Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety

Bioorg Med Chem Lett. 2006 Mar 15;16(6):1582-5. doi: 10.1016/j.bmcl.2005.12.027. Epub 2005 Dec 27.

Abstract

Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones are high affinity GABA(A) agonists. Compound 16d has good oral bioavailability in rat, functional selectivity for the GABA(A)alpha2 and alpha3-subtypes and is anxiolytic in a conditioned animal model of anxiety with minimal sedation observed at full BZ binding site occupancy.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Anxiety Agents / chemical synthesis
  • Anti-Anxiety Agents / pharmacology*
  • Anxiety Disorders / drug therapy*
  • Benzodiazepines / metabolism
  • Binding Sites
  • Biological Availability
  • Cell Line
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • GABA Agonists / chemical synthesis
  • GABA Agonists / pharmacology*
  • GABA-A Receptor Agonists*
  • Humans
  • Mice
  • Molecular Structure
  • Patch-Clamp Techniques
  • Rats
  • Receptors, GABA-A
  • Recombinant Proteins / agonists
  • Structure-Activity Relationship

Substances

  • Anti-Anxiety Agents
  • GABA Agonists
  • GABA-A Receptor Agonists
  • GABRA2 protein, human
  • GABRA3 protein, human
  • Gabra3 protein, mouse
  • Gabra3 protein, rat
  • Receptors, GABA-A
  • Recombinant Proteins
  • Benzodiazepines