Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1523-6. doi: 10.1016/j.bmcl.2010.12.107. Epub 2010 Dec 28.

Abstract

A novel series of agonists at the benzodiazepine binding site of the GABA(A) receptor was prepared by functionalizing a known template. Adding substituents to the pyrazolone-oxygen of CGS-9896 led to a number of compounds with selectivities for either α2- or α1-containing GABA(A) receptor subtypes offering an entry into indications such as anxiety and insomnia. In this communication, structure-activity relationship and efforts to increase in vitro stabilities are discussed.

MeSH terms

  • Benzodiazepines / chemistry*
  • Benzodiazepines / metabolism
  • Binding Sites
  • Drug Stability
  • GABA-A Receptor Agonists / chemical synthesis*
  • GABA-A Receptor Agonists / chemistry
  • GABA-A Receptor Agonists / pharmacology
  • Inhibitory Concentration 50
  • Ligands
  • Molecular Structure
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Receptors, GABA-A* / metabolism
  • Structure-Activity Relationship

Substances

  • GABA-A Receptor Agonists
  • Ligands
  • Pyrazoles
  • Receptors, GABA-A
  • Benzodiazepines
  • 2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one