Determining the relative efficacy of positive allosteric modulators of the GABAA receptor: design of a screening approach

J Biomol Screen. 2014 Mar;19(3):462-7. doi: 10.1177/1087057113501555. Epub 2013 Aug 29.


Gamma amino butyric acid receptors (GABA) are major therapeutic targets for the development of drugs in neurological and psychiatric disorders. The new generation of GABAA modulators is targeting subtype selectivity and low/partial efficacy on the receptor to potentially overcome the adverse effects described for drugs with full agonist profile. We evaluated a screening approach to measure the relative efficacy of GABAA positive allosteric modulators (PAM) using automated patch clamp and fluorescence membrane potential assays. We determined that the use of an internal comparator (zolpidem), tested on each cell in parallel to the test compound, provides a reliable approach to measure and compare the relative efficacy of PAM ligands. Patch clamp recordings on recombinant GABAA receptors, using a multiple drug addition protocol, allows us to rank PAM ligands with different levels of efficacies. We observed that fluorescence membrane potential assays are not predictive of the relative efficacies of GABAA PAM ligands.

Keywords: GABAA receptors; automated patch clamp; benzodiazepine; positive allosteric modulator; relative efficacy.

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • CHO Cells
  • Cell Line
  • Cricetulus
  • Drug Discovery
  • Drug Evaluation, Preclinical / methods*
  • GABA-A Receptor Agonists / pharmacology*
  • GABA-A Receptor Antagonists / pharmacology*
  • Humans
  • Patch-Clamp Techniques
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / metabolism*


  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Receptors, GABA-A