Subtype selectivity of α+β- site ligands of GABAA receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors

Br J Pharmacol. 2013 May;169(2):384-99. doi: 10.1111/bph.12153.


Background and purpose: GABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) elicits a strong and subtype-dependent enhancement of GABA-induced currents via a novel drug-binding site at extracellular αx+βy- (x = 1-6, y = 1-3) interfaces. Here, we investigated 16 structural analogues of CGS 9895 for their ability to modulate GABA-induced currents of various GABAA receptor subtypes.

Experimental approach: Recombinant GABAA receptor subtypes were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method.

Key results: Most of the compounds investigated were able to modulate GABA-induced currents of αβ and αβγ receptors to a comparable extent, suggesting that the effect of these drugs is not dependent on the benzodiazepine site of GABAA receptors. Steric hindrance experiments demonstrated that these compounds exert their action predominantly via the αx+βy- (x = 1-6, y = 1-3) interfaces. Whereas some compounds are unselectively modulating a broad range of receptor subtypes, other compounds feature remarkable functional selectivity for the α6β3γ2 receptor, or behave as null modulators at some receptor subtypes investigated.

Conclusion and implications: Pyrazoloquinolinones and pyrazolopyridinones represent the first prototypes of drugs exerting benzodiazepine-like modulatory effects via the α+β- interface of GABAA receptors. The discovery of modulators with functional subtype selectivity at this class of binding sites provides a highly useful tool for the investigation of α6β2/3γ2 receptor function, and may lead to novel therapeutic principles.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Female
  • GABA Modulators / pharmacology*
  • Humans
  • Ligands
  • Oocytes
  • Patch-Clamp Techniques
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Receptors, GABA-A / drug effects*
  • Receptors, GABA-A / metabolism
  • Xenopus laevis


  • GABA Modulators
  • Ligands
  • Pyrazoles
  • Receptors, GABA-A
  • 2,5-dihydro-2-(4-methoxyphenyl)-3H-pyrazolo(4,3-c)quinolin-3-one