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

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Abstract

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(1H)-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.

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Funding

The synthetic part of the work was carried out with the financial support of the Ministry of Science and Higher Education of the Russian Federation within the framework of the project part of the state assignment (no. 0778-2020-0005).

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Authors and Affiliations

  1. Samara State Technical University, 443100, Samara, Russia

    Yu. N. Klimochkin, I. M. Tkachenko, A. N. Reznikov, V. A. Shiryaev & M. S. Kazachkova

  2. Volgograd State Medical University, Ministry of Health of the Russian Federation, 400131, Volgograd, Russia

    N. S. Kovalev, D. A. Bakulin, E. E. Abrosimova, D. V. Kurkin & I. N. Tyurenkov

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  1. Yu. N. Klimochkin
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  2. I. M. Tkachenko
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  3. A. N. Reznikov
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  4. V. A. Shiryaev
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  5. M. S. Kazachkova
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  6. N. S. Kovalev
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  8. E. E. Abrosimova
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  10. I. N. Tyurenkov
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Corresponding author

Correspondence to D. A. Bakulin.

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COMPLIANCE WITH ETHICAL STANDARDS

Statement on the welfare of animals. All studies were carried out in accordance with the Eurasian Economic Union legislation and technical standards for good laboratory practice (GOST (State Standards) 53434-2019 and D 51000.4-2011, Directive 2010/63/ of the European Parliament and Council of the European Union, and the interstate standard (GOST (State Standard) 33044-2014)). The study protocol was approved by the local ethics committee (Regional Research Ethics Committee of the Volgograd oblast, no. 2010–2019 dated April 2, 2019).

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The authors declare that they have no conflict of interest.

Additional information

Translated by G. Levit

  Abbreviations: BBB, blood–brain barrier; CNS, central nervous system; EET, extrapolation escape test; EPM, Elevated plus maze; GABA, gamma-aminobutyric acid; PAT, Passive avoidance test; XRD, X-ray diffraction analysis; ANR-10, 4-(adamantan-1-yl)pyrrolidin-2-one; IE-1, 1-(3-hydroxyadamantan-1-yl)-pyrrolidin-2-one; TIM-1, (3aS*,10aS*)-decahydro-4,8:6,10-dimethanocyclononane[b]pyrrol-2(1H)-one; TIM-2, 1-(adamantan-1-yl)pyrrolidin-2-one.

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Klimochkin, Y.N., Tkachenko, I.M., Reznikov, A.N. et al. Synthesis and Evaluation of the Psychotropic Activity of Framework Derivatives of Alpha-Pyrrolidone. Russ J Bioorg Chem 47, 1276–1287 (2021). https://doi.org/10.1134/S1068162021060108

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