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 CH 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.

The quest for supernatural products: the impact of total synthesis in complex natural products medicinal chemistry

“…17). 194 Compound 89 benefited from the removal of the epimerization prone semi planar lactone conformation in the trans isomer 88 by adopting a strain-released chair conformation. It exhibited complete stability to epimerization while maintaining selective and potent KOR agonist activity (EC 50 for cAMP accumulation = 3.3 nM).…”

Intermolecular Heck Coupling with Hindered Alkenes Directed by Potassium Carboxylates

“…Heck reactions with sterically hindered and unbiased olefins remain non‐trivial in many cases, evidenced by recent syntheses of κ‐opioid receptor agonists 20‐nor‐SalA and O6C‐20‐nor‐SalA . A late‐stage Heck arylation on a hindered, unbiased olefin could not be achieved using traditional or oxidative Heck conditions.…”

Intermolecular Heck Coupling with Hindered Alkenes Directed by Potassium Carboxylates

“…[13,14] With the exception of enelactams,r edox-relay Heck reactions do not tolerate cyclic substrates,w hich tend to yield mixtures of regioisomers. [17] Al ate-stage Heck arylation on ah indered, unbiased olefin could not be achieved using traditional or oxidative Heck conditions.H owever,i ncorporation of acarboxylic acid close to the alkene significantly accelerated arylation relative to deactivation of the palladium catalyst or decomposition of the aryl halide,3 -bromofuran (Figure 1c). [17] Al ate-stage Heck arylation on ah indered, unbiased olefin could not be achieved using traditional or oxidative Heck conditions.H owever,i ncorporation of acarboxylic acid close to the alkene significantly accelerated arylation relative to deactivation of the palladium catalyst or decomposition of the aryl halide,3 -bromofuran (Figure 1c).…”

“…[15] Heck reactions with sterically hindered and unbiased olefins remain non-trivial in many cases,evidenced by recent syntheses of k-opioid receptor agonists 20-nor-SalA [16] and O6C-20-nor-SalA. [17] Al ate-stage Heck arylation on ah indered, unbiased olefin could not be achieved using traditional or oxidative Heck conditions.H owever,i ncorporation of acarboxylic acid close to the alkene significantly accelerated arylation relative to deactivation of the palladium catalyst or decomposition of the aryl halide,3 -bromofuran ( Figure 1c). [16] Reactivity enhancement from the direction of carboxylic acids has been observed in the C À Ha ctivation literature,b ut until now it has not been established in Heck arylation.…”