Pharmacology of pyrazolopyridines

Abstract

Pyrazolopyridines (PZP's) in general represent a chemically unique class of non-sedative anxiolytic agents. Tracazolate (ICI 136,753) is a member of pyrazolopyridine series that has shown anxiolytic properties in animal models. Tracazolate demonstrates a wider separation between sedative and therapeutic doses than do benzodiazepines. In addition, tracazolate appears to cause fewer adverse interactions than the benzodiazepines in combination with barbiturates and alcohol. In interaction studies, tracazolate potentiated both the antimetrazol and anticonflict effects of chlordiazepoxide. Pyrazolopyridines cause enhancement of both 3H-flunitrazepam (3H-FLU) and 3H-GABA to their binding sites in brain. The enhancement of 3H-FLU binding by PZP's and GABA are additive and reversed by bicuculline. The enhancement of 3H-GABA binding by PZP's and benzodiazepines are additive and reversed by picrotoxin. It is hypothesized that the action of PZP's, and particularly tracazolate, may be related to their effects upon a GABA-stimulated chloride ionophore site. Finally, benzodiazepine antagonists (e.g., RO-15 1788) fail to reverse either the anxiolytic properties of 3H-FLU enhancers or their 3H-GABA binding enhancement effects. In contrast, benzodiazepine antagonists readily reverse the anxiolytic effects of benzodiazepines and non-benzodiazepines which cause 3H-FLU displacement. These data suggest that tracazolate, a non-benzodiazepine, has a pharmacological profile suggestive of novel anxiolytic activity.