Neuroactive Type-A Gamma-Aminobutyric Acid Receptor Allosteric Modulator Steroids From The Hypobranchial Gland Of Marine Mollusk, Conus Geographus

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 gamma-aminobutyric acid receptors (GABA(A)Rs). In a patch-clamp experiment, out of the six subunit combinations tested, 6 exhibited subtype selectivity, most strongly antagonizing alpha(1)beta(1)gamma(2) and alpha(4)beta(3)gamma(2) receptors (IC50 1.5 and 1.0 mu M, respectively). Although the structures of 1-6 differ from those of known neuroactive steroids, they are cell-type-selective modulators of GABA(A)Rs, expanding the known chemical space of neuroactive steroids.