5-HT receptor antagonism a potential therapeutic approach for the treatment of depression and other disorders.

Background: Depression or Major depressive disorder (MDD) is a prolonged condition of sadness. MDD is the most common mental disorder that affects more than 264 million people worldwide. According to the monoamine hypothesis, serotonin (5-hydroxy tryptamine, 5-HT), dopamine (DA) and norepinephrine (NE) are the major neurotransmitters (NTs) involved in depression.

Construction of a novel quinoxaline as a new class of Nrf2 activator.

Background: The transcription factor Nuclear factor erythroid-2-related factor 2 (NRF2) and its principal repressive regulator, Kelch-like ECH-associated protein 1 (KEAP1), are perilous in the regulation of inflammation, as well as maintenance of homeostasis. Thus, NRF2 activation is involved in cytoprotection against many inflammatory disorders. '-Nicotinoylquinoxaline-2-carbohdyrazide (NQC) was structurally designed by the combination of important pharmacophoric features of bioactive compounds reported in the literature.

Novel 5-HT receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice.

Rationale: Depression associated with obesity remains an interesting area to study the biological mechanisms and novel therapeutic intervention.

Objectives: The present study investigates the effect of a novel 5-HT receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on several pathogenic markers of depression associated with obesity such as plasma insulin resistance, hippocampal cyclic adenosine monophosphate (cAMP), brain-derived neurotrophic factor (BDNF), serotonin (5-HT) concentrations, hippocampal neuronal damage, and p53 protein expression in high-fat-diet (HFD)-fed mice.

Methods: Obesity was experimentally induced in mice by feeding with HFD for 14 weeks followed by administration of QCM-4 (1 and 2 mg/kg, p.

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice.

Background: 5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.

Neuropharmacological and neurochemical evaluation of N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n): a novel serotonergic 5-HT3 receptor antagonist for co-morbid antidepressant- and anxiolytic-like potential using traumatic brain injury model in rats.

Background: Several preclinical studies have shown that serotonergic 5-HT3 receptor antagonists play an important role in the management of neuropsychiatric disorders, such as depression and anxiety. In the present study the compound "6n" (N-n-propyl-3-ethoxyquinoxaline-2-carboxamide), a novel 5-HT3 receptor antagonist with an optimal log P (2.52) and pA2 (7.

A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes.

Pharmacological evaluation of novel 5-HT3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery.

Objective: In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as potential targets for anxiety disorders. In preclinical studies, 5-HT3 antagonists have shown promising antianxiety effects. In this study, a novel 5-HT3 receptor antagonist, QCM-13(N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) was evaluated for anxiolytic-like activity in rodent behavioral test battery.

QCM-4, a 5-HT₃ receptor antagonist ameliorates plasma HPA axis hyperactivity, leptin resistance and brain oxidative stress in depression and anxiety-like behavior in obese mice.

Several preclinical studies have revealed antidepressant and anxiolytic-like effect of 5-HT3 receptor antagonists. In our earlier study, we have reported the antidepressive-like effect of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in obese mice subjected to chronic stress. The present study deals with the biochemical mechanisms associated with depression co-morbid with obesity.

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression.

Aim: To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression.

Methods: 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.

Antidepressant-like effect of a novel 5-HT3 receptor antagonist N-(benzo[d] thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide 6k using rodents behavioral battery tests.

Objective: To investigate the antidepressant-like effect of N-(benzo[d] thiazol-2-yl)-3- ethoxyquinoxalin-2-carboxamide 6k, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist using rodents behavioral battery tests.

Materials And Methods: 6k screening was performed with behavioral assays for depression-like forced swim test (FST) at several single doses (0.25-4 mg/kg, intraperitoneal injection (i.

Neuropharmacological effect of novel 5-HT3 receptor antagonist, N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n) on chronic unpredictable mild stress-induced molecular and cellular response: Behavioural and biochemical evidences.

Background: Chronic unpredictable stressors can produce a situation similar to human depression and such animal models can be used for the preclinical evaluation of antidepressants. The 5-HT3 receptor antagonists modulate serotonergic pathways and show antidepressant-like effect in various animal models of depression.

Methods: In this study, a novel and potential 5-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n) with good Log P (2.

QCM-4, a serotonergic type 3 receptor modulator attenuates depression co-morbid with obesity in mice: an approach based on behavioral and biochemical investigations.

Previous studies in our laboratory examined the antidepressant potential of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4), a 5-HT3 receptor antagonist in acute and chronic rodent models of depression. The aim of present study was to investigate the effect of QCM-4 on chronic unpredictable mild stress (CUMS) induced depression in obese mice using behavioral based battery tests and biochemical assessments. Depressive behavior was induced in obese mice by subjecting to different stress procedures for 28 days.

Design, synthesis, and pharmacological evaluation of novel 2-(4-substituted piperazin-1-yl)1, 8 naphthyridine 3-carboxylic acids as 5-HT3 receptor antagonists for the management of depression.

