CGS-17867A

[3H]Ro 15-4513, a negative modulator at the benzodiazepine receptor, binds with high affinity to all known benzodiazepine binding sites associated with the GABAA receptors. The present experiments surveyed a number of benzodiazepine receptor ligands with different chemical structures and different intrinsic pharmacological profiles for their ability to displace [3H]Ro 15-4513 binding in rat cerebellar membranes. The latter have been shown to possess two types of binding sites, one sensitive to positive modulators such as diazepam and the other insensitive to them (diazepam-insensitive). Whereas the full positive modulators from the benzodiazepine, beta-carboline, and quinoline classes did not displace binding at the diazepam-insensitive sites, the partial positive modulators' affinities for these sites varied much more, some being very potent and others having no affinity at all. All the neutral antagonists tested displaced binding at both types of binding sites, while some of the negative modulators were apparently not potent at the diazepam-insensitive sites. In an alcohol-sensitive rat line (ANT, alcohol non-tolerant), with an enhanced affinity for positive modulators at the diazepam-insensitive sites, these sites also exhibited enhanced affinity for some of the partial positive and negative modulators. The results suggest that the cerebellar diazepam-insensitive [3H]Ro 15-4513 binding sites have unique substrate specificity. It remains to be established which behaviours are affected by activation or inhibition of these receptors that are characterized by their insensitivity to benzodiazepine-positive modulators.