Benzodiazepines GABAa receptor binding

Hong, X. and Hopfinger, A.J. (2003) 3D-pharmacophores of fiavonoid binding at the benzodiazepine GABAA receptor site using 4D-QSAR analysis. J. Chem. Inf. Comput. Sci.,... 

Maddalena, D. J. and Johnston, G. A. R. (1995) Prediction of receptor properties and binding affinity of ligands to benzodiazepine/GABAA receptors using artificial neural networks. J. Med. Chem. 38, 715-724. 

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

GABAa receptors that contain the al, a2, a3, and a5 subunits in combination with (3 and y subunits can bind classical benzodiazepines, e.g., diazepam, whereas GABAa receptors that contain the a4 and a6 subunits do not bind classical benzodiazepines. Essentially, all benzodiazepines that are currently in clinical use bind indiscriminately to GABAa receptors that contain the... 

Although flumazenil binds with high affinity to the benzodiazepine site of GABAa receptors, it has practically no action when given alone. However, flumazenil competitively blocks the action of benzodiazepine site agonists. Flumazenil can be used to terminate the action of benzodiazepines, e.g., after a benzodiazepine overdose. It may also serve as a diagnostic tool in this regard. 

The binding site for barbiturates on the GABAa receptor is less well defined. Barbiturates act by increasing the conductance level. In contrast to benzodiazepines, they also display direct agonistic action on GABAa receptors. Also in contrast to... 

Figure 19.7 The activity spectrum for different generic groups of compounds that bind to the benzodiazepine domain on the GABAa receptor...

Duggan, MJ and Stephenson, FA (1988) Benzodiazepine binding site heterogeneity in the purified GABAa receptor. Eur. J. Pharmacol. 154 293-298. 

Churn, S. B., Rana, A., Lee, K. el al. (2002). Calcium/calmodulin-dependent kinase II phosphorylation of the GABAa receptor alphal subunit modulates benzodiazepine binding. J. Neurochem. 82, 1065-76. 

Sigel, E. Buhr, A. (1997). The benzodiazepine binding site of GABAA receptors. Trends Pharmacol. Sci. 18, 425-9. 

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