Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations.
Charles Chavkin, Sumit Sud, Wenzhen Jin, Jeremy Stewart, Jordan K Zjawiony, Daniel J Siebert, Beth Ann Toth, Sandra J Hufeisen, Bryan L. Roth
The Journal of pharmacology and experimental therapeutics March 1, 2004 DOI: 10.1124/jpet.103.059394 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells and Xenopus oocytes |
| Interventions | Salvinorin A salvinorinyl-2-propionate salvinorinyl-2-heptanoate |
| Topics | Salvia divinorum |
| Keywords | Natural compound Non-nitrogenous activator Unique chemical structure Kappa-opioid receptors Receptor binding Receptor activation Brain pathways Agonist Full activator Potent Highly effective Novel mechanism Cellular models Xenopus oocytes Pharmacology research |
| Citations | 212 |
| Key findings | Salvinorin A is the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors. |
Abstract
The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective kappa-opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production. Additional studies of agonist potency and efficacy of salvinorin A, performed by cotransfecting either the chimeric G proteins Gaq-i5 or the universal G protein Ga16 and quantification of agonist-evoked intracellular calcium mobilization, affirmed that salvinorin A was a potent and effective kappa-opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for kappa-opioid receptor binding and activation. Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K(+) channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593) (two standard kappa-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for kappa-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.