BITS Faculty Publications
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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 4i (N-(3-Chloro-2-methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist alleviates depressive behavior evoked in streptozotocin-induced diabetic mice: Role of oxidative stress(Elsevier, 2016-01) Mahesh, R.The prevalence of depression is about 2-3 times higher in diabetic patients compared to the general population, yet this comorbidity is poorly treated. This may partly be contributed to the inefficient pharmacotherapy. We evaluated if a novel 5HT3 receptor antagonist 4i (N-(3-Chloro-2-methylphenyl) quinoxalin-2-carboxamide), can prevent depression-like behavior associated with diabetes in mice. Also, the role of oxidative stress in antidepressant action of 4i was investigated.Item Antidepressant- and anxiolytic-like effect of novel 5-hydroxytryptamine3 receptor antagonist 2-[4-(3-chlorophenyl) piperazin-1-yl]-1,8-naphthyridine -3-carboxylic acid (7e)- An approach using rodent behavioral antidepressant and anxiolytic test battery(Wolters Kluwer, 2016-06) Mahesh, R.Depression and anxiety are among the most common and prevalent forms of mental disorder. The 5-hydroxytryptamine3 (5-HT 3) receptor antagonists modulate serotonergic pathways and show antidepressant- and anxiolytic-like effect in various animal models of depression. The present study was designed to investigate the antidepressant and anxiolytic potential of 2-[4-(3-chlorophenyl) piperazin-1-yl]- 1,8-naphthyridine-3-carboxylic acid (7e), a novel 5-HT 3 receptor antagonist in rodent behavioral models of depression and anxiety.Item Role of Serotonin Type-1A/B (Hydroxytryptamine) Receptors in Depression Revisited(Systematic Reviews in Pharmacy, 2014-04) Mahesh, R.Depression is among the common psychiatric disorders, therefore the common pathways and pathogenesis associated with depression is required to be studied. In few years, role of 5-hydroxytryptamine-1A/B (5-HT1A/B) receptors in depressive disorders have been revealed. Both preclinical and clinical studies reported that the potential agonist and antagonist at 5-HT1A/B receptors have significant modulatory effects in depression. However, the collective details regarding the involvement of 5-HT1A/B receptors and the molecular pathways associated in depression is lacking. Thus, the present review evidence the link between 5-HT1A/B receptors in the brain and depression, the possible pathways involved and their alterations in depression. Further, it reviews the preclinical evidences of 5-HT1A/B receptor modulators as antidepressant agents and their effectiveness. The current review also details the clinical relevance of 5-HT1A/B receptors etiopathogenesis of major depression in humans.Item Anti-depressant like activity of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (6o) a 5-HT3 receptor antagonist(NISCAIR, 2013-06) Mahesh, R.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. Moreover, 6o (2 mg/kg, ip), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and at 1 and 2 mg/kg, ip antagonized the reserpine-induced hypothermia (RIH) in rats. In interaction studies with various standard drugs/ligands using FST, 6o (1 and 2 mg/kg, ip) potentiated the anti-depressant effect fluoxetine (5 mg/kg, ip) and reversed the depressant effect of parthenolide (1 mg/kg, ip) by reducing the duration of immobility. Furthermore, 6o (1 and 2 mg/kg, ip) potentiated the effect of bupropion (10 mg/kg, ip) in TST. The behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic 6o (1 and 2 mg/kg) treatment as observed from the modified open field test (parameters: ambulation, rearing, fecal pellet). The results suggest that compound 6o exhibited anti-depressant like effect in rodent models of depression.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 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.Item Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2-Methoxy 1, 8 Naphthyridine 3-Carboxamides as 5-HT3 Receptor Antagonists(Wiley, 2013-12) Mahesh, R.A series of novel 1,8-naphthyridine-3-carboxamides as 5-HT3 receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand-based approach keeping in consideration the structural requirement of the pharmacophore of 5-HT3 receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5-HT3 receptor antagonism of all the compounds, which was denoted in the form of pA2 value, was determined in longitudinal muscle myenteric plexus preparation from guinea-pig ileum against 5-HT3 agonist, 2-methyl-5-HT. Compound 8g (2-methoxy-1, 8-naphthyridin-3-yl) (2-methoxy phenyl piperazine-1-yl) methanone was identified as the most active compound, which expressed a pA2 value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA2 value exhibited promising antidepressant-like activity, whereas compounds with lower pA2 value did not show antidepressant-like activity as compared to the control group.Item Antidepressant-like effect of novel 5-HT3 receptor antagonist N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p): An approach using rodent behavioral antidepressant tests(Wolters Kluwer, 2013) Mahesh, R.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.Item Antidepressant Potential of 5-HT3 Receptor Antagonist, N-n- propyl-3-ethoxyquinoxaline-2-carboxamide (6n)(Elsevier, 2012-12) Mahesh, R.The present study was designed to evaluate the antidepressant potential of 5-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n). The Compound '6n' with Optimum log P and pA2 value identified from a series of Compounds synthesized in our laboratory was subjected to forced Swim Test (FST) (1, 2, and 4 mg/kg, i.p) and Tail Suspension Test (TST) (1, 2, and 4 mg/kg, i.p.). The Compound '6n' significantly reduced the duration of immobility in mice without affecting the baseline locomotion. Moreover, '6n' (2 mg/kg, i.p.) potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and '6n' attested dose (1 and 2 mg/kg, i.p.) reversed the reserpine-induced hypothermia in rats. In interaction studies of '6n' with various Standard drugs/ligands using FST, '6n' (1 mg/kg, i.p.) potentiated the antidepressant effect of venlafaxine (4 and 8 mg/kg, i.p.) and fluoxetine (10 and 20 mg/kg, i.p.). Additionally, '6n' (1 and 2 mg/kg, i.p.) influenced the effect of harmane (5 mg/kg, i.p.) as well as reversed the effect of parthenolide (1 mg/kg, i.p.) by reducing the duration of immobility in FST. Furthermore, '6n' (1 mg/kg, i.p.) potentiated the effect of bupropion (10 and 20 mg/kg, i.p.) in TST. Chronic '6n' (1 and 2 mg/kg, i.p.) treatment attenuated the behavioral abnormalities in olfactory bulbectomized rats. In conclusion, these various findings reiterated the antidepressant-like effects of'6n' in behavioral models of depression.