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

Alexey Sarapultsev,Alexander Kiss,Oleg Chupakhin,Maxim Rantsev,Petr Sarapultsev,Pavel Vassiliev,Larisa Sidorova,Daniil Grinchii,Eliyahu Dremencov,Alexander Spasov,Mojmir Mach,Andrey Kochetkov,Jana Osacka,Alexandra Balloova,Ruslan Paliokha

doi:10.3390/ijms222413626

Abstract

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-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A 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-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A 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.

Highlights

L-17 (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide; Figure 1) is a thiadiazine derivative, synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide [1].receptor antagonist WAY100135 (D).In our previous studies, we have shown, using animal models, a putative therapeutic effect of L-17 in myocardial infarction (MI) [2,3,4] and pancreatitis [5]
We performed a complex in silico assessment of the pharmacotherapeutic properties of L-17, as well as In Vivo electrophysiological assessment of the effect of this compound on the firing activity of 5-HT neurons in the rat dorsal raphe nucleus (DRN)
PASS 10.4 Professional Extended predicted that the antidepressant-like effect of L-17 can be explained, at least in part, via its 5-HT reuptake inhibition property

Summary

Introduction

We have shown, using animal models, a putative therapeutic effect of L-17 in myocardial infarction (MI) [2,3,4] and pancreatitis [5]. In these models, L-17 significantly decreased the initial infection area and accelerated the granulocytotic and suppressed cytokine component of the inflammatory reaction in rats after coagulation of the left coronary artery [2,3]. We aimed to investigate the mechanism of the putative beneficial effect of L-17 on the central nervous system (CNS), using a combination of in silico, Ex Vivo, and In Vivo methods [7]

Objectives

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Conclusion