Combined In Silico, Ex Vivo, and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro- and Cardioprotective and Antidepressant Effects.

Autor: Sarapultsev A; Institute of Immunology and Physiology of the Ural Branch of RAS, Pervomayskaya 106, 620049 Ekaterinburg, Russia.; School of Medical Biology, South Ural State University, Lenina 76, 454080 Chelyabinsk, Russia., Vassiliev P; Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Square 1, 400131 Volgograd, Russia., Grinchii D; Center of Biosciences, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravská Cesta 9, 840 05 Bratislava, Slovakia., Kiss A; Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Dúbravská Cesta 9, 845 05 Bratislava, Slovakia., Mach M; Center of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská Cesta 9, 840 04 Bratislava, Slovakia., Osacka J; Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Dúbravská Cesta 9, 845 05 Bratislava, Slovakia., Balloova A; Center of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská Cesta 9, 840 04 Bratislava, Slovakia., Paliokha R; Center of Biosciences, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravská Cesta 9, 840 05 Bratislava, Slovakia., Kochetkov A; Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Square 1, 400131 Volgograd, Russia., Sidorova L; Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira Street, 620002 Ekaterinburg, Russia., Sarapultsev P; Institute of Immunology and Physiology of the Ural Branch of RAS, Pervomayskaya 106, 620049 Ekaterinburg, Russia., Chupakhin O; Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira Street, 620002 Ekaterinburg, Russia.; The IJ Postovsky Institute of Organic Synthesis of the Ural Branch of RAS, Akademicheskaya/S. Kovalevskoi, 22/20, 620990 Ekaterinburg, Russia., Rantsev M; Ural State Medical University, Repina 3, 620014 Ekaterinburg, Russia., Spasov A; Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Square 1, 400131 Volgograd, Russia., Dremencov E; Center of Biosciences, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravská Cesta 9, 840 05 Bratislava, Slovakia.; Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Dúbravská Cesta 9, 845 05 Bratislava, Slovakia.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Dec 20; Vol. 22 (24). Date of Electronic Publication: 2021 Dec 20.
DOI: 10.3390/ijms222413626
Abstrakt: Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c- Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT 3 and 5-HT 1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT 3 and 5-HT 1A receptors, respectively. L-17 robustly increased c- Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT 1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT 3 and 5-HT 1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs.
Databáze: MEDLINE
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