Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3-0593.
Endogeneously occurring neuroactive steroids, metabolites of progesterone and deoxycorticosterone, have been shown previously to interact with the GABAA receptor with great specificity in vitro and to have anticonvulsant, anxiolytic and sedative activity in vivo. However, these endogenously occurring steroids are not useful as therapeutic agents due to their potential metabolism to hormonally active steroids and their poor oral bioavailability. In an attempt to develop therapeutic agents which would maintain the pharmacological profiles of endogeneous neuroactive steroids but with increased oral bioavailability and reduced metabolic liability, we explored simple substitutions at the 3 beta-position of the endogenous neuroactive steroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-P). This report describes part of the in vitro and in vivo pharmacological profile of a 3 beta-substituted analog, 3 beta-ethenyl-3 alpha-hydroxy-5 alpha-pregnan-20-one (Co 3-0593). The compound exhibited anticonvulsant activity against pentylenetrazol-induced seizures in mice and rats (ED50 = 5.6 and 11.5 mg/kg, i.p., respectively). Co 3-0593 showed robust anxiolytic effects, comparable to benzodiazepines in the Geller-Seifter test after both SC and oral administration. Furthermore, the anxiolytic activity was maintained after chronic administration suggesting an absence of tolerance. The compound did not affect the acquisition of a learned response at both anticonvulsant and anxiolytic doses. However, at higher doses the compound showed rotorod deficit which was further enhanced by ethanol. In summary, 3 beta-ethenyl-substituted 3 alpha, 5 alpha-P appeared to maintain the pharmacological activities of the endogenous neuroactive steroid with apparent oral activity.
Wieland
S
S
CoCensys Inc., Irvine, CA 92618, USA.
Belluzzi
J
J
Hawkinson
J E
JE
Hogenkamp
D
D
Upasani
R
R
Stein
L
L
Wood
P L
PL
Gee
K W
KW
Lan
N C
NC
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D018755:GABA Agonists / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009118:Muscimol / Q000378:metabolism; D010637:Phenolsulfonphthalein / Q000031:analogs & derivatives / Q000378:metabolism; D004856:Postural Balance / Q000187:drug effects; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; C109793:Co 3-0593; D018755:GABA Agonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; C076970:3,4,5,6-tetrabromophenolsulfonephthalein; D009118:Muscimol; D005445:Flunitrazepam; D011280:Pregnanolone; D010637:Phenolsulfonphthalein