title: Modification of pyrazoloquinolinone affinity by GABA predicts efficacy at the benzodiazepine receptor.
abstract: A series of pyrazoloquinolinones CGS 9896, CGS 9895 and CGS 8216 have been reported to exhibit agonist, partial agonist and antagonist properties, respectively, at the benzodiazepine receptor. We have examined the effects of these compounds and of diazepam on pentylenetetrazole seizure thresholds in mice and found CGS 9896 to be a partial agonist and CGS 8216 a weak inverse agonist in this respect; CGS 9895 was essentially devoid of efficacy. In the presence of 100 microM GABA and 150 mM NaCl, the affinity of CGS 9896 for the benzodiazepine receptor at 37 degrees C was significantly increased whereas the affinity of CGS 8216 was similarly decreased and that of CGS 9895 was unchanged. The effect of GABA on the affinity of these ligands for the benzodiazepine receptor at 37 degrees C was thus predictive of the pharmacological efficacy which we observed.
mesh_terms: D000818:Animals; D003975:Diazepam / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole / Q000633:toxicity; D011720:Pyrazoles / Q000494:pharmacology*; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011720:Pyrazoles; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one; C039232:2,5-dihydro-2-(4-methoxyphenyl)-3H-pyrazolo(4,3-c)quinolin-3-one; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; D003975:Diazepam; D010433:Pentylenetetrazole