5-HT3 receptor antagonists. 1. New quinoline derivatives

J Med Chem. 1992 Dec 25;35(26):4893-902. doi: 10.1021/jm00104a016.


A series of esters and amides of 1-alkyl-2-oxo-1,2-dihydroquinoline-4- carboxylic acid or 2-alkoxy-quinoline-4-carboxylic acid containing a basic azabicycloalkyl moiety has been synthesized and evaluated for affinity for the [3H]quipazine-labeled 5-HT3 receptors. Most of the esters exhibited 10-fold more potent activity than that of ondansetron (1; Ki = 7.6 nM). Lipophilic substituents at the 1- or 2-position of the quinoline ring enhanced affinity for the receptors. Compounds 21 and 37 showed the highest affinity (Ki = 0.32 and 0.31 nM, respectively) among them. On the other hand, most of the amides showed 100-fold lower affinity than that of the esters. Molecular modeling studies indicated that the carbonyl moiety in 19 (ester) or 31 (amide) was not coplanar to the plane of an aromatic ring (over 20 degrees deviation). Although some of the selected compounds exhibited potent activity in the Bezold-Jarisch (B-J) reflex test, good correlation was not observed between the affinity for the 5-HT3 receptors and the activity in the B-J reflex test (in vivo). From these data, it was suggested that our quinoline derivatives might interact with the 5-HT3 receptors in a different way from that of the reported 5-HT3 receptor antagonists presumably due to the presence of the heterogeneity of the 5-HT3 receptors between brain and heart.

MeSH terms

  • Animals
  • Male
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism


  • Quinolines
  • Receptors, Serotonin
  • Serotonin Antagonists