O6C-20-nor-salvinorin A is a stable and potent KOR agonist

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Hirasawa, Shun¹  Cho, Min¹  Brust, Tarsis F.^2,3  Roach, Jeremy J.¹  Bohn, Laura M.^2,3  Shenvi, Ryan A.¹ 

[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA

[3] Scripps Res Inst, Dept Neurosci, Jupiter, FL 33458 USA

关键词: Salvinorin;    Kappa opioid receptor;    Total synthesis;    Heck reaction;    Conformational analysis;   

DOI  :  10.1016/j.bmcl.2018.01.055

来源: Elsevier

【 摘 要 】

Salvinorin A (SalA) is a potent and selective agonist of the kappa-opioid receptor (KOR), but its instability has frustrated medicinal chemistry efforts. Treatment of SalA with weak bases like DBU leads to C8 epimerization with loss of receptor affinity and signaling potency. Here we show that replacement of C20 with H and replacement of O6 with CH2 stabilizes the SalA scaffold relative to its C8 epimer, so much so that epimerization is completely supressed. This new compound, O6C-20-nor-SalA, retains high potency for agonism of KOR. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

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