Department of Management
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Item Effects of adhatoda vasica leaf extract in depression co‑morbid with alloxan‑induced diabetes in mice(IJGP, 2014) Mahesh, R.Context: Increased neuronal oxidative stress as a consequence of diabetes may result in neuropsychological complications such as depression. Depression co‑morbid with diabetes further hampers the quality life years in diabetic patients. Aim: Thus, the present study was aimed at investigating the effects of Adhatoda vasica leaf extract (EAV), as a natural remedy, in alloxan‑induced diabetes and co‑morbid depression in mice. Materials and Methods: Experimentally, mice were rendered diabetic with a single dose of alloxan of 200 mg/kg, intraperitoneally (i.p.). After 3 weeks of having chronic diabetic state, mice were given EAV (100-400 mg/kg, orally)/ vehicle/standard control (escitalopram, ESC; 10 mg/kg, orally) for 7 days. After dosing, anti‑diabetic effect was detected by the fasted blood glucose levels and anti‑depressant effect was evaluated by behavioural despair tests, followed by monoamine oxidase (MAO) activity and oxidative stress analysis. Results and Discussion: EAV treatment effectively reduced the elevated blood glucose levels and reversed co‑morbid depressive behaviour. Furthermore, EAV inhibited diabetes induced increased oxidative stress and MAO activity in the brain. Thus, EAV demonstrated the potential protective action against oxidative stress and revealed monoamine modulatory activity in the brain, which may contribute to its anti‑depressant effect. Conclusion: This work demonstrates the efficacious effect of EAV in reversing the depression co‑morbid with alloxan‑induced diabetes in mice.Item Ligand-Based Design, Synthesis, and Pharmacological Evaluation of 3-Methoxyquinoxalin-2-carboxamides as Structurally Novel Serotonin Type-3 Receptor Antagonists(Wiley, 2012-06) Mahesh, R.Employing a ligand-based approach, 3-methoxyquinoxalin-2-carboxamides were designed as serotonin type-3 (5-HT3) receptor antagonists and synthesized from the starting material o-phenylenediamine in a sequence of reactions. The structures of the synthesized compounds were confirmed by spectral data. These carboxamides were investigated for their 5-HT3 receptor antagonisms in longitudinal muscle myenteric plexus preparations from guinea-pig ileum against a standard 5-HT3 agonist, 2-methy-5-HT, and their antagonism activities are expressed as pA2 values. Compounds 6a (pA2: 7.2), 6e (pA2: 7.0), 6f (pA2: 7.5), 6g (pA2: 7.5), 6n (pA2: 7.0), and 6o (pA2: 7.2) exhibited antagonism greater than that of the standard 5-HT3 antagonist, ondansetron (pA2: 6.9).Item Anxiolytic-like effect of (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl)methanone (6g) in experimental mouse models of anxiety(Wolters Kluwer, 2013) Mahesh, R.The present study was designed to investigate the anxiolytic activity of 6g, a novel serotonin type-3 receptor (5-HT 3) receptor antagonist in experimental mouse models of anxiety.Item Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT3 Receptor Antagonists with Antidepressant‐Like Activity(Wiley, 2015-01) Mahesh, R.Series of piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides were designed using a ligand-based approach with consideration of the pharmacophoric requirements for 5-HT3 receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5-HT3 receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5-HT3 agonist, 2-methyl-5-hydroxytryptamine, which was denoted in the form of pA2 values. The structure–activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5-HT3 pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h exhibited prominent 5-HT3 receptor antagonism with pA2 values of 7.5 and 7.3, respectively. Subsequent investigation of the antidepressant activities of selected compounds in the mouse forced swim test (FST) led to the identification of the piperazine analogs of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h as the most promising compounds. Both 13i and 8h demonstrated significant reduction in the duration of immobility as compared to the control. Importantly, none of the tested compounds affected the baseline locomotion of mice at the tested dose levels.Item 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(Elsevier, 2014-07) Mahesh, R.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 (7.7) values was examined for its effect on the behavioral and biochemical changes induced by the chronic unpredictable mild stress (CUMS) model. In the current investigation mice were introduced to different stress procedures daily for a period of 28 days to induce a depressive-like behavior. The results show that CUMS caused a depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and locomotor activity and increase in immobility in the forced swim test (FST). Moreover, it was found that oxidative stress markers such as lipid peroxide and nitrite levels were significantly increased, whereas, antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were decreased in the brain tissue of CUMS-subjected mice. “Compound 6o” (1 and 2 mg/kg, p.o.) and fluoxetine treatment (20 mg/kg, p.o.) for a period of 21 days altered the CUMS-induced behavioral (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxide, increased brain nitrite; decreased GSH, SOD and CAT levels) alterations. Moreover normal mice treated with “compound 6o” (2 mg/kg, p.o.) showed a significant decrease in the duration of immobility in FST as compared to normal vehicle