Psychopharmacology

, Volume 231, Issue 17, pp 3325–3332 | Cite as

Anticonvulsant potencies of the enantiomers of the neurosteroids androsterone and etiocholanolone exceed those of the natural forms

  • Dorota Zolkowska
  • Ashish Dhir
  • Kathiresan Krishnan
  • Douglas F. Covey
  • Michael A. Rogawski
Original Investigation

Abstract

Rationale

Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms.

Objectives

The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models.

Methods

Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ).

Results

In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5β-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5β,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5β,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5β,3α-A also persisted longer (~3 h) than for 5β,3α-A (~2 h).

Conclusions

The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.

Keywords

Androsterone Etiocholanolone Enantiomer Six-Hertz test Pentylenetetrazol test Maximal electroshock test 

Abbreviations

5α,3α-A

Androsterone

5β,3α-A

Etiocholanolone

ent-5α,3α-A

ent-Androsterone

ent-5β,3α-A

ent-Etiocholanolone

PTZ

Pentylenetetrazol

MES

Maximal electroshock

PI

Protective index

SAR

Structure–activity relationship

Notes

Acknowledgments

This study was supported in part by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number NS079202 (M.A.R.) and the National Institute of General Medical Sciences of the National Institutes of Health under award number GM47969 (D.F.C.). The experiments were conducted in compliance with all applicable laws and regulations.

Conflict of interest

The authors declare no conflicts of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Dorota Zolkowska
    • 1
  • Ashish Dhir
    • 1
    • 3
  • Kathiresan Krishnan
    • 2
  • Douglas F. Covey
    • 2
  • Michael A. Rogawski
    • 1
    • 4
  1. 1.Department of NeurologyUniversity of California, Davis School of MedicineSacramentoUSA
  2. 2.Department of Developmental BiologyWashington University in St. Louis School of MedicineSt. LouisUSA
  3. 3.Department of BiotechnologyGovernment of India, c/o Gujarat Forensic Sciences UniversityGandhinagarIndia
  4. 4.Department of NeurologyUniversity of CaliforniaSacramentoUSA

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