Piperazine Analogs of Naphthyridine‐3‐carboxamides and Indole‐2‐carboxamides: Novel 5‐HT3 Receptor Antagonists with Antidepressant‐Like Activity. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Dhar, Arghya K.; Mahesh, Radhakrishnan; Jindal, Ankur; Bhatt, Shvetank
• Is Part Of: Archiv der Pharmazie. Volume 348:Issue 1(2015:Jan.)
• Page Start: 34
• Page End: 45
• Publication Date: 2015-01
• Subjects: Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201400293
• Languages: English
• ISSNs: 0365-6233

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="ardp201400293-sec-0001" sec-type="section"> <p>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‐HT<sub>3</sub> receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5‐HT<sub>3</sub> receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5‐HT<sub>3</sub> agonist, 2‐methyl‐5‐hydroxytryptamine, which was denoted in the form of p<italic>A</italic><sub>2</sub> values. The structure–activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5‐HT<sub>3</sub> pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole‐2‐carboxamide <bold>13i</bold> and naphthyridine‐3‐carboxamide <bold>8h</bold> exhibited prominent 5‐HT<sub>3</sub> receptor antagonism with p<italic>A</italic><sub>2</sub> 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 <bold>13i</bold> and naphthyridine‐3‐carboxamide <bold>8h</bold> as the most promising compounds. Both <bold>13i</bold> and <bold>8h</bold> 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.</p> </sec> </abstract>