Abstract
The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3α, 21-dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one), on γ-aminobutyric acidA 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 γ-aminobutyric acidA receptor subunit combinations of α1β2γ2L, α2β2γ2L, α3β2γ2L, α4β3γ2L, α5β2γ2L, and α6β3γ2L 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.
Footnotes
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Send reprint requests to: Kimberly E. Vanover, Ph.D., In Vivo Pharmacology, ACADIA Pharmaceuticals, 3911 Sorrento Valley Blvd., San Diego, CA 92121-1402. E-mail:kvanover{at}acadia-pharm.com
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↵1 Present address: ACADIA Pharmaceuticals, 3911 Sorrento Valley Blvd., San Diego, CA 92121-1402.
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↵2 Present address: Elan Pharmaceuticals, 3760 Haven Ave., Menlo Park, CA 94025-1012.
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↵3 Present address: Centaur Pharmaceuticals, 484 Oakmead Pkwy., Sunnyvale, CA 94086.
- Abbreviations:
- GABA
- γ-aminobutyric acid
- 3α,5α-P
- allopregnanolone, 3α-hydroxy-5α-pregnan-20-one
- 3α,5β-P
- pregnanolone, 3α-hydroxy-5β-pregnan-20-one
- Co 2-6749
- 3α, 21-dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one (GMA-839
- WAY-141839)
- PCR, polymerase chain reaction
- TBPS
- t-butylbicyclophosphorothionate
- VI
- variable interval
- MED
- minimum effective dose
- MSD
- minimum suppressive dose
- FR
- fixed ratio
- HPβCD
- hydroxypropyl-β-cyclodextrin
- PEG
- polyethylene glycol
- TD50
- toxic dose50
- TI
- therapeutic index
- Received March 23, 2000.
- Accepted June 26, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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