Abstract
In a program to identify pain treatments with low addiction potential, we isolated five steroids, conosteroids A-E (1-5), from the hypobranchial gland of the mollusk Conus geographus. Compounds 1-5 were active in a mouse dorsal root ganglion (DRG) assay that suggested that they might be analgesic. A synthetic analogue 6 was used for a detailed pharmacological study. Compound 6 significantly increased the pain threshold in mice in the hot-plate test at 2 and 50 mg/kg. Compound 6 at 500 nM antagonizes type-A γ-aminobutyric acid receptors (GABAARs). In a patch-clamp experiment, out of the six subunit combinations tested, 6 exhibited subtype selectivity, most strongly antagonizing α1β1γ2 and α4β3γ2 receptors (IC50 1.5 and 1.0 μM, respectively). Although the structures of 1-6 differ from those of known neuroactive steroids, they are cell-type-selective modulators of GABAARs, expanding the known chemical space of neuroactive steroids.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Action Potentials / drug effects
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Analgesics / chemical synthesis
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Analgesics / chemistry*
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Analgesics / pharmacology
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Analgesics / therapeutic use
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Animals
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Conus Snail / chemistry*
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Conus Snail / metabolism
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Disease Models, Animal
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GABA Antagonists / chemistry*
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GABA Antagonists / isolation & purification
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GABA Antagonists / pharmacology
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GABA Antagonists / therapeutic use
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Ganglia, Spinal / cytology
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / physiology
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Mice
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Mice, Inbred C57BL
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Molecular Conformation
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Neurosteroids / chemistry*
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Neurosteroids / isolation & purification
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Neurosteroids / pharmacology
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Neurosteroids / therapeutic use
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Pain / chemically induced
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Pain / drug therapy
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Pain / pathology
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Protein Subunits / chemistry
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Protein Subunits / metabolism
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Receptors, GABA / chemistry*
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Receptors, GABA / metabolism
Substances
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Analgesics
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GABA Antagonists
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Neurosteroids
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Protein Subunits
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Receptors, GABA