Discovery of new anti-depressants from structurally novel 5-HT3 receptor antagonists: design, synthesis and pharmacological evaluation of 3-ethoxyquinoxalin-2-carboxamides.
A novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT(3) receptor antagonist using ligand-based approach. The desired carboxamides were synthesized from the key intermediate, 3-ethoxyquinoxalin-2-carboxylic acid by coupling with appropriate amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The 5-HT(3) receptor antagonism was evaluated in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methy-5-HT, which was expressed in the form of pA(2) values. Compound 6h (3-ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-yl)methanone was found to be the most active compound, which expressed a pA(2) value of 7.7. In forced swim test, the compounds with higher pA(2) value exhibited good anti-depressant-like activity and compounds with lower pA(2) value failed to show activity as compared to the vehicle-treated group.
Pharmacy Group, FD-III, Birla Institute of Technology & Science, Pilani, Rajasthan 333 031, India.
Radhakrishnan
R
Mahesh
Thangaraj
T
Devadoss
Dilip Kumar
DK
Pandey
Shvetank
S
Bhatt
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D009197:Myenteric Plexus / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C558293:(3-ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-yl)methanone; D000577:Amides; D000928:Antidepressive Agents; D010879:Piperazines; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists