CCD-3693 - AN ORALLY BIOAVAILABLE ANALOG OF THE ENDOGENOUS NEUROACTIVE STEROID, PREGNANOLONE, DEMONSTRATES POTENT SEDATIVE HYPNOTIC ACTIONSIN THE RAT

An endogenous neuroactive steroid, pregnanolone, and an orally availab le synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroenc ephalogram-defined sleep-wake states, locomotor activity and body temp erature were concurrently measured 30 hr before and after treatment. I dentical procedures were used to test triazolam and zolpidem. Triazola m (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) and the neuroactive steroid s (10-30 mg/kg) produced dose-dependent increases in non-rapid eye mov ement (NREM) sleep. At this dose and time of day (in which the rats we re predominantly awake during the 6 hr before treatment) the neuroacti ve steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, howe ver, significantly interfere with rapid eye movement sleep and were mo re selective in reducing (EEG) wakefulness, with relatively less locom otor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct ''rebou nd'' wakefulness after the NREM sleep-promoting effect subsided, altho ugh the neuroactive steroids did not. In addition, in vitro binding st udies and in vivo pharmacological data confirmed that CCD-3693 was ora lly active in standard tests of anxiety, anticonvulsant, loss-of-right ing and passive avoidance.