Non-benzodiazepine anxiolytics: potential activity of phenylpiperazines without 3H-diazepam displacing action.

Four phenylpiperazine derivatives exhibited an activity similar to benzodiazepines and meprobamate in the 4-plate test. One of these (compound IV) demonstrated anxiolytic like activity in a step-down avoidance technique, in electroshock induced aggression and in the staircase test. In contrast to benzodiazepines, compound IV was not anticonvulsant, myorelaxant or sedative. Confirmation of the anxiolytic activity of compound IV in animal models was obtained in 3 separate clinical trials in anxious patients. The mechanism of action of these phenylpiperazines appears to be different from the benzodiazepines as they do not displace 3H-diazepam binding nor do they interact with other elements of the GABA receptor macromolecular complex. Instead, compound IV interacts with both dopaminergic and serotoninergic neuron systems. Thus, from this data it would appear that an activity at the benzodiazepine recognition site is not obligatory for anxiolytic activity in man or in animals models.