1, 8-naphthyridine-3-carboxylic acid analogs were synthesized and found to possess potential 5-HT3 receptor antagonism as well as antidepressant-like activity. Initially, 5-HT3 receptor antagonism of all the compounds was determined in the form of pA2 value against agonist 2-methyl 5-HT in longitudinal muscle-myenteric plexus preparation from guinea-pig ileum. Among all the compounds tested, compound 7a demonstrated most promising pA2 value of 7.

Protective effects of a novel 5-HT3 receptor antagonist, N-n-butyl-3-methoxy quinoxaline-2-carboxamide (6o) against chronic unpredictable mild stress-induced behavioral changes and biochemical alterations.

Stimulation of high oxidative stress in the brain is considered as an important factor for neurotoxicity towards the pathophysiology of chronic stress-induced depression disorder. In the present research, a potential 5-HT₃ receptor antagonist N-n-butyl-3-methoxy quinoxaline-2-carboxamide (6o) having good Log P (2.60) and pA₂ (7.

Antidepressant and anti-anxiety like effects of 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist in acute and chronic neurobehavioral rodent models.

Depression and anxiety are the most debilitating mood disorders with poor therapeutic recovery rates. In the last decades, 5-HT3 receptor antagonists have been identified as potential agents for mood disorders. The current investigation focuses on evaluating the, antidepressant and anti-anxiety like effects of a novel 5-HT3 antagonist, 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide).

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (6g) on chronic unpredictable mild stress-induced changes in behavioural and brain oxidative stress parameters in mice.

Aim: The aim of the study was to evaluate a novel 5 HT3 receptor antagonist (6g) on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body's reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants.

Effect of (4a) a novel 5-HT3 receptor antagonist on chronic unpredictable mild stress induced depressive-like behavior in mice: an approach using behavioral tests battery.

Background: The inconsistent therapeutic outcome necessitates designing and identifying novel therapeutic interventions for depression. Hence, the present study deals with the investigation of antidepressant-like effects of a novel 5-HT3 receptor antagonist (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a) on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alterations.

Methods: Animals were subjected to different stressors for a period of 28 days.

Anti-anxiety effect of a novel 5-HT₃ receptor antagonist N-(benzo[d]thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide (6k) using battery tests for anxiety in mice.

Objective: To investigate the anti-anxiety activity of "6k", a novel 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist in in mice.

Materials And Methods: Anti-anxiety activity of "6k" (1, 2, and 4 mg/kg, intraperitoneally (i.p.

QCM-4 a novel 5-HT3 antagonist attenuates the behavioral and biochemical alterations on chronic unpredictable mild stress model of depression in Swiss albino mice.

Objectives: The inconsistent therapeutic outcome necessitates identifying novel compounds for the treatment of depression. Therefore, the present study is aimed at evaluating the antidepressant-like effects of a novel 5-HT3 receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alterations in mice.

Methods: Animals were subjected to different stressors for a period of 28 days.

Antidepressant-like effect of novel 5-HT3 receptor antagonist N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p): an approach using rodent behavioral antidepressant tests.

Objective: The present study was designed to investigate the antidepressant potential of N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p), a novel 5-HT3 receptor antagonist in rodent behavioral models of depression.

Materials And Methods: The compound 6p was examined in various behavioral models like forced swim test (FST), tail suspension test (TST), mechanistic models [5-hydroxytryptophan (5-HTP)-induced head twitch and reserpine-induced hypothermia (RIH)], and in chronic surgery model-olfactory bulbectomy in rats.

Results: Compound 6p (1, 2, and 4 mg/kg, i.

Anti-depressant like activity of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (6o) a 5-HT3 receptor antagonist.

The compound 6o (at 0.5, 1 and 2 mg/kg, ip) with optimum log P and pA2 value, was subjected to forced swim test (FST) and tail suspension test (TST). The compound 6o significantly reduced the duration of immobility in mice without affecting the base line locomotion in actophotometer.

Anxiolytic-like effect of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (60) in experimental mouse models of anxiety.

The present research was designed to explore the anxiolytic-like activity of a novel 5-HT3 receptor antagonist (60) in experimental mouse models of anxiety. The anxiolytic activity of '6o' at (1 and 2 mg/kg, ip) was evaluated in mice by using a battery of behavioural tests of anxiety such as elevated plus maze (EPM), light/dark aversion test, hole board (HB) and open field test (OFT) with diazepam (2 mg/kg, ip) as a standard anxiolytic. None of the tested doses of '6o' affected the base line locomotion.

Anxiolytic-like effect of (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl)methanone (6g) in experimental mouse models of anxiety.

Aim: The present study was designed to investigate the anxiolytic activity of 6g, a novel serotonin type-3 receptor (5-HT3) receptor antagonist in experimental mouse models of anxiety.

Materials And Methods: The anxiolytic activity of "6g" (1 and 2 mg/kg, intraperitoneally [i.p.

Antidepressant and anxiolytic-like effects of 4n, a novel 5-HT3 receptor antagonist using behaviour based rodent models.

The present study was designed to investigate the putative antidepressant and anxiolytic-like effects of N-n-Butylquinoxalin-2-carboxamide (4n), a novel 5-HT3 receptor antagonist, with an optimal log P (2.01) and pA2 value (7.3) greater than ondansetron (6.