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

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 16; pp. 2770 - 2772
• Main Authors: Hirasawa, Shun, Cho, Min, Brust, Tarsis F., Roach, Jeremy J., Bohn, Laura M., Shenvi, Ryan A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2018; Elsevier
• Subjects: Carbon - chemistry; Carbon - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Conformational analysis; Diterpenes, Clerodane - chemical synthesis; Diterpenes, Clerodane - chemistry; Diterpenes, Clerodane - pharmacology; Heck reaction; Humans; Kappa opioid receptor; Life Sciences & Biomedicine; Molecular Conformation; Oxygen - chemistry; Oxygen - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Receptors, Opioid, kappa - agonists; Salvinorin; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Total synthesis; Heck reaction; Salvinorin; Total synthesis; Kappa opioid receptor; Conformational analysis; SALVINORIN-A
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.01.055

[Display omitted] 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.