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

Published online by Cambridge University Press:  13 August 2021

T. Shushpanova ,
N. Bokhan ,
K. Stankevich ,
T. Novozheeva ,
O. Shushpanova ,
V. Udut ,
N. Garganeeva ,
E. Markova ,
E. Knyazeva  and
S. Safronov
...Show all authors
T. Shushpanova*
Affiliation:
The Department Of Addictive States, Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation
N. Bokhan
Affiliation:
The Department Of Addictive States, Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation Department Of Psychiatry, Narcology And Psychotherapy, Siberian State Medical University, Tomsk, Russian Federation
K. Stankevich
Affiliation:
Institute Of Physics Of High Technologies, National Research Tomsk Polytechnic University, Tomsk, Russian Federation
T. Novozheeva
Affiliation:
Neurobiology, Mental Health Research Institute Tomsk National Research Medical Center Russia Academy of Science, Tomsk, Russian Federation
O. Shushpanova
Affiliation:
Child Psychiatry, Mental Health Scientific Center, Moscow, Russian Federation
V. Udut
Affiliation:
Pathophysiology And Pharmacology,Scientific Research Institute of Pharmacology and Regenerative Medicine named after E. D. Goldberg “Tomsk National Research Medical Center of the Russian Academy of Sciences”, Tomsk, Russian Federation
N. Garganeeva
Affiliation:
Department Of Outpatient Therapy, Siberian State Medical University, Tomsk, Russian Federation
E. Markova
Affiliation:
Neuroimmunology Lab, State Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russian Federation
E. Knyazeva
Affiliation:
Institute Of Physics Of High Technologies, National Research Tomsk Polytechnic University, Tomsk, Russian Federation
S. Safronov
Affiliation:
Pathophysiology And Pharmacology,Scientific Research Institute of Pharmacology and Regenerative Medicine named after E. D. Goldberg “Tomsk National Research Medical Center of the Russian Academy of Sciences”, Tomsk, Russian Federation
R. Boev
Affiliation:
Pathophysiology And Pharmacology,Scientific Research Institute of Pharmacology and Regenerative Medicine named after E. D. Goldberg “Tomsk National Research Medical Center of the Russian Academy of Sciences”, Tomsk, Russian Federation
A. Solonskii
Affiliation:
Neurobiology, Mental Health Research Institute Tomsk National Research Medical Center Russia Academy of Science, Tomsk, Russian Federation
*
*Corresponding author.

Abstract

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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.

Keywords

anticonvulsantcytochromereceptorhomeostasisneuromorphology
Type
Abstract
Information
European Psychiatry , Volume 64 , Special Issue S1: Abstracts of the 29th European Congress of Psychiatry , April 2021 , pp. S777 - S778
Creative Commons
Creative Common License - CCCreative Common License - BY
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.
Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of the European Psychiatric Association
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