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Tytuł:
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Searching for new anxiolytic agents among derivatives of 11-dialkylaminoethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazole.
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Autorzy:
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Maltsev DV; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia; Volgograd Medical Research Center; 1 Pavshikh Bortsov sq., Volgograd, Russia. Electronic address: .
Spasov AA; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia; Volgograd Medical Research Center; 1 Pavshikh Bortsov sq., Volgograd, Russia.
Yakovlev DS; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia; Volgograd Medical Research Center; 1 Pavshikh Bortsov sq., Volgograd, Russia.
Vassiliev PM; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia.
Skripka MO; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia.
Miroshnikov MV; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia.
Sultanova KT; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia; Volgograd Medical Research Center; 1 Pavshikh Bortsov sq., Volgograd, Russia.
Kochetkov AN; Volgograd State Medical University, Department of Pharmacology and Bioinformatics; 1 Pavshikh Bortsov sq., Volgograd, Russia.
Divaeva LN; Southern Federal University, Research Institute of Physical and Organic Chemistry; 105/42 Bolshaya Sadovaya str., Rostov-on-Don, Russia.
Kuzmenko TA; Southern Federal University, Research Institute of Physical and Organic Chemistry; 105/42 Bolshaya Sadovaya str., Rostov-on-Don, Russia.
Morkovnik AS; Southern Federal University, Research Institute of Physical and Organic Chemistry; 105/42 Bolshaya Sadovaya str., Rostov-on-Don, Russia.
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Źródło:
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European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2021 Jun 01; Vol. 161, pp. 105792. Date of Electronic Publication: 2021 Mar 08.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Amsterdam : Elsevier Science B.V
Original Publication: Amsterdam ; New York : Elsevier, c1993-
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MeSH Terms:
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Anti-Anxiety Agents*/pharmacology
Animals ; Behavior, Animal ; Benzimidazoles ; Diazepam/pharmacology ; Maze Learning ; Receptors, GABA-A
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Contributed Indexing:
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Keywords: DAB-21; HepG2 cell line; anxiolytic; diazepino[1,2-a]benzimidazole; neuropsychotropic activity; privileged scaffolds
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Substance Nomenclature:
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0 (Anti-Anxiety Agents)
0 (Benzimidazoles)
0 (Receptors, GABA-A)
E24GX49LD8 (benzimidazole)
Q3JTX2Q7TU (Diazepam)
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Entry Date(s):
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Date Created: 20210311 Date Completed: 20210621 Latest Revision: 20210621
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Update Code:
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20240104
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DOI:
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10.1016/j.ejps.2021.105792
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PMID:
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33705965
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A study on the anxiolytic activity of the new derivatives of 11-dialkylaminoethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazole, containing privileged scaffolds of benzodiazepine and benzimidazole in their structure, was conducted. The cytotoxic properties of low levels of six compounds were preliminary determined in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. The screening of these substances for anxiolytic activity was conducted using elevated plus maze (EPM) test in vivo, and DAB-21 was found to be the most active compound. The acute toxicity of DAB-21 was determined as less toxic than that of diazepam. The dose-dependent effect of the most active compound revealed a minimum dose of 1.26 mg/kg, which resulted in the maximum counterphobic effect. The effect of DAB-21 was superior in a number of tests compared with that of diazepam, which indicated a high level of tranquilizing activity for DAB-21. The results of in silico docking analysis suggest that DAB-21 should have a slightly lower anxiolytic activity than diazepam, but should exhibit greater specific affinity for the benzodiazepine site of the GABA A receptor, in comparison with its GABA-binding site. The interaction between DAB-21 and flumazenil in terms of EPM verifies the GABAergic mechanism of action of DAB-21. Our results highlight the potential of 11-dialkylaminomethyl-2,3,4,5-tetrahydrodiazepino[1,2-a]benzimidazoles as promising compounds in the search for new highly effective anxiolytics.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
