Pyrazolo[1,5-a]pyrimidines: receptor binding and anxiolytic behavioral studies.

Pyrazolo[1,5-a]pyrimidines (PZP) have been reported to be specific anxiolytic agents which do not potentiate ethanol or barbiturates. To further investigate these compounds, three of the most promising analogs were synthesized and a tritium-labeled analog of one of them prepared by a new synthetic procedure. These analogs did not compete with [3H]flunitrazepam or [3H]beta-carboline ethyl ester binding nor did they potentiate the [3H]flunitrazepam binding. Receptor binding studies with the [3H]PZP revealed a low affinity receptor site, distinct from that of the benzodiazepines, but with only a small fraction (20%) of specific binding. Behavioral tests using three different animal models for anxiety: muricide, approach/avoidance conflict and two-chamber exploration tests gave conflicting results, positive in the first and negative in the latter two. Furthermore, these compounds were found not to be antagonists of diazepam's anticonvulsant activity. Taken together, these results, while provocative, do not support evidence that these analogs are promising specific anxiolytic agents.