Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Combined in silico, ex vivo, and in vivo Assessment of L-17, a Thiadiazine Derivative With Putative Neuroprotective and Antidepressant-Like Effects

Alexey Sarapultsev
ORCID logo ,
Pavel Vassiliev
,
Daniil Grinchii
,
Alexander Kiss
,
Mojmír Mach
ORCID logo ,
Jana Osacká
,
Alexandra Balloova
,
Ruslan Paliokha
,
Andrey N. Kochetkov
,
Larisa Sidorova
,
Petr Sarapultsev
,
Oleg Chupakhin
,
Maxim Rantsev
,
Pavel Vassiliev
ORCID logo ,
Eliyahu Dremencov
* ORCID logo
Version 1 : Received: 25 October 2021 / Approved: 26 October 2021 / Online: 26 October 2021 (12:32:43 CEST)

A peer-reviewed article of this Preprint also exists.

Sarapultsev, A.; Vassiliev, P.; Grinchii, D.; Kiss, A.; Mach, M.; Osacka, J.; Balloova, A.; Paliokha, R.; Kochetkov, A.; Sidorova, L.; Sarapultsev, P.; Chupakhin, O.; Rantsev, M.; Spasov, A.; Dremencov, E. Combined In Silico, Ex Vivo, and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro- and Cardioprotective and Antidepressant Effects. Int. J. Mol. Sci. 2021, 22, 13626. Sarapultsev, A.; Vassiliev, P.; Grinchii, D.; Kiss, A.; Mach, M.; Osacka, J.; Balloova, A.; Paliokha, R.; Kochetkov, A.; Sidorova, L.; Sarapultsev, P.; Chupakhin, O.; Rantsev, M.; Spasov, A.; Dremencov, E. Combined In Silico, Ex Vivo, and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro- and Cardioprotective and Antidepressant Effects. Int. J. Mol. Sci. 2021, 22, 13626.

Abstract

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico, ex vivo, and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) receptors are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. Acute pre-treatment with L-17 robustly increased c-Fos immunoreactivity in the amygdala (central nucleus), suggesting increased neuronal excitability in this brain area after L-17 administration. Acute L-17 also dose-dependently inhibited of 5-HT neurons of the dorsal raphe nucleus (DRN). This inhibition was partially reversed by subsequent administration of WAY100135, suggesting the involvement of extracellular 5-HT. Based on in silico predictions, c-Fos immunohistochemistry, and in vivo electrophysiology, we suggest that L-17 is a potent 5-HT reuptake inhibitor and/or partial 5-HT1A receptor antagonist. Thus, L-17 might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardio-protective properties, it can be useful in post-stroke and post-myocardial infarction (MI) depression. In general, combined in silico predictions and ex vivo neurochemical and in vivo electrophysiological assessment might be a useful strategy for early preclinical assessment of the affectivity and neural mechanism in action of the novel CNS drugs.

Keywords

thiadizines; serotonin transporter (SERT); serotonin-1A receptor; serotonin-3 receptor; docking; docking energy; binding affinity; binding mechanism; c-Fos; immunohistochemistry; electrophysiology

Subject

Medicine and Pharmacology, Psychiatry and Mental Health

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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