In recent years, the κ-opioid receptor (κOR) has become an attractive therapeutic target for the treatment of a number of disorders including depression, visceral pain, and drug addiction. A search for natural products with novel scaffolds targeting κOR has been intensive. Here, we report the discovery of a natural product (Colly) from the fungus Collybia maculata as a novel scaffold that contains a furyl-δ-lactone core structure similar to that of Salvinorin A, another natural product isolated from the mint Salvia divinorum. We show that Colly functions as a κOR agonist with antinociceptive and antipruritic activity. Interestingly, Colly exhibits biased agonistic activity, suggesting that it could be used as a backbone for the generation of novel therapeutics targeting κOR with reduced side effects.

Abstract

Among the opioid receptors, the κ-opioid receptor (κOR) 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 κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-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 κOR 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 κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼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 κOR with reduced side effects.