On the central effects of a new partial benzodiazepine agonist Ro 16-6028 in man: pharmaco-EEG and psychometric studies.

In a double-blind placebo-controlled study, the encephalotropic and psychotropic properties of a new partial benzodiazepine agonist Ro 16-6028 were investigated as compared to a pure agonist diazepam utilizing quantitative EEG and psychometric analysis as well as clinical observations. Ten normal volunteers received randomized (latin square design) and at weekly intervals, single oral doses of placebo, 0.05 mg, 0.1 mg and 0.2 mg Ro 16-6028 and 10 mg diazepam as reference substance. EEG-recordings, psychometric tests and evaluation of blood pressure, pulse and side effects were carried out at 0, 1, 2, 3, 4 and 6 h. 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 total activity. Ro 16-6028 induced in the vigilance-controlled recordings a similar profile thereby exhibiting tranquilizing properties too. However, in the resting condition we observed also an increase of delta/theta activity along with a decrease of alpha activity while the beta augmentation was observed mostly in the fast frequency bands and not so much in the middle fast frequency bands as is the case with the known full agonists. The latter findings were somewhat reminiscent of the pharmaco-EEG profiles seen often in certain neuroleptics. Our data indicate a selective sedation after the novel partial agonist. Dose/treatment-efficacy calculations demonstrated 10 mg diazepam as the most CNS-effective drug followed closely by 0.2 mg Ro 16-6028, 0.1 mg and 0.05 mg, while placebo induced the least changes. Only 0.2 mg Ro 16-6028 and the reference compound differed from placebo at all times. Time-efficacy calculations showed a peak effect of the novel partial agonist around the 3rd h and that of diazepam in the 1st h. Psychometric tests demonstrated similar findings. After 0.2 mg Ro 16-6028 a decrease of attention, numerical memory, psychomotor activity, wakefulness and CFF was observed, while mood improved at later time periods outlasting the sedation. After 10 mg diazepam 10 out of 13 psychometric and psychophysiological variables showed significant findings previously described as typical for anxiolytic sedatives in normals. On the whole, the partial agonist induced less sedation than the full agonist, which is reflected in its superiority in regard to noopsychic and thymopsychic functions. Evaluation of pulse and blood pressure showed no clinically relevant findings. The new partial agonist was well tolerated.