Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors

Koprdova, Romana; Csatlósová, Kristína; Durisova, Barbora; Bögi, Eszter; Májeková, Magdaléna; Dremencov, Eliyahu; Mach, Mojmı́r

doi:10.3390/molecules24234218

Cited by 15 publications

(22 citation statements)

References 46 publications

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“…It has indeed been reported that various CNS drugs, such typical [12] and atypical antipsychotics [12-14], tricyclic antidepressants [13], and selective 5-HT reuptake inhibitors (SSRIs) [13,15,16], increased c-Fos immunoreactivity in the amygdala, indicating an increased neural excitability in this brain area. In our previous studies, we have found that pyridoindole derivate SMe1EC2M3, a molecule with putative 5-HT reuptake inhibition properties and antidepressant-like behavioral effect [7], stimulated amygdaloid c-Fos immunoreactivity, as well [11]. The fact that SSRIinduced amygdaloid c-Fos immunoreactivity was potentiated by an antagonist of 5-HT1A autoreceptors indicated that 5-HT system is involved in the modulation of amygdaloid neural excitability by antidepressant drugs.…”

Section: Discussionmentioning

confidence: 96%

“…In vivo electrophysiological assessment of the excitability of 5-HT neurons of the DRN was performed as previously described [7,[42][43][44]. Adult male Wistar rats, weighing 300-350 g, were ordered from the Animal Breeding Facility of The Institute of Experimental Pharmacology and Toxicology, Center of Experimental Medicine, Slovak Academy of Sciences in DobráVoda, Slovakia.…”

Section: In Vivo Electrophysiologymentioning

confidence: 99%

“…Neuroprotective [1] and antidepressant-like [6] effects of L-17 in rats have been demonstrated, as well. In this study, 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].…”

Section: Introductionmentioning

confidence: 99%

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

Sarapultsev¹,

Vassiliev²,

Grinchii³

et al. 2021

Preprint

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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.

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Section: Discussionmentioning

confidence: 96%

Section: In Vivo Electrophysiologymentioning

confidence: 99%

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

Sarapultsev¹,

Vassiliev²,

Grinchii³

et al. 2021

Preprint

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“…13 , 97 , 98 Aforementioned reflections shall be considered, if study designs on the efficacy of SMe1EC2M3, a novel MRT-I with dopamine reuptake inhibiting properties, are planned in PD patients. 99 A future approval of SMe1EC2M3 is very likely, when this drug demonstrates symptomatic, motor symptoms enhancing effects in PD as initial step of the clinical development. Then as a second step, one may consider to perform long-term trials with a combination of DRT-I plus MAO-B inhibitor plus dopamine oxidation inhibitors, such as potent iron chelators, as promising future therapeutic concept to slow down progression of PD.…”

Section: Discussionmentioning

confidence: 99%

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

Müller¹

2021

JEP

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Parkinson's disease (PD) is the second most chronic neurodegenerative disorder worldwide. Deficit of monoamines, particularly dopamine, causes an individually varying compilation of motor and non-motor features. Constraint of presynaptic uptake extends monoamine stay in the synaptic cleft. This review discusses possible benefits of dopamine reuptake inhibition for the treatment of PD. Translation of this pharmacologic principle into positive clinical study results failed to date. Past clinical trial designs did not consider a mandatory, concomitant stable inhibition of glial monoamine turnover, i.e. with monoamine oxidase B inhibitors. These studies focused on improvement of motor behavior and levodopa associated motor complications, which are fluctuations of motor and non-motor behavior. Future clinical investigations in early, levodopa-and dopamine agonist naïve patients shall also aim on alleviation of non-motor symptoms, like fatigue, apathy or cognitive slowing. Oral levodopa/dopa decarboxylase inhibitor application is inevitably necessary with advance of PD. Monoamine reuptake (MRT) inhibition improves the efficacy of levodopa, the blood brain barrier crossing metabolic precursor of dopamine. The pulsatile brain delivery pattern of orally administered levodopa containing formulations results in synaptic dopamine variability. Ups and downs of dopamine counteract the physiologic principle of continuous neurotransmission, particularly in nigrostriatal, respectively mesocorticolimbic pathways, both of which regulate motor respectively non-motor behavior. Thus synaptic dopamine pulsatility overwhelms the existing buffering capacity. Onset of motor and non-motor complications occurs. Future MRT inhibitor studies shall focus on a stabilizing and preventive effect on levodopa related fluctuations of motor and non-motor behavior. Their long-term study designs in advanced levodopa treated patients shall allow a cautious adaptation of oral l-dopa therapy combined with a mandatory inhibition of glial monoamine turnover. Then the evidence for a preventive and beneficial, symptomatic effect of MRT inhibition on motor and non-motor complications will become more likely.

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“…As in our previous study [9], we used a combination of in silico and in vivo experimental techniques to test the hypothesis that the anti-inflammatory, neuroprotective, and antidepressantlike effect of L-17 is mediated, at least in part, via the targeting of the 5-HT system. The 3-D model of L-17 was constructed, and its interaction with different 5-HT targets, such as serotonin transporter (SERT) and 5-HT receptors 3 and 1A (5-HT3/5-HT1A) was examined, used in silico calculation of the minimum binding energy.…”

Section: Introductionmentioning

confidence: 99%

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

Sarapultsev¹,

Grinchii²,

Paliokha³

et al. 2021

Preprint

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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.

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Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors

Cited by 15 publications

References 46 publications

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

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

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

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

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