Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 21, Pages 6041-6046Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1521825113
Keywords
G-protein-coupled receptors; natural compounds; salvinorin A; dynorphin; antinociception
Categories
Funding
- National Institutes of Health [DA008863, NS026880, T32 DA007135]
- University of Oklahoma
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Among the opioid receptors, the kappa-opioid receptor (kappa OR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting kappa OR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-delta-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective kappa OR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10-to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of kappa OR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits similar to 10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting kappa OR with reduced side effects.
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