Early clinical pharmacological trials with a novel partial benzodiazepine agonist/antagonist Ro 17-1812 using pharmaco-EEG and psychometry.

In a double-blind, placebo-controlled study the encephalotropic and psychotropic properties of a new partial benzodiazepine agonist Ro 17-1812 were investigated as compared to the pure agonist diazepam utilizing quantitative EEG and psychometric analysis as well as clinical observations. Ten normal volunteers received randomized (latin square) and at weekly intervals single oral doses of placebo, 0.05 mg, 0.1 mg and 0.2 mg Ro 17-1812 and 10 mg diazepam as reference drug. EEG recordings, psychometric tests and evaluation of pulse, blood pressure and side effects were carried out at the hours 0,1,2,3,4, and 6. Computer-assisted spectral-analysis of the EEG demonstrated after 10 mg diazepam a typical "anxiolytic" pharmaco-EEG profile characterized by an increase of beta activity, decrease of alpha activity and acceleration of the centroid of the total activity. Total power tended to decrease while delta activity tended to increase, although only in the resting condition. Ro 17-1812 induced in the vigilance controlled recordings a similar profile thereby exhibiting tranquilizing properties. However, in the resting condition the most consistent change was an increase of delta/theta activity along with a decrease of alpha activity, whereas only in the higher dosage range was beta activity also augmented. These data indicate a selective sedation after the novel partial agonist but are also reminiscent of changes seen after neuroleptic drugs. Dose/treatment efficacy calculations demonstrated 10 mg diazepam as the most CNS-effective drug followed closely by 0.2 mg Ro 17-1812, 0.1 and 0.05 mg while-placebo induced the least changes. Time-efficacy calculations showed a peak effect after 10 mg diazepam in the 1st hour with a gentle decline up to the 4th hour and thereafter again an increase (active metabolites), while the peak of Ro 17-1812 was consistently found in the 2nd hour with a steady decline thereafter as the encephalotropic effect in the 6th hour was less marked than in the 1st hour. Psychometric investigations showed the same time course of both compounds, with the most psychoactivity observed after 0.2 mg Ro 17-1812 and the least after placebo. The fact that the partial agonist induced more decrement in the noopsyche, but specifically in the thymopsyche, of the normal volunteers than the pure agonist may indicate a lower dependency risk of the former than the latter. Evaluation of pulse and blood pressure showed no clinically relevant findings.