Synthesis and Evaluation of the Psychotropic Activity of Framework Derivatives of Alpha-Pyrrolidone

Derivatives of alpha-pyrrolidone and some derivatives of adamantane possess a wide spectrum of psychotropic activity. The synthesis of adamantane and homoadamantane derivatives of alpha-pyrrolidone and the assessment of their psychotropic activity were performed. A number of framework compounds cont...

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Published in:Russian journal of bioorganic chemistry 2021-11, Vol.47 (6), p.1276-1287
Main Authors: Klimochkin, Yu. N., Tkachenko, I. M., Reznikov, A. N., Shiryaev, V. A., Kazachkova, M. S., Kovalev, N. S., Bakulin, D. A., Abrosimova, E. E., Kurkin, D. V., Tyurenkov, I. N.
Format: Article
Language:English
Subjects:
Acetic acid
Antidepressants
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Chemical synthesis
Evaluation
Life Sciences
Molecular docking
Organic Chemistry
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Summary:Derivatives of alpha-pyrrolidone and some derivatives of adamantane possess a wide spectrum of psychotropic activity. The synthesis of adamantane and homoadamantane derivatives of alpha-pyrrolidone and the assessment of their psychotropic activity were performed. A number of framework compounds containing a pyrrolidin-2-one fragment either in the side chain or as part of the framework system were synthesized. N -(Adamantan-1-yl)pyrrolidin-2-one (TIM-2) was obtained by the reaction of 1-bromadamantane with pyrrolidin-2-one. Homoadamantane-fused pyrrolidin-2-one (TIM-1) was obtained from β-dicarbonyl derivatives of homoadamantane. Synthesis of the starting 2-(5-oxohomoadamantyl)acetic acid was carried out by cleavage of the corresponding keto diester or cyanoketo ester of homoadamantane under the conditions of the Holler–Bauer reaction with sonication. Then, the resulting γ-keto acid was introduced into the Leuckart–Wallach reaction to obtain cis -decahydro-4,8:6,10-dimethanocyclononane[ b ]pyrrol-2(1 H )-one (TIM-1). The psychotropic activity of the obtained compounds was evaluated in standard behavioral tests in experimental animals. Compound TIM-2 exhibited pronounced anxiolytic, antidepressant, and nootropic activity. Compound binding assays were performed by molecular docking of the synthesized compounds to the GABA-B receptor, which also showed high binding energies for TIM-2.
ISSN:1068-1620
1608-330X
DOI:10.1134/S1068162021060108