Neuroactive Type-A γ-Aminobutyric Acid Receptor Allosteric Modulator Steroids from the Hypobranchial Gland of Marine Mollusk, <i>Conus geographus</i>
Changshan Niu, Lee S. Leavitt, Zhenjian Lin, Noemi D. Paguigan, Lili Sun, Jie Zhang, Joshua P. Torres, Shrinivasan Raghuraman, Kevin Chase, Roberto Cadeddu, Manju Karthikeyan, Marco Bortolato, Christopher A. Reilly, Ronald W. Hughen, Alan R. Light, Baldomero M. Olivera, Eric W. Schmidt
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.