

Organization

Physico-Chemical Institute O. Bogatsky National Academy of Sciences of Ukraine

Description

 The purpose of the research: Establishing the pharmacological properties of the obtained compounds and screening according to the affinity of benzodiazepine receptors of the central nervous system. Synthesis of chiral 3-alkyl-3-alkoxy derivatives of 1,4-benzdiazepin-2-one. Screening studies of individual S- and R-enantiomers of 3-methyl derivatives of 7-nitro-substituted 1,4-benzdiazepines and 7-bromo-5-(2,4-dichlorophenyl)-3-methyl-1,4-benzdiazepine were carried out in mice in the "open field", corazol-induced seizure and "rotating trident" tests. (3R)-7-bromo-5-(2,4-dichlorophenyl)-3-methyl-1,4-benzdiazepine exhibits anxiolytic properties in the dose range of 4-12.7 μmol/kg. 3-(S)-7-bromo-5-(2,4-dichlorophenyl)-3-methyl-1,4-benzdiazepine at a dose of 4 μmol/kg causes an increase in the time spent by experimental animals in the central zone, which indicates the manifestation of significant anxiolytic properties of the compound. (3S)-5-(2-chlorophenyl)-3-methyl-7-nitro- and (3S)-7-bromo-5-(2,4-dichlorophenyl)-3-methyl-1,4-benzdiazepine were not detected anticonvulsant properties in antagonism tests with corazol. (3R)-3-methyl-7-nitro-5-phenyl-1,4-benzdiazepin-2-one showed moderate anticonvulsant activity. The most active were (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 and phenazepam. In the "rotating rod" test, the compounds mostly showed a moderate muscle relaxant effect at doses of 4-40 μmol/kg. Only (3S)-3-methyl-7-nitro-5-phenyl-1,4-benzdiazepin-2-one exhibits a pronounced myorelaxant effect; in the tested dose range, the compound causes 100% of the effect. A low level of 3-alkyl-3-alkoxy derivatives of 1,4-benzdiazepin-2-one was synthesized. The affinity of individual S- and R-enantiomers of 3-methyl derivatives of 1,4-benzdiazepin-2-one to central benzodiazepine receptors was established by radioligand analysis.

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Illyushko Nataliia О.
Bachinsky Serhii Yu.
Burenkova Nataliia O.
Holovenko Mykola Ya.
Kornilov Oleksandr Yu.
Krysko Andrii A.
Krysko Olha L.
Larionov Vitalii B.
Tsapenko Zhanna М.