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

作者：Zolkowska Dorota; Dhir Ashish; Krishnan Kathiresan; Covey Douglas F; Rogawski Michael A^*

来源：Psychopharmacology, 2014, 231(17): 3325-3332.

DOI：10.1007/s00213-014-3546-x

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

Androsterone [(3 alpha,5 alpha)-3-hydroxyandrostan-17-one; 5 alpha,3 alpha-A] and its 5 beta-epimer etiocholanolone [(3 alpha,5 beta)-3-hydroxyandrostan-17-one; 5 beta,3 alpha-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABA(A) receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5 alpha,3 alpha-A and 5 beta,3 alpha-A, the unnatural enantiomers are more potent at GABA(A) receptors than the natural forms.
The aim of this study was to compare the anticonvulsant potencies and time courses of 5 alpha,3 alpha-A and 5 beta,3 alpha-A with their enantiomers in mouse seizure models.
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).
In the 6-Hz test, the ED50 values of ent-5 alpha,3 alpha-A was 5.0 mg/kg whereas the value for 5 alpha,3 alpha-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABA(A) 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-5 alpha,3 alpha-A and 5 alpha,3 alpha-A, respectively. Similar relationships were obtained for the 5 beta-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5 beta,3 alpha-A were 11.8 and 20.4 mg/kg whereas the values for 5 beta,3 alpha-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5 alpha,3 alpha-A persisted for somewhat longer (5 h) than for 5 alpha,3 alpha-A (4 h); protection by ent-5 beta,3 alpha-A also persisted longer (3 h) than for 5 beta,3 alpha-A (2 h).
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.

• 出版日期2014-9