title: Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), a selective modulator of gamma-aminobutyric acid(A) receptors.
abstract: The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), on gamma-aminobutyric acid(A) receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [(35)S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC(50) value of 230 nM and in human gamma-aminobutyric acid(A) receptor subunit combinations of alpha1beta2gamma2L, alpha2beta2gamma2L, alpha3beta2gamma2L, alpha4beta3gamma2L, alpha5beta2gamma2L, and alpha6beta3gamma2L receptors (IC(50) 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.
authors.affiliation: CoCensys, Inc., Irvine, California, USA. kvanover@acadia-pharm.com
authors.forename: K E
authors.initials: KE
authors.lastname: Vanover
authors.forename: S
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: J E
authors.initials: JE
authors.lastname: Hawkinson
authors.forename: N C
authors.initials: NC
authors.lastname: Lan
authors.forename: J D
authors.initials: JD
authors.lastname: Belluzzi
authors.forename: L
authors.initials: L
authors.lastname: Stein
authors.forename: J E
authors.initials: JE
authors.lastname: Barrett
authors.forename: P L
authors.initials: PL
authors.lastname: Wood
authors.forename: R B
authors.initials: RB
authors.lastname: Carter
mesh_terms: D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002460:Cell Line; D010856:Columbidae; D003220:Conflict, Psychological; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D012453:Saimiri
chemical_list: D014151:Anti-Anxiety Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C414545:Co 2-6749; D018757:GABA Modulators; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone; D000525:Alprazolam