Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation
Version of Record online: 29 JAN 2009
2005 British Pharmacological Society
British Journal of Pharmacology
Volume 145, Issue 7, pages 894–906, August 2005
How to Cite
Downing, S. S., Lee, Y. T., Farb, D. H. and Gibbs, T. T. (2005), Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation. British Journal of Pharmacology, 145: 894–906. doi: 10.1038/sj.bjp.0706251
- Issue online: 29 JAN 2009
- Version of Record online: 29 JAN 2009
- (Received January 25, 2005, Revised March 31, 2005, Accepted April 6, 2005)
- Two state model;
- kojic amine;
- partial agonist
- 1Benzodiazepines (BZDs) have been used extensively for more than 40 years because of their high therapeutic index and low toxicity. Although BZDs are understood to act primarily as allosteric modulators of GABAA receptors, the mechanism of modulation is not well understood.
- 2The applicability of an allosteric model with two binding sites for γ-aminobutyric acid (GABA) and one for a BZD-like modulator was investigated.
- 3This model predicts that BZDs should enhance the efficacy of partial agonists.
- 4Consistent with this prediction, diazepam increased the efficacy of the GABAA receptor partial agonist kojic amine in chick spinal cord neurons.
- 5To further test the validity of the model, the effects of diazepam, flurazepam, and zolpidem were examined using wild-type and spontaneously active mutant α1(L263S)β3γ2 GABAA receptors expressed in HEK-293 cells.
- 6In agreement with the predictions of the allosteric model, all three modulators acted as direct agonists for the spontaneously active receptors.
- 7The results indicate that BZD-like modulators enhance the amplitude of the GABA response by stabilizing the open channel active state relative to the inactive state by less than 1 kcal, which is similar to the energy of stabilization conferred by a single hydrogen bond.
British Journal of Pharmacology (2005) 145, 894–906. doi:10.1038/sj.bjp.0706251