title: Piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides: novel 5-HT3 receptor antagonists with antidepressant-like activity.
abstract: 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.
authors.affiliation: Department of Pharmacy, FD-III, Birla Institute of Technology & Science, Pilani, Rajasthan, India.
authors.forename: Arghya K
authors.initials: AK
authors.lastname: Dhar
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Mahesh
authors.forename: Ankur
authors.initials: A
authors.lastname: Jindal
authors.forename: Shvetank
authors.initials: S
authors.lastname: Bhatt
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004195:Disease Models, Animal; D015195:Drug Design; D006168:Guinea Pigs; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013550:Swimming; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D007211:Indoles; D009287:Naphthyridines; D010879:Piperazines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists
keywords: 5-HT3 receptor antagonist; Antidepressant; Forced swim test; Indole-2-carboxamide; Naphthyridine-3-carboxamide