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Molecular Pharmacology

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Research ArticleArticle

Enantioselective Blockade of T-type Ca2+ Current in Adult Rat Sensory Neurons by a Steroid That Lacks γ-Aminobutyric Acid-Modulatory Activity

Slobodan M. Todorovic, Murali Prakriya, Yasunori M. Nakashima, Kent R. Nilsson, Mingchen Han, Charles F. Zorumski, Douglas F. Covey and Christopher J. Lingle
Molecular Pharmacology November 1998, 54 (5) 918-927; DOI: https://doi.org/10.1124/mol.54.5.918
Slobodan M. Todorovic
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Murali Prakriya
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Yasunori M. Nakashima
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Kent R. Nilsson
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Mingchen Han
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Charles F. Zorumski
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Douglas F. Covey
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Christopher J. Lingle
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Abstract

A number of steroids seem to have anesthetic effects resulting primarily from their ability to potentiate currents gated by γ-aminobutyric acidA (GABAA) receptor activation. One such compound is (3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile [(+)-ACN]. We were interested in whether carbonitrile substitution at other ring positions might result in other pharmacological consequences. Here we examine effects of (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile [(+)-ECN] on GABAA receptors and Ca2+channels. In contrast to (+)-ACN, (+)-ECN does not potentiate GABAA-receptor activated currents, nor does it directly gate GABAA-receptor mediated currents. However, both steroids produce an enantioselective reduction of T-type current. (+)-ECN blocked T current with an IC50 value of 0.3 μm with a maximal block of 41%. (+)-ACN produced a partial block of T current (44% maximal block) with an IC50 value of 0.4 μm. Block of T current showed mild use- and voltage-dependence. The (−)-ECN enantiomer was about 33 times less potent than (+)-ECN, with an IC50 value of 10 μm and an amount of maximal block comparable to (+)-ECN. (+)-ECN was less effective at blocking high-voltage-activated Ca2+ current in DRG neurons (IC50 value of 9.3 μm with maximal block of about 27%) and hippocampal neurons. (+)-ECN (10 μm) had minimal effects on voltage-gated sodium and potassium currents in rat chromaffin cells. The results identify a steroid with no effects on GABAAreceptors that produces a partial inhibition of T-type Ca2+current with reasonably high affinity and selectivity. Further study of steroid actions on T currents may lead to even more selective and potent agents.

Footnotes

    • Received June 18, 1998.
    • Accepted August 14, 1998.
  • Send reprint requests to: Dr. Christopher Lingle, Box 8054, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110. E-mail:clingle{at}morpheus.wustl.edu

  • ↵1 Current affiliation: Surgical Operating Theatre, Kyushu University Hospital, Fukuoka, 812-8582, Japan

  • This work was supported by National Institutes of Health Grants GM47969 (C.F.Z., D.F.C., and C.J.L.) and MH00964 (C.F.Z.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

Enantioselective Blockade of T-type Ca2+ Current in Adult Rat Sensory Neurons by a Steroid That Lacks γ-Aminobutyric Acid-Modulatory Activity

Slobodan M. Todorovic, Murali Prakriya, Yasunori M. Nakashima, Kent R. Nilsson, Mingchen Han, Charles F. Zorumski, Douglas F. Covey and Christopher J. Lingle
Molecular Pharmacology November 1, 1998, 54 (5) 918-927; DOI: https://doi.org/10.1124/mol.54.5.918

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Research ArticleArticle

Enantioselective Blockade of T-type Ca2+ Current in Adult Rat Sensory Neurons by a Steroid That Lacks γ-Aminobutyric Acid-Modulatory Activity

Slobodan M. Todorovic, Murali Prakriya, Yasunori M. Nakashima, Kent R. Nilsson, Mingchen Han, Charles F. Zorumski, Douglas F. Covey and Christopher J. Lingle
Molecular Pharmacology November 1, 1998, 54 (5) 918-927; DOI: https://doi.org/10.1124/mol.54.5.918
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