O6C-20-nor-salvinorin A is a stable and potent KOR agonist.
Shun Hirasawa, Min Cho, Tarsis F Brust, Jeremy J Roach, Laura M Bohn, Ryan A Shenvi
Bioorganic & medicinal chemistry letters September 1, 2018 DOI: 10.1016/j.bmcl.2018.01.055 via PubMed
Summary
AI-generated from the abstractSalvinorin A (SalA) is a potent and selective kappa-opioid receptor agonist, but its chemical instability has hindered medicinal chemistry. Weak bases cause C8 epimerization, which destroys receptor affinity and signaling. Replacing C20 with hydrogen and O6 with CH2 stabilizes the scaffold so completely that epimerization is suppressed. The resulting compound, O6C-20-nor-SalA, retains high potency for kappa-opioid receptor agonism.
Study at a glance
| Characteristics | Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Keywords | Conformational analysis Heck reaction Kappa opioid receptor Total synthesis |
| Key finding | Replacing C20 with H and O6 with CH2 in Salvinorin A yields a compound, O6C-20-nor-SalA, that is stable against C8 epimerization and retains high KOR agonism potency. |
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.