Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2018-01-31 , DOI: 10.1016/j.bmcl.2018.01.055 Shun Hirasawa 1 , Min Cho 1 , Tarsis F Brust 2 , Jeremy J Roach 1 , Laura M Bohn 2 , Ryan A Shenvi 1
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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.
中文翻译：
O6C-20-nor-salvinorin A 是一种稳定、有效的 KOR 激动剂
Salvinorin A (SalA) 是一种有效的、选择性的kappa -阿片受体 (KOR) 激动剂，但其不稳定性阻碍了药物化学研究。用 DBU 等弱碱处理 SalA 会导致 C8 差向异构化，从而丧失受体亲和力和信号传导效力。在这里，我们表明，用 H 取代 C20 并用 CH 2取代 O6 可以稳定 SalA 支架相对于其 C8 差向异构体的稳定性，以至于完全抑制差向异构化。这种新化合物 O6C-20-nor-SalA 保留了 KOR 激动剂的高效力。
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