Vol. 282, Issue 1, 420-429, 1997

CCD-3693: An Orally Bioavailable Analog of the Endogenous Neuroactive Steroid, Pregnanolone, Demonstrates Potent Sedative Hypnotic Actions in the Rat

Dale M. Edgar, Wesley F. Seidel, Kelvin W. Gee, Nancy C. Lan, George Field, Haiji Xia, Jon E. Hawkinson, Scott Wieland, Richard B. Carter and Paul L. Wood

Sleep Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford (D.M.E., W.F.S.); Department of Pharmacology, College of Medicine, University of California, Irvine (K.W.G.); and CoCensys Inc., Irvine, California (N.C.L., G.F., H.X., J.E.H., S.W., R.B.C., P.L.W.)

An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroencephalogram-defined sleep-wake states, locomotor activity and body temperature were concurrently measured 30 hr before and after treatment. Identical procedures were used to test triazolam and zolpidem. Triazolam (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) and the neuroactive steroids (10-30 mg/kg) produced dose-dependent increases in non-rapid eye movement (NREM) sleep. At this dose and time of day (in which the rats were predominantly awake during the 6 hr before treatment) the neuroactive steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, however, significantly interfere with rapid eye movement sleep and were more selective in reducing (EEG) wakefulness, with relatively less locomotor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct "rebound" wakefulness after the NREM sleep-promoting effect subsided, although the neuroactive steroids did not. In addition, in vitro binding studies and in vivo pharmacological data confirmed that CCD-3693 was orally active in standard tests of anxiety, anticonvulsant, loss-of-righting and passive avoidance.