Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

In Silico and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Serotonin Reuptake Properties

Version 1 : Received: 24 February 2021 / Approved: 25 February 2021 / Online: 25 February 2021 (15:23:26 CET)

How to cite: Sarapultsev, A.; Vassiliev, P.; Grinchii, D.; Paliokha, R.; Kochetkov, A.; Sidorova, L.; Sarapultsev, P.; Chupakhin, O.; Rantsev, M.; Spasov, A.; Dremencov, E. In Silico and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Serotonin Reuptake Properties. Preprints 2021, 2021020589 (doi: 10.20944/preprints202102.0589.v1). Sarapultsev, A.; Vassiliev, P.; Grinchii, D.; Paliokha, R.; Kochetkov, A.; Sidorova, L.; Sarapultsev, P.; Chupakhin, O.; Rantsev, M.; Spasov, A.; Dremencov, E. In Silico and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Serotonin Reuptake Properties. Preprints 2021, 2021020589 (doi: 10.20944/preprints202102.0589.v1).

Abstract

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico 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) are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. However, while the binding mechanisms of L-17 to the SERT and 5-HT1A receptor were similar to fluoxetine and WAY100135, its interacting with 5-HT3 receptor might be substantially different from this of granisetron. Acute administration of L-17 led to dose-dependent inhibition of firing activity of 5-HT neurons of the dorsal raphe nucleus. This inhibition was partially reversed by subsequent administration of WAY100135. Based on both in silico and in vivo electrophysiology assessments, we suggest that L-17 is a potent 5-HT reuptake inhibitor and a putative partial agonist of 5-HT1A receptors. As such, L-17 in particular and thiadiazine derivatives, in general, might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardioprotective properties, it can be useful in affective illness developing due to the general medical condition, such as post-stroke and post-myocardial infarction (MI) depression.

Keywords

serotonin transporter (SERT); thiadiazines; serotonin receptors 3 and 1A (5-HT3 and 5-HT1A); docking energy; binding affinity; binding mechanisms; electrophysiology in vivo

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