Scalable and modular synthesis enables pharmacological diversification of salvinorins
Yuyang Ai, Jiangwen Gui, Boxu Lin, Min Liu, Yujun Wang, Tuoping Luo
November 4, 2026 DOI: 10.65215/ltspreprints.2026.11.04.000373 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper |
|---|---|
| Topics | Salvia divinorum |
| Key points | The authors report concise, scalable syntheses of salvinorin A and EOM-salvinorin B and a modular platform yielding 28 new analogs, including C17-modified ligands with distinct signaling bias and pharmacokinetics. An aminomethyl C17 analog is described as ultrapotent with delayed-onset, sustained antinociception, in contrast to the rapid, short-lived action of salvinorin A and EOM-salvinorin B, with no locomotor impairment detected under the tested conditions. |
Abstract
Salvinorin A is an atypical opioid characterized by a non-nitrogenous scaffold and potent, selective κ-opioid receptor (KOR) agonistic activity. Its distinctive pharmacology has motivated studies of pain and neuropsychiatric function, but structural complexity and limited synthetic access have constrained mechanistic investigation and pharmacological optimization. Here we report concise and scalable syntheses of EOM-salvinorin B and salvinorin A, together with modular access to 28 new analogs. Temporary skeletal rewiring generates a pyrone that enables photochemical construction of the congested C9 all-carbon quaternary center while directly furnishing a versatile intermediate for diversification at the underexplored C17 position. Notably, C17 substitution yielded potent, selective ligands with distinct signaling bias, binding kinetics and pharmacokinetic behavior. Replacing the C17 carbonyl with an aminomethyl group yielded an ultrapotent analogue with delayed onset and sustained antinociception, contrasting with the rapid, short-lived action of SalA and EOM-SalB, with no locomotor impairment detected under the tested conditions. This work establishes a modular synthetic platform that expands the accessible salvinorin chemical space, providing a foundation for further biological studies.
Comparable studies
Other theoretical and historical papers on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A. | 2008 | Theoretical or philosophical paper | |
| The claustrum's proposed role in consciousness is supported by the effect and target localization of Salvia divinorum. | 2014 | Theoretical or philosophical paper | |
| Total Synthesis of (-)-Salvinorin A. | 2016 | Theoretical or philosophical paper | |
| Title: DMT, Salvinorin A, and Stress Regulation: An Exploratory Neuropharmacological Research Proposal | 2026 | Theoretical or philosophical paper | |
| Salvia Divinorum: entrSalvia divinorum: Entre la prohibición y la construcción de su conocimientoe a proibição e a construção do seu saber | 2022 | Theoretical or philosophical paper |