Pharmacological Characterization Of Cgs-17867a As A Benzodiazepine Receptor Agonist Devoid Of Limiting Behavioral-Effects

CGS 17867A (2-(4-chlorophenyl)-2,5,6,7,8,9,-hexahydor-3H-pyrazolo [4,3,-c]quinoline-3-one-hydrochloride salt) is a tetrahydorpyrazoloquinoline related to the benzodiazepine (BZ) receptor agonist, CGS 9896. The compound is an effective inhibitor of [3H]flunitrazepam binding to the central BZ receptor (IC50 = 1.0 nM). Activity at the GABA-A receptor and chloride channel components of the BZ receptor complex indicate a profile predictive of a partial agonist. CGS 17867A is orally active, block PTZ discriminative stimuli, produces an increase in conflict responding, and generalizes to CGS 9896 discriminative stimuli, indicating potential anxiolytic efficacy comparable to that of diazepam. This compound is more potent than diazepam in protecting rats against pentylenetetrazol-induced convulsions and is effective in delaying the development of kindled seizures. Only moderate protection is noted against picrotoxin-induced convulsions and no effect is produced by CGS 17867A against maximal electroshock- or strychnine-induced convulsions. An absence of muscle relaxant properties is suggested by the inability of CGS 17867A to impair rotorod performance or to generalize to diazepam discriminative stimuli. Unlike CGS 9896, CGS 17867A does not antagonize diazepam-induced rotorod deficit or diazepam discriminative stimuli. CGS 17867A potentiates ethanol-induced rotorod impairment only at doses in excess of those producing therapeutic efficacy, in contrast to the BZs, which induce both effects at comparable doses. Mice treated chronically with CGS 17867A do not show any tolerance or withdrawal effects upon subsequent testing. CGS 17867A produces a preclinical profile indicative of a partial BZ receptor agonist. The compound has anxiolytic and anticonvulsant potential and a reduced propensity to produce the limiting effects of the classical BZs.