Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity
- PMID: 27162327
- PMCID: PMC4889365
- DOI: 10.1073/pnas.1521825113
Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity
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.
Keywords: G-protein–coupled receptors; antinociception; dynorphin; natural compounds; salvinorin A.
Conflict of interest statement
The authors declare no conflict of interest.
Figures










Similar articles
-
Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A.Br J Pharmacol. 2015 Jan;172(2):515-31. doi: 10.1111/bph.12692. Epub 2014 Jul 1. Br J Pharmacol. 2015. PMID: 24641310 Free PMC article.
-
Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.Molecules. 2018 Oct 11;23(10):2602. doi: 10.3390/molecules23102602. Molecules. 2018. PMID: 30314288 Free PMC article.
-
Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse.Adv Pharmacol. 2014;69:481-511. doi: 10.1016/B978-0-12-420118-7.00012-3. Adv Pharmacol. 2014. PMID: 24484985 Free PMC article. Review.
-
Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11934-9. doi: 10.1073/pnas.182234399. Epub 2002 Aug 21. Proc Natl Acad Sci U S A. 2002. PMID: 12192085 Free PMC article.
-
A review of salvinorin analogs and their kappa-opioid receptor activity.Bioorg Med Chem Lett. 2018 May 15;28(9):1436-1445. doi: 10.1016/j.bmcl.2018.03.029. Epub 2018 Mar 12. Bioorg Med Chem Lett. 2018. PMID: 29615341 Free PMC article. Review.
Cited by
-
Natural Products for the Treatment of Pain: Chemistry and Pharmacology of Salvinorin A, Mitragynine, and Collybolide.Biochemistry. 2021 May 11;60(18):1381-1400. doi: 10.1021/acs.biochem.0c00629. Epub 2020 Sep 22. Biochemistry. 2021. PMID: 32930582 Free PMC article. Review.
-
Kappa Opioid Receptor on Pulmonary Macrophages and Immune Function.Transl Perioper Pain Med. 2020;7(3):225-233. doi: 10.31480/2330-4871/117. Epub 2020 Feb 20. Transl Perioper Pain Med. 2020. PMID: 33204767 Free PMC article.
-
Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch.Front Pharmacol. 2021 Nov 16;12:773204. doi: 10.3389/fphar.2021.773204. eCollection 2021. Front Pharmacol. 2021. PMID: 34867403 Free PMC article.
-
A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists.Front Pharmacol. 2019 Apr 17;10:407. doi: 10.3389/fphar.2019.00407. eCollection 2019. Front Pharmacol. 2019. PMID: 31057409 Free PMC article. Review.
-
G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder.Br J Pharmacol. 2020 Apr;177(7):1497-1513. doi: 10.1111/bph.14913. Epub 2020 Jan 24. Br J Pharmacol. 2020. PMID: 31705528 Free PMC article.
References
-
- Kieffer BL, Gavériaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol. 2002;66(5):285–306. - PubMed
-
- Gavériaux-Ruff C. Opiate-induced analgesia: Contributions from mu, delta and kappa opioid receptors mouse mutants. Curr Pharm Des. 2013;19(42):7373–7381. - PubMed
-
- Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;73:953–990. - PubMed
-
- Dykstra LA, Gmerek DE, Winger G, Woods JH. Kappa opioids in rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects. J Pharmacol Exp Ther. 1987;242(2):413–420. - PubMed
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials