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.G-protein-coupled receptors | natural compounds | salvinorin A | dynorphin | antinociception

Biased Receptor Signaling in Drug Discovery

“…Similarly, protein mutation has been employed to generate SAR data for biased signaling (G protein receptor 183, Daugvilaite et al, 2017;GLP-1, Wootten et al, 2016). Chemical scaffolds yielding biased molecules range from modification of natural endogenous agonists to natural products (Gupta et al, 2016). In general, there has been a steady increase in the number of studies on the structural features of molecules required for biased signaling (Tan et al, 2018; and see Table 5).…”

Biased Opioid Ligands

“…Initially extracted from the mushroom Collybia maculata ( Basidomycota ) in 1974 by the group of Dr. Pierre Potier, Collybolide (Colly) is a natural product pertaining to the class of sesquiterpenes [ 80 ]. It was only later in 2016 that a study demonstrated the potential of Colly and its diastereoisomers (9-epi-Colly) in pain attenuation [ 66 ]. Due to its structural similarities with Salvinorin A (a common furyl-δ-lactone motif), this agent was tested on human hMOR, hDOR, and hKOR and was found to be very selective of KOR.…”

“…Due to its structural similarities with Salvinorin A (a common furyl-δ-lactone motif), this agent was tested on human hMOR, hDOR, and hKOR and was found to be very selective of KOR. When the authors looked at functional selectivity, they showed that Colly was a very potent agonist in [ 35 S]GTPγS assays (EC 50 ≈ 1 nM) and dose-dependently inhibited adenylyl cyclase activity, but was also potent for ERK1/2 phosphorylation suggesting that it acts as a biased agonist of the hKOR though β-arrestin 2 recruitment with this natural product remains unknown [ 66 ]. The effects were reversed upon treatment with NorBNI showing a KOR-mediated effect.…”

“…However, at the same doses of both Colly and Salvinorin A (2 mg/kg), only Colly was uncovered to significantly attenuate chloroquine-mediated scratching behavior, with the effects here again reversed upon the administration of NorBNI. Finally, the authors noticed that this agent could exhibit antidepressant and anxiogenic activity in the forced swim test and open field test instead of prodepressant and anxiolytic phenotype expected of classical KOR agonists [ 66 ].…”

Harnessing cyclotides to design and develop novel peptide GPCR ligands

“…In recent years, a considerable amount of literature has been accumulated, highlighting the potential of natural products as ligands of G protein-coupled receptors (GPCRs). 4,5 These transmembrane receptors with more than 800 members encoded in the human genome are targeted by approximately 35% of US Food and Drug Administration-approved drugs, thus highlighting their…”