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

2021 ◽  
Author(s):  
Alexey Sarapultsev ◽  
Pavel Vassiliev ◽  
Daniil Grinchii ◽  
Ruslan Paliokha ◽  
Andrey Kochetkov ◽  
...  
Keyword(s):  
Reuptake Inhibitor ◽  
In Silico ◽  
Serotonin Reuptake ◽  
Medical Condition ◽  
Partial Agonist ◽  
Antidepressant Drugs ◽  
Acute Administration ◽  
In Vivo Electrophysiology ◽  
General Medical Condition

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.

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

2021 ◽  
Author(s):  
Alexey Sarapultsev ◽  
Pavel Vassiliev ◽  
Daniil Grinchii ◽  
Alexander Kiss ◽  
Mojmír Mach ◽  
...  
Keyword(s):  
Reuptake Inhibitor ◽  
In Silico ◽  
Ex Vivo ◽  
Brain Area ◽  
Antidepressant Drugs ◽  
Neural Mechanism ◽  
Central Nucleus ◽  
In Vivo Electrophysiology ◽  
In Silico Predictions

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.

Identifying potential PPARγ agonist/partial agonist from plant molecules to control type 2 diabetes using in silico and in vivo models

2016 ◽  
Vol 25 (9) ◽  
pp. 1980-1992 ◽  
Author(s):  
Antony Stalin ◽  
Santiagu Stephen Irudayaraj ◽  
Dhandapani Ramesh Kumar ◽  
Kedike Balakrishna ◽  
Savarimuthu Ignacimuthu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
In Silico ◽  
Partial Agonist ◽  
In Vivo Models ◽  
Pparγ Agonist

scholarly journals Trends and Advances in Separation and Detection of SSRIs and SNRIs in Biological Matrices

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Ruchita Das ◽  
Y. K. Agrawal
Keyword(s):  
Reuptake Inhibitor ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Date Rape ◽  
Antidepressant Drugs ◽  
Selective Serotonin ◽  
Biological Matrices ◽  
First Choice ◽  
Analytical Approaches ◽  
Norepinephrine Reuptake

Nowadays antidepressant drugs like selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) represent the first choice in the treatment of moderate to severe depressive illness, various phobias, and personality disorders. In spite of the therapeutic aspects, they often produce very severe and toxic effects in deliberate and accidental cases of poisoning. These are also considered as date-rape drugs used for drugged victims for raping or robbing. Therefore, in recent years, their analyses in different biological matrices for clinical and toxicological analysis purposes has been a target worthy of interest. Thus, the review focuses on recent advancements of various separation techniques like chromatography and electrophoresis that are concernd with the determination of selective serotonin reuptake inhibitor and selective norepinephrine reuptake inhibitor drugs and their metabolites in various biological matrices. In addition to this, a critical discussion on analytical approaches has also been incorporated, suggesting their applicability and limitations for further implementations. Thus, this paper will definitely help in the selection and development of proper analytical methodologies to achieve satisfactory results, better scientific understanding, and test interpretation.

Antipsychotic Adjuvant Treatment in OCD

2017 ◽  
Vol 41 (S1) ◽  
pp. S642-S642
Author(s):  
L. Monte. Reula ◽  
H. Saiz García ◽  
A. Portilla Fernández
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Serotonin Reuptake ◽  
Partial Agonist ◽  
Antidepressant Drugs ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Low Mood ◽  
Component Traits ◽  
Potential Risks ◽  
Competing Interest

