Determining the relative efficacy of positive allosteric modulators of the GABAA receptor: design of a screening approach
| Autor: | Nathalie Pacico, Philippe Ghisdal, Nadine Noel, Etienne Hanon, Patrik Foerch, Murielle Martini, Christian Wolff |
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| Rok vydání: | 2013 |
| Předmět: |
Agonist
Zolpidem Patch-Clamp Techniques medicine.drug_class Allosteric regulation Drug Evaluation Preclinical CHO Cells Pharmacology Biology Biochemistry Analytical Chemistry Cell Line Cricetulus Automated patch clamp Allosteric Regulation Drug Discovery medicine Animals Humans Patch clamp GABA-A Receptor Agonists GABA-A Receptor Antagonists Receptor Benzodiazepine GABAA receptor Receptors GABA-A Molecular Medicine Biotechnology medicine.drug |
| Zdroj: | Journal of biomolecular screening. 19(3) |
| ISSN: | 1552-454X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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