Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT<sub>3</sub>) receptor antagonists

Mahesh, Radhakrishnan; Devadoss, Thangaraj; Pandey, Dilip K.; Yadav, Shushil Kumar

doi:10.3109/14756366.2010.543419

Cited by 12 publications

(8 citation statements)

References 17 publications

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“…[19] The oxidative cyclization of o -phenylenediamine with D-fructose in presence of acetic acid afforded the compound 2 in moderate yield, which on oxidation with alkaline hydrogen peroxide afforded the key intermediate quinoxalin-2-carboxylic acid with the yield of 50%. The carboxylic acid group of quinoxalin-2-carboxylic acid (3) was coupled with N -phenylpiperazine in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt) under nitrogen atmosphere yield the desired compound 4a in 70% yield.…”

Section: Methodsmentioning

confidence: 99%

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Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT ₃ receptor antagonist: An investigation in behaviour-based rodent models of depression

et al. 2012

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Aim:The present study was designed to investigate the antidepressant potential of (4-phenylpiperazin-1-yl) (quinoxalin-3-yl) methanone (4a), a novel 5-HT3 receptor antagonist, with an optimal log P (2.84) and pA2 value (7.3) greater than ondansetron (6.9) using rodent behavioural models of depression.Materials and Methods:Swiss albino mice were used in actophotometer test, forced swim test (FST) and 5-hydroxytryptophan (5-HTP) induced head twitch response. Reserpine induced hypothermia (RIH) and olfactory bulbectomy were performed in male Wistar rats. Statistical analysis was carried out by using one-way analysis of variance followed by Tukey's test.Results:Acute treatment of 4a (1-4 mg/kg, i.p.) in mice produced antidepressant-like effects in FST without affecting the baseline locomotion in actophotometer test. Further, 4a (2-4 mg/kg, i.p.) potentiated the 5-HTP induced head twitches response in mice and also antagonized RIH in rats. Furthermore, sub-chronic (14 days) treatment with 4a (2-4 mg/ kg, p.o.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in modified open field exploration.Conclusions:These preliminary investigations confirm that 4a exhibits antidepressant-like activity in behaviour based rodent models of depression.

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Section: Methodsmentioning

confidence: 99%

“…In the present study, compound 4a was selected from a series of compounds[19] for preliminary antidepressant potential based on the optimal log P (2.84) and p A 2 value (7.3) greater than 5-HT 3 receptor antagonist, OND (6.9) using rodent behavioural models of depression.…”

Section: Introductionmentioning

confidence: 99%

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT ₃ receptor antagonist: An investigation in behaviour-based rodent models of depression

et al. 2012

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“…The proposed pharmacophoric elements (Figure ) that are necessary for 5‐HT 3 receptor antagonistic activity are an aromatic moiety, a basic moiety, and an intervening hydrogen bond acceptor moiety arranged at specific distances . Our earlier studies have indicated that nitrogen containing fused six‐membered aromatic ring (aromatic moiety) may constitute a suitable template in the design of novel 5‐HT 3 receptor antagonists . Previously, we had synthesized and screened few compounds based on the above pharmacophoric pattern , and the results were encouraging enough to prompt us for further synthesizing some closely related compounds with a similar approach.…”

Section: Physical Constants Of Synthesized Compounds 8a‐8omentioning

confidence: 99%

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

et al. 2014

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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.

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“…) proposed for the interaction of 5‐HT 3 receptor antagonists with the 5‐HT 3 receptor‐binding site: consist of a heteroaromatic core, a hydrogen‐bond acceptor moiety, and a basic nitrogen located at a specific distance . In recent years, we have been engaged in the preparation and screening of compounds based on the above pharmacophoric pattern and our earlier studies have indicated that nitrogen‐containing fused aromatic rings (heteroaromatic core) may serve as a suitable starting point for the design of novel 5‐HT 3 receptor antagonists . In addition, compounds based on the indolyl aromatic core were reported as being potential 5‐HT 3 receptor antagonists .…”

Section: Introductionmentioning

confidence: 99%

Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT₃ Receptor Antagonists with Antidepressant‐Like Activity

Dhar

Mahesh

Jindal

et al. 2015

Archiv der Pharmazie

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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.

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Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT₃) receptor antagonists

Cited by 12 publications

References 17 publications

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT ₃ receptor antagonist: An investigation in behaviour-based rodent models of depression

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT ₃ receptor antagonist: An investigation in behaviour-based rodent models of depression

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT₃ Receptor Antagonists with Antidepressant‐Like Activity

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Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT3) receptor antagonists

Cited by 12 publications

References 17 publications

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT 3 receptor antagonist: An investigation in behaviour-based rodent models of depression

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT 3 receptor antagonist: An investigation in behaviour-based rodent models of depression

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT3 Receptor Antagonists with Antidepressant‐Like Activity

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Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT₃) receptor antagonists

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT ₃ receptor antagonist: An investigation in behaviour-based rodent models of depression

Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT ₃ receptor antagonist: An investigation in behaviour-based rodent models of depression

Design, Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT₃ Receptor Antagonists

Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT₃ Receptor Antagonists with Antidepressant‐Like Activity