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Pharmacological profile of a 17β-heteroaryl-substituted neuroactive steroid

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Abstract

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 17β-acetyl side chain with an isoxazole bioisostere.

Objectives

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.

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Abbreviations

ACN:

Acetonitrile

AD50 :

Ataxogenic half-maximal dose where half of the mice fail the RR assay

ANOVA:

Analysis of variance

BZ:

Benzodiazepine

CNS:

Central nervous system

DMRM:

Daughter multiple reaction monitoring

DMSO:

Dimethyl sulfoxide

EC10 :

Concentration that evokes 10 % of the maximum response

EC50 :

Concentration eliciting half the maximum response

EC100 :

Concentration that evokes a maximum response

ED50 :

Effective dose of drug at which half of the animals respond

EPM:

Elevated plus maze

GABAAR:

Gamma-aminobutyric acid(A) receptor

Ganaxolone:

3α-hydroxy-3β-methyl-5α-pregnan-20-one

HPβCD:

2-Hydroxypropyl-β-cyclodextrin

HPLC:

High performance liquid chromatograph

IACUC:

Institutional Animal Care and Use Committee

LC/MS:

Liquid chromatography/mass spectrometry

LGIC:

Ligand-gated ion channel

MED:

Minimum effective dose

MTBE:

Methyl tert-butyl ether

PAM:

Positive allosteric modulator

PD:

Pharmacodynamic

PK:

Pharmacokinetic

PTZ:

Pentylenetetrazol

RR:

Rotarod

SAR:

Structure-activity relationship

SEM:

Standard error of the mean

UCI-50027:

3-[3α-hydroxy-3β-methyl-5α-androstan-17β-yl]-5-(hydroxymethyl)isoxazole

UCI-50031:

(S)-3-[3α-hydroxy-3β-methyl-5α-androstan-17β-yl]-5-(1-hydroxyethyl)isoxazole

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Acknowledgments

Grant was from the Center for Autism Research & Translation at the University of California Irvine to K.W.G.

Conflict of interest

The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA, 92697, USA

    Derk J. Hogenkamp, Minhtam B. Tran, Ryan F. Yoshimura, Timothy B. Johnstone & Kelvin W. Gee

  2. Anvyl LLC, 18092 Sky Park South, Suite F, Irvine, CA, 92614, USA

    Richard Kanner

Authors
  1. Derk J. Hogenkamp
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  2. Minhtam B. Tran
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  3. Ryan F. Yoshimura
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  4. Timothy B. Johnstone
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  5. Richard Kanner
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  6. Kelvin W. Gee
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Corresponding author

Correspondence to Kelvin W. Gee.

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Hogenkamp, D.J., Tran, M.B., Yoshimura, R.F. et al. Pharmacological profile of a 17β-heteroaryl-substituted neuroactive steroid. Psychopharmacology 231, 3517–3524 (2014). https://doi.org/10.1007/s00213-014-3494-5

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  • DOI: https://doi.org/10.1007/s00213-014-3494-5

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