Cargando…

An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties

INTRODUCTION: The development of original drugs - new generation GABAA receptor modulators (GABAAR), with an anti-alcohol orientation, non-addictive and stimulating detoxification processes, makes it possible to increase the effectiveness of therapy and reduce the cost of treatment. OBJECTIVES: Stud...

Descripción completa

Detalles Bibliográficos
Autores principales: Shushpanova, T., Bokhan, N., Stankevich, K., Novozheeva, T., Shushpanova, O., Udut, V., Garganeeva, N., Markova, E., Knyazeva, E., Safronov, S., Boev, R., Solonskii, A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9480363/
http://dx.doi.org/10.1192/j.eurpsy.2021.2057
_version_ 1784791037535846400
author Shushpanova, T.
Bokhan, N.
Stankevich, K.
Novozheeva, T.
Shushpanova, O.
Udut, V.
Garganeeva, N.
Markova, E.
Knyazeva, E.
Safronov, S.
Boev, R.
Solonskii, A.
author_facet Shushpanova, T.
Bokhan, N.
Stankevich, K.
Novozheeva, T.
Shushpanova, O.
Udut, V.
Garganeeva, N.
Markova, E.
Knyazeva, E.
Safronov, S.
Boev, R.
Solonskii, A.
author_sort Shushpanova, T.
collection PubMed
description INTRODUCTION: The development of original drugs - new generation GABAA receptor modulators (GABAAR), with an anti-alcohol orientation, non-addictive and stimulating detoxification processes, makes it possible to increase the effectiveness of therapy and reduce the cost of treatment. OBJECTIVES: Study the mechanism of interaction between m-Cl-BHU and GABAA - receptor METHODS: Molecular docking was performed to study the molecular docking of m-Cl-BHU with at the binding site of the target protein GABAAR.Radioreceptor studies were carried out using [3H] flunitrazepam binding with synaptosomal receptors in the cerebral cortex of Wistar rats in experimental alcoholism under the influence of therapy with m-CL-BHU. Kinetic parameters (T1/2, Clt, MRT, MET, AUC) of a model substrate - antipyrine were determined in the saliva of healthy volunteers and alcoholic patients. RESULTS: IResults of molecular docking (Schrödinger program (Glide) showed: m-CL-BHU (meta-chlorobenzhydryl urea) is complementary to the benzodiazepine GABAAR. Binding energy is low) (scoring (GScore) -11.14 kKal/mol); m-CL-BHU interacts with key amino acids at the α1γ2 interface: Tyr159, Tyr209, H101 Phe77 and is characterized by a high degree of model fit - dG insert: 0.741 Binding of [3H] flunitrazepam to the benzodiazepine site of GABAAR in rat brain in experimental alcoholism, who received 14 days of m-CL-BHU at 100 mg/kg /day, increased in receptor affinity. Changes in the kinetic parameters (T1/2, Clt, MRT, MET, AUC) of a model substrate - antipyrine in the saliva of healthy volunteers and alcoholic patients using Galodif (m-CL-BHU) at 300 mg/day 21 days CONCLUSIONS: m-CL-BHU - GABAA receptor modulator with an alternative mechanism of action DISCLOSURE: No significant relationships.
format Online
Article
Text
id pubmed-9480363
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Cambridge University Press
record_format MEDLINE/PubMed
spelling pubmed-94803632022-09-29 An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties Shushpanova, T. Bokhan, N. Stankevich, K. Novozheeva, T. Shushpanova, O. Udut, V. Garganeeva, N. Markova, E. Knyazeva, E. Safronov, S. Boev, R. Solonskii, A. Eur Psychiatry Abstract INTRODUCTION: The development of original drugs - new generation GABAA receptor modulators (GABAAR), with an anti-alcohol orientation, non-addictive and stimulating detoxification processes, makes it possible to increase the effectiveness of therapy and reduce the cost of treatment. OBJECTIVES: Study the mechanism of interaction between m-Cl-BHU and GABAA - receptor METHODS: Molecular docking was performed to study the molecular docking of m-Cl-BHU with at the binding site of the target protein GABAAR.Radioreceptor studies were carried out using [3H] flunitrazepam binding with synaptosomal receptors in the cerebral cortex of Wistar rats in experimental alcoholism under the influence of therapy with m-CL-BHU. Kinetic parameters (T1/2, Clt, MRT, MET, AUC) of a model substrate - antipyrine were determined in the saliva of healthy volunteers and alcoholic patients. RESULTS: IResults of molecular docking (Schrödinger program (Glide) showed: m-CL-BHU (meta-chlorobenzhydryl urea) is complementary to the benzodiazepine GABAAR. Binding energy is low) (scoring (GScore) -11.14 kKal/mol); m-CL-BHU interacts with key amino acids at the α1γ2 interface: Tyr159, Tyr209, H101 Phe77 and is characterized by a high degree of model fit - dG insert: 0.741 Binding of [3H] flunitrazepam to the benzodiazepine site of GABAAR in rat brain in experimental alcoholism, who received 14 days of m-CL-BHU at 100 mg/kg /day, increased in receptor affinity. Changes in the kinetic parameters (T1/2, Clt, MRT, MET, AUC) of a model substrate - antipyrine in the saliva of healthy volunteers and alcoholic patients using Galodif (m-CL-BHU) at 300 mg/day 21 days CONCLUSIONS: m-CL-BHU - GABAA receptor modulator with an alternative mechanism of action DISCLOSURE: No significant relationships. Cambridge University Press 2021-08-13 /pmc/articles/PMC9480363/ http://dx.doi.org/10.1192/j.eurpsy.2021.2057 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Abstract
Shushpanova, T.
Bokhan, N.
Stankevich, K.
Novozheeva, T.
Shushpanova, O.
Udut, V.
Garganeeva, N.
Markova, E.
Knyazeva, E.
Safronov, S.
Boev, R.
Solonskii, A.
An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties
title An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties
title_full An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties
title_fullStr An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties
title_full_unstemmed An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties
title_short An innovative anticonvulsant - a GABAA receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties
title_sort innovative anticonvulsant - a gabaa receptor modulator with an alternative mechanism of action and enzyme-inducing detoxifying properties
topic Abstract
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9480363/
http://dx.doi.org/10.1192/j.eurpsy.2021.2057
work_keys_str_mv AT shushpanovat aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT bokhann aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT stankevichk aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT novozheevat aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT shushpanovao aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT udutv aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT garganeevan aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT markovae aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT knyazevae aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT safronovs aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT boevr aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT solonskiia aninnovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT shushpanovat innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT bokhann innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT stankevichk innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT novozheevat innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT shushpanovao innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT udutv innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT garganeevan innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT markovae innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT knyazevae innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT safronovs innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT boevr innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties
AT solonskiia innovativeanticonvulsantagabaareceptormodulatorwithanalternativemechanismofactionandenzymeinducingdetoxifyingproperties