Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives

J Med Chem. 1993 Nov 12;36(23):3693-9. doi: 10.1021/jm00075a026.

Abstract

On the basis of the structures of ondansetron and GR 65,630, its ring-opened C-linked methylimidazole analogue, novel 1,7-annelated indole derivatives were synthesized as potential 5-HT3 antagonists. Receptor binding studies show that all compounds display a high affinity for the 5-HT3 receptors. In both series annelation results in compounds being 7 and 4 times more potent than the references ondansetron and GR 65,630, respectively. Similar to ondansetron, the 1,7-annelated indoles show little stereoselectivity. The (-)-isomers are only slightly more potent than the (+)-isomers. The receptor binding profile of l-10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,8,9,10,11-hexahydro-4H-pyri do [3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT3 receptors (Ki = 0.19 nM), a weak affinity for sigma-receptors (Ki = 340 nM), muscarine M1 receptors (Ki = 910 nM), and 5-HT4 receptors (Ki = 960 nM) and no affinity (Ki > or = 5000 nM) for all the other receptor types tested (n = 37). The new compounds fit the proposed necessary chemical template for binding: a heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center at well-defined distances. The enhanced potency of the annelated 1,7-indole derivatives indicates that the extra ring provides a favorable hydrophobic area for interaction with the 5-HT3 receptor site. In vivo cilansetron is more potent and induces less central side effects than ondansetron. At present cilansetron is in clinical trials.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Carbazoles / chemical synthesis*
  • Carbazoles / pharmacology
  • Cell Membrane / metabolism
  • Cerebral Cortex / metabolism
  • Guinea Pigs
  • Ileum / drug effects
  • Ileum / physiology
  • Imidazoles / chemistry*
  • Indoles / chemical synthesis*
  • Indoles / chemistry*
  • Indoles / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Ondansetron / chemistry*
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Rats
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiology

Substances

  • Carbazoles
  • Imidazoles
  • Indoles
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • GR 65630
  • cilansetron
  • Ondansetron