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

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Author(s)

    • SAITO TOSHIYUKI
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • SUGA OSAMU
    • Medicinal Biology Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • SUJAKU TETSUJO
    • Medicinal Biology Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • NAGAHISA ATSUSHI
    • Medicinal Biology Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • KOJIMA YASUHIRO
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • KOJIMA NAKAO
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • AOKI FUKUMATSU
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • HIRAI HIDEO
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • INAGAKI TAISUKE
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • MATSUNAGA YASUE
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • SAKAKIBARA TATSUO
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • SAKEMI SHINICHI
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • SUZUKI YUMIKO
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.
    • WATANABE SHUZO
    • Natural Product & Lead Discovery Laboratory, Central Research Division, Pfizer Pharmaceuticals Inc.

Abstract

A κ opioid receptor binding inhibitor was isolated from the fermentation broth of a basidiomycete, <i>Hericium ramosum</i> CL24240 and identified as erinacine E (<b>1</b>). Three analogs of <b>1</b> were produced by fermentation in other media and by microbial biotransformation. Of these compounds, <b>1</b> 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 <b>1</b> was a highly-selective binding inhibitor for the κ opioid receptor: 0.8 μM (IC<sub>50</sub>) for κ, > 200 μM for μ, and > 200 μM for δ opioid receptor. Compound <b>1</b> suppressed electrically-stimulated twitch responses of rabbit vas deferens with an ED<sub>50</sub> of 14 μM. The suppression was recovered by adding a selective κ opioid receptor antagonist nor-binaltorphimine, indicating that <b>1</b> is a κ opioid receptor agonist.

Journal

  • The Journal of Antibiotics

    The Journal of Antibiotics 51(11), 983-990, 1998

    JAPAN ANTIBIOTICS RESEARCH ASSOCIATION

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