Antidepressant drugs selective inhibitors of serotonin reuptake (IRS) are the drugs effective in obsessive compulsive disorder. It has not been proven more effective none of them except clomipramine. Around 40–60% of the Patients with obsessive-compulsive disorder (OCD) remain unimproved by serotonin reuptake inhibitors (SRIs).Two cases are presented in relation to this disorder and its treatment.Twenty-three year old woman begins to present anhedonia, apathy, isolation and low mood. Treatment was initiated with escitalopram with partial improvement.Obsessive component traitsThirty year old man with obsessive clinic of years of evolution, with worsening in recent months treatment with 200 mg sertraline.In both cases treatment with oral aripiprazole it was associated with a dose of 5 mg daily with improvement in obsessive symptoms.ResultsThe efficacy of aripiprazole as adjunctive drug treatment and obsessive anxiety is observed. However, we must take into account the potential risks posed as neuroleptic malignant syndrome and QTc prolongation.ConclusionAripiprazole is an antipsychotic which has a novel mechanism of action to be a partial agonist of dopamine D2 receptors. This fact has led to its inclusion in the group of antipsychotics called third generation, also called partial dopamine agonists, dopamine stabilizers or “dopamine-serotonin modulators system.” Its most common side effects such as nausea, headaches, agitation and akathisia were observed in studies on schizophrenia, schizoaffective disorder and bipolar disorder. Unlike other atypical antipsychotics, is considered a relatively neutral drug to weight gain, hyperprolactinemia, changes in metabolic parameters and sedation.Disclosure of interestThe authors have not supplied their declaration of competing interest.

To evaluate the effects of antidepressant drugs on pregnancy outcomes in a university hospital in Turkey

2020 ◽  
pp. 1-14
Author(s):  
Tugba Cavusoglu ◽  
Omer Can Atak ◽  
Erhan Eser ◽  
Ertan Dariverenli ◽  
Pelin Akca ◽  
...  
Keyword(s):  
Selective Serotonin Reuptake Inhibitor ◽  
Spontaneous Abortion ◽  
Reuptake Inhibitor ◽  
Pregnancy Outcomes ◽  
Serotonin Reuptake ◽  
Antidepressant Drugs ◽  
Abortion Rate ◽  
Selective Serotonin ◽  
Serotonin Reuptake Inhibitor ◽  
Single Drug

Abstract Objective: To assess the effects of antidepressant use on pregnancy outcomes. Methods: The cross-sectional study was conducted at the Department of Pharmacology, Manisa Celal Bayar University, Manisa, Turkey, and comprised pregnant women who were admitted to the Department of Gynaecology between 2008 and 2017 who had been prescribed antidepressant drugs before pregnancy and continued to use them during any week of their respective pregnancies. The women were contacted by telephone after delivery to obtain information about the pregnancy outcomes. Data was analysed using SPSS 23. Results: There were 183 women with a mean age of 31.3 ± 5.3 years (range: 18-44 years). There were congenital defects in the newborn in 11(7.65%) cases. The most commonly used antidepressant group was selective serotonin reuptake inhibitor 138(75.4%), and escitalopram was the most frequently used drug 46(25.1%). Spontaneous abortion rate was higher with escitalopram than the other antidepressants (p=0.062). Induced abortion rate was significantly higher in multidrug users compared to those on a single drug (p<0.05). Conclusion: selective serotonin reuptake inhibitor was found to be the most used class of antidepressants during pregnancy due to the low side effects and teratogenic effects. When antidepressant treatment is necessary during pregnancy, a single drug can be more suitable. Key Words: Antidepressant, Pregnancy, Spontaneous abortion, Teratogenic effect.

scholarly journals Effect of antidepressant drugs on the brain sphingolipid system

2020 ◽  
Vol 34 (7) ◽  
pp. 716-725
Author(s):  
Estabraq Jaddoa ◽  
Jinit Masania ◽  
Eva Masiero ◽  
Tiziana Sgamma ◽  
Randolph Arroo ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Reuptake Inhibitor ◽  
Antidepressant Drugs ◽  
Brain Regions ◽  
Acid Sphingomyelinase ◽  
Acute Administration ◽  
Acid Ceramidase ◽  
Drug Induced ◽  
Noradrenaline Reuptake ◽  
Mouse Macrophages

