Developing dual functional allosteric modulators of GABA(A) receptors

Bioorg Med Chem. 2010 Dec 1;18(23):8374-82. doi: 10.1016/j.bmc.2010.09.058. Epub 2010 Sep 29.


Positive modulators at benzodiazepine sites of α2- and α3-containing GABA(A) receptors are believed to be anxiolytic. Negative allosteric modulators of α5-containing GABA(A) receptors enhance cognition. By oocyte two-electrode voltage clamp and subsequent structure-activity relationship studies, we discovered cinnoline and quinoline derivatives that were both positive modulators at α2-/α3-containing GABA(A) receptors and negative modulators at α5-containing GABA(A) receptors. In addition, these compounds showed no functional activity at α1-containing GABA(A) receptors. Such dual functional modulators of GABA(A) receptors might be useful for treating comorbidity of anxiety and cognitive impairments in neurological and psychiatric illnesses.

MeSH terms

  • Allosteric Regulation
  • Benzodiazepines / chemistry
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Patch-Clamp Techniques
  • Quantum Theory
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Receptors, GABA-A / chemistry*
  • Receptors, GABA-A / metabolism
  • Structure-Activity Relationship


  • Heterocyclic Compounds, 2-Ring
  • Quinolines
  • Receptors, GABA-A
  • Benzodiazepines
  • quinoline
  • cinnoline