title: Enhancement of GABA binding by the benzodiazepine partial agonist CGS9896.
abstract: 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.
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors*; D001570:Benzodiazepinones / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D005442:Flumazenil; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D001570:Benzodiazepinones; D011720:Pyrazoles; D011724:Pyridazines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C021604:CL 218872; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; D008274:Magnesium; D002122:Calcium Chloride; D003975:Diazepam