Hogenkamp_2014_Psychopharmacology.(Berl)_231_3517

RATIONALE: In order to improve upon the pharmacological properties of the neuroactive steroid ganaxolone, it was used as the starting point in the design of novel neurosteroids that replace the 17beta-acetyl side chain with an isoxazole bioisostere. OBJECTIVES: UCI-50027 (3-[3alpha-hydroxy-3beta-methyl-5alpha-androstan-17beta-yl]-5-(hydroxymethyl)isox azole) was designed as an orally active neuroactive steroid specifically targeted at the gamma-aminobutyric acid(A) receptor (GABAAR).
METHODS: UCI-50027 was tested in vitro in Xenopus oocytes expressing human GABAARs and in vivo as an anticonvulsant, for ataxic effects and for anxiolytic activity.
RESULTS: In vitro, UCI-50027 dose-dependently enhanced the activity of GABA at human alpha1beta2gamma2L, alpha2beta1gamma2L, and alpha4beta3delta GABAARs. Consistent with its action as a positive allosteric modulator (PAM), it had no direct activity in the absence of GABA. UCI-50027 protected against acute pentylenetetrazol (PTZ)-induced convulsions with an ED50 of 6 mg/kg p.o. In the rotarod (RR) paradigm in mice, the AD50 (the ataxic dose where half of the animals fail the RR test) was found to be 38 mg/kg p.o., giving a therapeutic index (TI = RR AD50/PTZ ED50) approximately 6 versus 2.8 for ganaxolone. In the mouse-elevated plus maze (EPM) model for anxiety, UCI-50027 showed a minimum effective dose (MED) CONCLUSIONS: UCI-50027 is an orally active neuroactive steroid with pharmacological activity consistent with a GABAAR PAM that has an improved separation between anticonvulsant/anxiolytic and rotarod effects, potent activity as an anticonvulsant and anxiolytic when compared to ganaxolone.