Background: Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the action of antidepressant drugs on sphingolipid levels in rat brain regions, plasma and in cultured mouse macrophages. Methods: Two antidepressant drugs were tested: the serotonin reuptake inhibitor paroxetine and the noradrenaline reuptake inhibitor desipramine, either following acute or chronic treatments. Content of sphingosine and ceramide were analysed using LC-MS or HPLC-UV, respectively. This was from samples of brain, plasma and cultured mouse macrophages. Antidepressant-induced effects on mRNA expression for two key genes of the sphingolipid pathway, SMPD1 and ASAH1, were also measured by using quantitative real-time PCR. Results: Chronic but not acute administration of paroxetine or desipramine reduced sphingosine levels in the prefrontal cortex and hippocampus (only paroxetine) but not in the striatum. Ceramide levels were also measured in the hippocampus following chronic paroxetine and likewise to sphingosine this treatment reduced its levels. The corresponding collected plasma samples from chronically treated animals did not show any decrease of sphingosine compared to the corresponding controls. Both drugs failed to reduce sphingosine levels from cultured mouse macrophages. The drug-induced decrease of sphingolipids coincided with reduced mRNA expression of two enzymes of the central sphingolipid pathway, i.e. acid sphingomyelinase ( SMPD1) and acid ceramidase ( ASAH1). Conclusions: This study supports the involvement of brain sphingolipids in the mechanism of action by antidepressant drugs and for the first time highlights their differential effects on brain versus plasma levels.

Increased Brain GABA Concentrations Following Acute Administration of a Selective Serotonin Reuptake Inhibitor

2004 ◽  
Vol 161 (2) ◽  
pp. 368-370 ◽  
Author(s):  
Zubin Bhagwagar ◽  
Marzena Wylezinska ◽  
Matthew Taylor ◽  
Peter Jezzard ◽  
Paul M. Matthews ◽  
...  
Keyword(s):  
Selective Serotonin Reuptake Inhibitor ◽  
Reuptake Inhibitor ◽  
Serotonin Reuptake ◽  
Selective Serotonin ◽  
Acute Administration ◽  
Serotonin Reuptake Inhibitor ◽  
Brain Gaba

scholarly journals Computational evidence of a compound with nicotinic α4β2-Ach receptor partial agonist properties as possible coadjuvant for the treatment of obesity

2016 ◽  
Author(s):  
Helena den-Haan ◽  
Juan José Hernández Morante ◽  
Horacio Pérez-Sánchez
Keyword(s):  
In Silico ◽  
Partial Agonist ◽  
Scoring Function ◽  
Pharmacophore Model ◽  
Functional Activities ◽  
Complex Disorder ◽  
Treatment Of Obesity ◽  
Obesity Drugs

ABSTRACTBackgroundNowadays, the search for new anti-obesity drugs is oriented to the use of anti-addiction medications like bupropion and naltrexone. Other compounds like varenicline may be also useful to treat obesity. However, the low effectiveness of the former or the high number of adverse effects of the latter makes it necessary to search for new therapeutic agents.MethodsScreening database selected for the computational experiments was DrugBank. 3D global shape comparison with varenicline was performed by means of the Ligand Based Virtual Screening tool WEGA v2015. A pharmacophore model based in the structure of varenicline was created by means of LigandScout v4.08. The in-silico screening was performed using Relative Pharmacophore Fit (RPF) scoring function implemented in LigandScout. Up to 3 mismatches with varenicline pharmacophore model were allowed for hits retrieving.ResultsDrugbank database was screened in silico to find alternative molecules to varenicline, and the compound cevimeline was found to have strong similarity to varenicline in terms of 3D shape and pharmacophoric features. Thus, we propose this hit may interact with nicotinic α4β2-Ach receptor in the same mode as varenicline does.DiscussionThe functional activities of this compound and its validity as a drug therapy for obesity treatment must be confirmed in further in vitro, in vivo and preclinical studies; however, attending to our screening procedure, this compound should be a promising therapy for such a complex disorder such as obesity.

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