2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

J Med Chem. 1993 Sep 3;36(18):2645-57. doi: 10.1021/jm00070a008.


Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cisplatin
  • Computer Simulation
  • Dogs
  • Ferrets
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / metabolism
  • Isoquinolines / pharmacology
  • Male
  • Models, Molecular
  • Molecular Structure
  • Palonosetron
  • Pyridones / chemical synthesis*
  • Pyridones / metabolism
  • Quinuclidines / chemical synthesis*
  • Quinuclidines / metabolism
  • Quinuclidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Vomiting / chemically induced
  • Vomiting / drug therapy


  • Isoquinolines
  • Pyridones
  • Quinuclidines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Palonosetron
  • Cisplatin