Development of High-Affinity 5-HT3 Receptor Antagonists. 1. Initial Structure-Activity Relationship of Novel Benzamides

J Med Chem. 1992 Mar 6;35(5):895-903. doi: 10.1021/jm00083a014.

Abstract

This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antiemetics / chemical synthesis*
  • Antiemetics / pharmacology
  • Antiemetics / therapeutic use
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • Benzamides / therapeutic use
  • Benzofurans / chemical synthesis*
  • Benzofurans / pharmacology
  • Benzofurans / therapeutic use
  • Binding, Competitive
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / pharmacology
  • Bridged Bicyclo Compounds / therapeutic use
  • Bridged Bicyclo Compounds, Heterocyclic*
  • Cerebral Cortex / metabolism
  • Cisplatin / toxicity
  • Ferrets
  • Granisetron
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Indazoles / pharmacology
  • Indazoles / therapeutic use
  • Indoles / metabolism
  • Male
  • Metoclopramide / pharmacology
  • Metoclopramide / therapeutic use
  • Molecular Structure
  • Ondansetron
  • Rats
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists*
  • Structure-Activity Relationship
  • Vomiting / chemically induced
  • Vomiting / prevention & control

Substances

  • Antiemetics
  • Benzamides
  • Benzofurans
  • Bridged Bicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Imidazoles
  • Indazoles
  • Indoles
  • Receptors, Serotonin
  • Serotonin Antagonists
  • GR 65630
  • N-(1-azabicyclo(2.2.2)-oct-3-yl)-5-chlorospiro(benzofuran-2(3H),1'-cyclohexane)-7-carboxamide
  • Ondansetron
  • Metoclopramide
  • Cisplatin
  • Granisetron