Erinacine E as a Kappa Opioid Receptor Agonist and Its New Analogs from a Basidiomycete, Hericium ramosum

A κ opioid receptor binding inhibitor was isolated from the fermentation broth of a basidiomycete, Hericium ramosum CL24240 and identified as erinacine E (1). Three analogs of 1 were produced by fermentation in other media and by microbial biotransformation. Of these compounds, 1 was shown to be the most potent binding inhibitor. Preliminary SAR studies of these compounds indicated that all functional groups and side chains were required for the activity. Compound 1 was a highly-selective binding inhibitor for the κ opioid receptor: 0.8 μM (IC50) for κ, > 200 μM for μ, and > 200 μM for δ opioid receptor. Compound 1 suppressed electrically-stimulated twitch responses of rabbit vas deferens with an ED50 of 14 μM. The suppression was recovered by adding a selective κ opioid receptor antagonist nor-binaltorphimine, indicating that 1 is a κ opioid receptor agonist.