treated mice. In conclusion, “compound 6o” produced antidepressant-like effects in behavioral despair paradigm in chronically stressed mice by restoring antioxidant enzyme activityItem Novel 5-HT3 receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice(Springer, 2017-02) Mahesh, R.Depression associated with obesity remains an interesting area to study the biological mechanisms and novel therapeutic intervention.Item Microwave-assisted solvent-free synthesis of 3-[(4-substituted piperazin-1-yl)alkyl] imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones as serotonin3 (5-HT3) receptor antagonists(Avoxa, 2005-06) Mahesh, R.A series of novel 3-[(4-substituted piperazin-1-yl)alkyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones were prepared by microwave irradiation using alumina as solid support and also by a conventional method. The compounds were characterized by spectral data and the purity was ascertained by microanalysis. The synthesized compounds were evaluated for 5-hydroxytryptamine3 antagonisms in a longitudinal muscle-myenteric plexus preparation from guinea pig ileum against the 5-hydroxytryptamine3 agonist, 2-methyl-5-hydroxytryptamine. Among the test compounds, 3-[2-(4-methylpiperazin-1-yl)ethyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-one (3b) showed most favorable 5-hydroxytryptamine3 antagonism (pA2 6.7) in the isolated guinea pig ileum.Item Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors(Elsevier, 2019-11) Mahesh, R.The cysteine protease, falcipain-2 is an important drug target in human malaria parasite Plasmodium falciparum. A new series of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives 5(a–t) were designed as per pharmacophoric requirements of falcipain-2 inhibitors using ligand-based approach. The target compounds were synthesized from the key intermediate, 2-(1,4-Diazepan-1-yl)-N-phenylacetamide, by coupling it with appropriate carboxylic acids using carbodiimide chemistry. Structural features of target compounds were characterized by spectral data (1H NMR, and mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Five compounds 5b, 5g, 5h, 5j, 5k showed good inhibitory activity (>60%), against falcipain-2 at 10 μM concentration, and fifteen compounds showed weak to moderate inhibitor activity. Compound 5g, the most potent compound from this series showed 72% inhibition at 10 μM concentrationsItem Assessing the Neuronal Serotonergic Target-based Antidepressant Stratagem: Impact of In Vivo Interaction Studies and Knockout Models(Bentham Science, 2008) Mahesh, R.Depression remains a challenge in the field of affective neuroscience, despite a steady research progress. Six out of nine basic antidepressant mechanisms rely on serotonin neurotransmitter system. Preclinical studies have demonstrated the significance of serotonin receptors (5-HT1-3,6,7), its signal transduction pathways and classical down stream targets (including neurotrophins, neurokinins, other peptides and their receptors) in antidepressant drug action. Serotonergic control of depression embraces the recent molecular requirements such as influence on proliferation, neurogenesis, plasticity, synaptic (re)modeling and transmission in the central nervous system. The present progress report analyses the credibility of each protein as therapeutically relevant target of depression. In vivo interaction studies and knockout models which identified these targets are foreseen to unearth new ligands and help them transform to drug candidates. The importance of the antidepressant assay selection at the preclinical level using salient animal models/assay systems is discussed. Such test batteries would definitely provide antidepressants with faster onset, efficacy in resistant (and co-morbid) types and with least adverse effects. Apart from the selective ligands, only those molecules which bring an overall harmony, by virtue of their affinities to various receptor subtypes, could qualify as effective antidepressants. Synchronised modulation of various serotonergic sub-pathways is the basis for a unique and balanced antidepressant profile, as that of fluoxetine (most exploited antidepressant) and such a profile may be considered as a template for the upcoming antidepressants. In conclusion, 5-HT based multi-targeted antidepressant drug discovery supported by in vivo interaction studies and knockout models is advocated as a strategy to provide classic molecules for clinical trials.Item Anti-depressant-like activity of a novel serotonin type-3 (5-HT3) receptor antagonist in rodent models of depression(NISCAIR, 2011) Mahesh, R.N-Cyclohexyl-3-methoxyquinoxalin-2-carboxamide (QCM-13), a novel 5-HT3 antagonist identified from a series of compounds with higher pA2 (7.6) and good log P (2.91) value was screened in rodent models of depression such as forced swim test (FST), tail suspension test (TST), interaction studies with standard anti-depressants and confirmatory studies such as reversal of parthenolide induced depression and reserpine induced hypothermia. In FST (2 and 4 mg/kg) and TST (2 and 4 mg/kg), QCM-13 significantly reduced the duration of immobility in mice without affecting the base line locomotion. QCM-13 (2 and 4 mg/kg) was also found to have significant interaction with standard anti-depressants (fluoxetine and bupropion in FST and TST respectively). Further, reversal of parthenolide induced depression in mice and reserpine induced hypothermia in rat models indicate the serotonergic influence of QCM-13 for anti-depressant potential.