Pharmaco-EEG and psychometric studies with a novel selective benzodiazepine agonist/antagonist Ro 23-0364

In a double-blind, placebo-controlled study, the encephalotropic and psychotropic properties of Ro 23-0364, a novel imidazobenzodiazepine with mixed benzodiazepine agonist/antagonist properties, were investigated as compared with the pure agonist diazepam utilizing quantitative EEG and psychometric analyses as well as clinical observations. Ten normal volunteers received randomized (latin square) and at weekly intervals single oral doses of placebo, 0.25 mg, 0.5 mg and 1.0 mg Ro 23-0364 and 10 mg diazepam as reference drug. EEG-recordings and evaluation of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6, and 8; psychometric tests at the same times except the first hour. Computer-assisted spectral analyses 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 absolute and relative power of the dominant frequency, furthered by an acceleration of the centroid of the total activity and a slowing of the centroid of the combined delta/theta-activity. In addition, there was an increase of delta-activity specifically in the resting recording condition suggesting also sedative properties of the reference compound. Ro 23-0364 induced in the vigilance-controlled recordings a similar profile as diazepam-although less pronounced-thereby exhibiting tranquilizing qualities. However, in the resting condition the most consistent change was an augmentation of delta/theta-activity along with an attenuation of alpha-activity, which was evident already in the lower dosage range and is reminiscent also of changes seen after sedative neuroleptic drugs (although the centroid slowing was missing). These data indicate a selective sedation of the mixed agonist/antagonist in the resting state. Dose-efficacy calculations based on EEG-changes demonstrated the reference compound, 1.0 and 0.5 mg Ro 23-0364 different from placebo. 10 mg diazepam was by far the most CNS-active compound inducing significantly more changes than the three doses of the mixed agonist/antagonist. Within the latter the two higher doses were superior to 0.25 mg but could not be differentiated from each other. Time-efficacy calculations showed the maximal encephalotropic effect of diazepam within the first two hours while the peak effect of 1.0 mg and 0.5 mg Ro 23-0364 fell into the 6th and 4th hour, respectively. There were no differences between the time periods after 0.25 mg although there was a trend towards high activity in the first two hours followed by a trough in the 4th and 6th hour and thereafter again an increase.(ABSTRACT TRUNCATED AT 400 WORDS)