CGS 9896 and ZK 91296, but not CGS 8216 and RO 15-1788, are pure benzodiazepine receptor antagonists on mouse neurons in culture.
The effects of several benzodiazepine receptor ligands on gamma-aminobutyric acid (GABA) responses and on diazepam (DZ) enhancement of GABA responses on mouse spinal cord and cerebral hemisphere neurons are reported. The neurons were grown in primary dissociated cell culture, and intracellular microelectrode recording techniques were used. DZ and Ro 15-1788 reversibly enhanced GABA responses from spinal cord neurons in a concentration-dependent manner. Maximal enhancement was obtained for DZ at 500 nM (82%) and for Ro 15-1788 at 1 microM (18%). CGS 9896 and ZK 91296, in concentrations from 1 nM to 10 microM, were devoid of intrinsic effects in spinal cord and cerebral hemisphere neurons. CGS 8216 and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) reversibly and dose-dependently reduced GABA responses on spinal cord neurons. Maximal reduction was obtained for CGS 8216 at 50 nM (10%) and for DMCM at 1 microM (39%). CGS 8216 (IC50 = 2.6 nM), ZK 91296 (IC50 = 9 nM), CGS 9896 (IC50 = 17 nM) and Ro 15-1788 (IC50 = 40 nM) antagonized (100 nM) DZ enhancement of GABA responses in a concentration-dependent manner. In addition, CGS 9896 antagonized the effects of Ro 15-1788 and CGS 8216 on GABA responses, and CGS 9896 and ZK 91296 antagonized the reduction of GABA responses by DMCM. On the studied neurons, DZ can be classified as an agonist, Ro 15-1788 as a weak partial agonist, CGS 8216 as a weak partial inverse agonist and DMCM as an inverse agonist at the benzodiazepine receptor. CGS 9896 and ZK 91296 were pure antagonists at the benzodiazepine receptor.
D000818:Animals; D001921:Brain / Q000166:cytology; D002243:Carbolines / Q000494:pharmacology*; D002478:Cells, Cultured; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004594:Electrophysiology; D005442:Flumazenil / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002243:Carbolines; D011720:Pyrazoles; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; C038933:ZK 91296; D003975:Diazepam