title: 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.
authors.affiliation: Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Achla
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Ivone
authors.initials: I
authors.lastname: Gomes
authors.affiliation: Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Erin N
authors.initials: EN
authors.lastname: Bobeck
authors.affiliation: Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Fakira
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019;
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Massaro
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019;
authors.forename: Indrajeet
authors.initials: I
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Adrien
authors.initials: A
authors.lastname: Cavé
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Hamm
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Chemistry, Vanderbilt University, Nashville, TN 37232 joseph.parello@vanderbilt.edu lakshmi.devi@mssm.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Parello
authors.affiliation: Department of Pharmacology & Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; joseph.parello@vanderbilt.edu lakshmi.devi@mssm.edu.
authors.forename: Lakshmi A
authors.identifier: 0000-0002-2179-2874
authors.initials: LA
authors.lastname: Devi
mesh_terms: D000363:Agaricales / Q000737:chemistry*; D000818:Animals; D000982:Antipruritics / Q000737:chemistry / Q000494:pharmacology*; D045785:Diterpenes, Clerodane / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects*
chemical_list: D000982:Antipruritics; D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa
keywords: G-protein–coupled receptors; antinociception; dynorphin; natural compounds; salvinorin A