Synthesis and evaluation of N-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1H-indole-carboxamides as cholecystokinin antagonists

J Pharm Pharmacol. 2006 Mar;58(3):393-401. doi: 10.1211/jpp.58.3.0015.

Abstract

The structure-activity relationship optimization of the pyrazoline template 3a resulted in novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides 4a-4e. These non-peptidal CCK ligands have been shown to act as potent CCK1 ligands in a [125]I-CCK-8 receptor binding assay. The best amides (4c and 4d) of this series displayed an IC50 of 20/25 nM for the CCK1 receptor. In a subsequent in-vivo evaluation using various behaviour pharmacological assays, an anxiolytic effect of these novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides was found at high doses in the elevated plus-maze. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.33/0.41 mg kg(-1) was determined for amide 4c/4d and the antidepressant effect had a magnitude comparable to desimipramine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / pharmacology*
  • Analgesics / chemical synthesis
  • Analgesics / pharmacology
  • Animals
  • Antidepressive Agents / chemical synthesis
  • Antidepressive Agents / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred ICR
  • Motor Activity / drug effects
  • Pain Measurement
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology*
  • Radioligand Assay
  • Receptor, Cholecystokinin A / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Amides
  • Analgesics
  • Antidepressive Agents
  • Indoles
  • Pyrazoles
  • Receptor, Cholecystokinin A