title: Pharmacological profile of a 17β-heteroaryl-substituted neuroactive steroid.
abstract: BACKGROUND
  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 17β-acetyl side chain with an isoxazole bioisostere.
  
  
  OBJECTIVE
  UCI-50027 (3-[3α-hydroxy-3β-methyl-5α-androstan-17β-yl]-5-(hydroxymethyl)isoxazole) 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 α1β2γ2L, α2β1γ2L, and α4β3δ 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)∼6 versus 2.8 for ganaxolone. In the mouse-elevated plus maze (EPM) model for anxiety, UCI-50027 showed a minimum effective dose (MED) ≤0.3 mg/kg p.o. Thus, the TI (TI = RR AD50/EPM MED) for the compound as an anxiolytic is ≥127 versus 3.3 for ganaxolone.
  
  
  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.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA, 92697, USA.
authors.forename: Derk J
authors.initials: DJ
authors.lastname: Hogenkamp
authors.forename: Minhtam B
authors.initials: MB
authors.lastname: Tran
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Yoshimura
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Johnstone
authors.forename: Richard
authors.initials: R
authors.lastname: Kanner
authors.forename: Kelvin W
authors.initials: KW
authors.lastname: Gee
mesh_terms: D000731:Androstanes / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D004856:Postural Balance / Q000187:drug effects; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D014981:Xenopus
chemical_list: C000598241:3-(3alpha-hydroxy-3beta-methyl-5alpha-androstan-17beta-yl)-5-(hydroxymethyl)isoxazole; D000731:Androstanes; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; C105051:ganaxolone; D011280:Pregnanolone; D010433:Pentylenetetrazole