Vol. 295, Issue 1, 337-345, October 2000

Characterization of the Anxiolytic Properties of a Novel Neuroactive Steroid, Co 2-6749 (GMA-839; WAY-141839; 3, 21-Dihydroxy-3-trifluoromethyl-19-nor-5-pregnan-20-one), a Selective Modulator of -Aminobutyric Acid_A Receptors

Kimberly E. Vanover¹ , Sharon Rosenzweig-Lipson, Jon E. Hawkinson² , Nancy C. Lan, James D. Belluzzi, Larry Stein, James E. Barrett, Paul L. Wood³ and Richard B. Carter

CoCensys, Inc., Irvine, California (K.E.V., J.E.H., N.C.L., P.L.W., R.B.C.); Wyeth-Ayerst Research, Neuroscience Research Division, Princeton, New Jersey (S.R.-L., J.E.B.); and Department of Pharmacology, College of Medicine, University of California Irvine, Irvine, California (J.D.B., L.S.)

The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3, 21-dihydroxy-3-trifluoromethyl-19-nor-5-pregnan-20-one), on -aminobutyric acid_A receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [³⁵S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC₅₀ value of 230 nM and in human -aminobutyric acid_A receptor subunit combinations of 122L, 222L, 322L, 432L, 522L, and 632L receptors (IC₅₀ values of 200, 200, 96, 2300, 210, and 2000 nM). Rats were trained in a Geller-Seifter operant conflict paradigm. Co 2-6749 caused a dose-related increase in punished responding with a minimum effective dose of 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpunished responding and relative to ataxia, and no tolerance. Additionally, ethanol caused less than a 2-fold shift to the left in the dose-response function of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict paradigm, punished responding was maximally increased to 784% of vehicle control by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished responding at this dose. Similarly, punished responding in squirrel monkeys was maximally increased to 1774% of control by 10 mg/kg, p.o., with no effect on unpunished responding at this dose. With robust anxiolytic-like activity across species, a large separation between anxiolytic-like effects and sedation/ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for development as a novel anxiolytic drug.