title: Design, synthesis and structure-activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression.
abstract: A novel series of quinoxalin-2-carboxamides were designed based on the ligand-based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by spectral data. The target new chemical entities were evaluated for their 5-HT(3) receptor antagonisms in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methyl-5-HT, which was expressed in the form of pA(2) value. All the synthesized compounds showed antagonism towards 5-HT(3) receptor; based on this result, a structure-activity relationship was derived, which reveals that the aromatic residue in 5-HT(3) receptor antagonists may have hydrophobic interaction with 5-HT(3) receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA(2) values exhibited good anti-depressant-like activity as compared to the vehicle-treated group.
authors.affiliation: Pharmacy Group, FD-III, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Mahesh
authors.forename: Thangaraj
authors.initials: T
authors.lastname: Devadoss
authors.forename: Dilip Kumar
authors.initials: DK
authors.lastname: Pandey
authors.forename: Shvetank
authors.initials: S
authors.lastname: Bhatt
authors.forename: Shushil Kumar
authors.initials: SK
authors.lastname: Yadav
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D003863:Depression / Q000188:drug therapy*; D015195:Drug Design; D006168:Guinea Pigs; D051379:Mice; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists