Collybolide is a novel biased agonist of κ-opioid receptors

[Alchemica]

So a newly discovered κ-opioid receptor agonist... in a mushroom. I wonder if the biased agonism makes for an equally effective salvinorin A-esque antidepressant?

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity.

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.

 

"...to date, it is not known if Collys exhibit hallucinogenic effects. An extensive web search for information about the fungus C. maculata did not reveal any reports of hallucinogenic properties: only that the fungus is bitter to taste. If it holds true that Collys are not hallucinogenic, this would rule out the involvement of the furyl-δ-lactone motif in the hallucinogenic effects of Sal A. Structure–activity studies comparing modifications in Sal A and Colly structures could help elucidate the motifs required for the hallucinogenic properties. In addition, it would be important to examine the contribution of biased signaling toward the differences in the behavioral effects of Sal A and Colly. Such studies are particularly important given reports that biased signaling at κOR can distinguish the aversive effects of κOR agonists from the antinociceptive effects (8). Consistent with this, studies have shown that, whereas Sal A appears to be an unbiased ligand based on G-protein activation and β-arrestin recruitment assays, a structural derivative, RB-64, appears to exhibit G-protein–biased activity (32). Studies with this compound argue for a contribution of the G-protein pathway in κOR-mediated analgesia and aversion and of other pathways on κ OR-mediated motor coordination, sedation, and anhedonia (33). In the present study, we show that Colly exhibits biased agonistic activity and differs from Sal A in blocking chloroquine-mediated itch. This observation makes Colly an ideal compound
for further studies. "

 

 

" In this study, we find that Colly, like Sal A, exhibits antinociception and is aversive in mice. However, unlike Sal A, a 2-mg/kg dose of Colly tends to decrease immobility time in the forced swim test, suggesting that Colly may exhibit antidepressant activity. Interestingly, evaluation of the effects of Colly in the open field test suggests that at a dose of 2 mg/kg it tends to be anxiogenic, whereas Sal A has been reported to be anxiolytic (28)."

 

http://sci-hub.bz/10.1073/pnas.1521825113

Edited May 13, 2016 by Alchemica

[stonewolf]

Interesting but if has even marginally similar effects to sally d then it would be considered too risky for clinicians to want to go near.  Just look at the slow progress of ketamine for depression.

 

There is a lot of hype around psychedelics as anti depressants these days but it won't take off without a fundamental cultural shift vis a vis the war on drugs.