Enhancement of GABA binding by the benzodiazepine partial agonist CGS9896.

Compounds have been reported that act on the benzodiazepine receptor as full agonists (diazepam and CL218872), full antagonists (CGS8216 and RO15-1788), on partial agonists (CGS9896). We examined the effect of these compounds on [3H]GABA binding to membrane fragments from rat brain. Incubations were performed at 37 degrees C in a buffer containing EGTA to reduce free calcium ion levels. Centrifugation was then used to separate bound from free [3H]GABA. Diazepam caused a 20-45% enhancement of [3H]GABA binding and this effect was inhibited by 5 mM CaCl2. The magnitude of the enhancement of [3H]GABA by CL218872 was similar to that of diazepam. In contrast, the benzodiazepine antagonists, RO15-1788 and CGS8216 caused little enhancement of [3H]GABA binding. Finally, the partial agonist CGS9896 was distinguishable from both the benzodiazepine antagonists and full agonists by an intermediate level of enhancement of [3H]GABA binding. The extent of enhancement of [3H]GABA binding appears to be predictive of the pharmacological efficacy of compounds acting at the benzodiazepine receptor.