Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3 alpha, 21-dihydroxy-3 beta-trifluoromethyl-19-nor-5 beta-pregnan-20-one), a selective modulator of gamma-aminobutyric acid(A) receptors

The purpose of this study was to evaluate the effects of a novel neuroactiv e steroid, Co 2-6749 (GMA-839; WAY-141839; 3 alpha, 21-dihydroxy-3 beta-tri fluoromethyl-19-nor-5 beta-pregnan-20-one), on gamma-aminobutyric acid(A) r eceptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [S-35]t-butylbicyclophosphoroth ionate binding in rat brain cortical membranes with an IC50 value of 230 nM and in human gamma-aminobutyric acidA receptor subunit combinations of alp ha 1 beta 2 gamma 2L, alpha 2 beta 2 gamma 2L, alpha 3 beta 2 gamma 2L, alp ha 4 beta 3 gamma 2L, alpha 5 beta 2 gamma 2L, and alpha 6 beta 3 gamma 2L 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 d ose-related increase in punished responding with a minimum effective dose o f 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpun ished responding and relative to ataxia, and no tolerance. Additionally, et hanol caused less than a 2-fold shift to the left in the dose-response func tion of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict pa radigm, punished responding was maximally increased to 784% of vehicle cont rol by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished resp onding 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 sed ation/ ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for deve lopment as a novel anxiolytic drug.