New chemical methods using microwave heating enabled the first successful Diels-Alder cycloaddition reactions on the furan ring of salvinorin A, a neoclerodane diterpene natural product. This approach introduced electron-withdrawing groups and bulky aromatic rings at the C-12 position. Some of the resulting cycloadducts, specifically dimethyl- and diethylcarboxylate analogues, retained affinity and selectivity for kappa opioid receptors and acted as full agonists. However, converting these cycloadducts into planar phenyl ring systems reduced their receptor affinity. The work provides a novel strategy for rapidly exploring structure-activity relationships of furan-containing natural products.
After inhaling a high dose of vaporized salvinorin A (18–21 mcg/kg), plasma levels of the compound peak at 2 minutes and then rapidly decline. Higher drug levels are strongly linked to stronger subjective and observer-rated drug effects. Prolactin rises significantly from 5 minutes onward, peaking at 15 minutes, while cortisol increases are inconsistent across participants. Hormonal changes do not closely track drug levels. This work demonstrates a direct relationship between salvinorin A plasma concentrations and drug effects in humans, validating an efficient inhalation method.
A method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) measures the hallucinogen salvinorin A in non-human primate cerebrospinal fluid (CSF) and human plasma. For CSF, simple dilution with acetonitrile and formic acid replaces solid phase extraction. Human plasma requires centrifugation, then loading onto a C18 SPE column. A shallow acetonitrile/water gradient elutes the compound. Limits of quantification are 0.0125 ng/mL for CSF and 0.05 ng/mL for plasma. Interday precision and accuracy are below 1.7% and 9.42% for CSF and 3.47% and 12.37% for plasma. The method determined salvinorin A concentrations in a Rhesus monkey study and a human trial using behaviorally active doses.