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

ABSTRACT: 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.

SUBMITTER: Hirasawa S

PROVIDER: S-EPMC6067998 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Hirasawa Shun S Cho Min M Brust Tarsis F TF Roach Jeremy J JJ Bohn Laura M LM Shenvi Ryan A RA

Bioorganic & medicinal chemistry letters 20180131 16

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 CH<sub>2</sub> stabilizes the SalA scaffold relative to its C8 epimer, so much so that epimerization is completely supressed. This new compound, O6C-20- ...[more]

PMID: 29426768

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