posted on 2021-05-05, 15:10authored byChangshan 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
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.