ERINACINE E AS A KAPPA-OPIOID RECEPTOR AGONIST AND ITS NEW ANALOGS FROM A BASIDIOMYCETE, HERICIUM-RAMOSUM

A kappa opioid receptor binding inhibitor was isolated from the fermen tation broth of a basidiomycete, Hericium ramosum CL24240 and identifi ed as erinacine E (1). Three analogs of 1 were produced by fermentatio n in other media and by microbial biotransformation. Of these compound s, 1 was shown to be the most potent binding inhibitor. Preliminary SA R studies of these compounds indicated that all functional groups and side chains were required for the activity. Compound 1 was a highly-se lective binding inhibitor for the kappa opioid receptor: 0.8 mu M (IC5 0) for kappa, > 200 mu M for mu, and > 200 mu M for delta opioid recep tor. Compound 1 suppressed electrically-stimulated twitch responses of rabbit vas deferens with an ED50 of 14 mu M. The suppression was reco vered adding a selective kappa opioid receptor antagonist nor-binaltor phimine, indicating that 1 is a kappa opioid receptor agonist.