Natural product reports
November 18, 2020
Sarah J Hill, Aurélien U C M Brion, Ryan A Shenvi
Salvinorin A, a hallucinogenic compound from the plant Salvia divinorum, is a potent and selective activator of the kappa-opioid receptor (KOR), a promising target for new painkillers. Unlike typical opioids, it lacks a basic nitrogen, enters the brain rapidly, and has a short duration of action. Since 2000, extensive medicinal chemistry using semi-synthesis from plant extracts has explored its properties. Total synthesis efforts have produced multiple routes to create salvinorin A and related analogs, aiming to improve its activity for various therapeutic effects. This review covers those total syntheses and identifies remaining challenges for future synthetic chemistry to address.
ACS central science
August 23, 2023
Sarah J Hill, Nathan Dao, Vuong Q Dang et al.
A new chemical synthesis method produces salvinorin analogs that are more potent, selective, stable, and functionally biased than the natural compound salvinorin A. These analogs target the kappa-opioid receptor and could serve as templates for next-generation pain relievers, anti-itch treatments, and dissociative hallucinogens. The synthesis uses a special organocatalyst and a cobalt-catalyzed cycloaddition to efficiently create a library of these complex molecules, overcoming previous difficulties in modifying their structure.
Bioorganic & medicinal chemistry letters
September 1, 2018
Shun Hirasawa, Min Cho, Tarsis F Brust et al.
Salvinorin 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.
ACS central science
December 27, 2017
Jeremy J Roach, Yusuke Sasano, Cullen L Schmid et al.
Deleting a single carbon atom (C20) from the complex plant metabolite salvinorin A stabilizes its molecular skeleton, simplifies its laboratory synthesis to just 10 steps, and preserves its high affinity and selectivity for the human kappa-opioid receptor. The work also introduces a general workflow for identifying structural changes that keep molecular complexity high while reducing synthetic complexity.