PT  - JOURNAL ARTICLE
AU  - Charles Chavkin
AU  - Sumit Sud
AU  - Wenzhen Jin
AU  - Jeremy Stewart
AU  - Jordan K. Zjawiony
AU  - Daniel J. Siebert
AU  - Beth Ann Toth
AU  - Sandra J. Hufeisen
AU  - Bryan L. Roth
TI  - Salvinorin A, an Active Component of the Hallucinogenic Sage <em>Salvia divinorum</em> Is a Highly Efficacious κ-Opioid Receptor Agonist: Structural and Functional Considerations
AID  - 10.1124/jpet.103.059394
DP  - 2004 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1197--1203
VI  - 308
IP  - 3
4099  - http://jpet.aspetjournals.org/content/308/3/1197.short
4100  - http://jpet.aspetjournals.org/content/308/3/1197.full
SO  - J Pharmacol Exp Ther2004 Mar 01; 308
AB  - The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective κ-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 κ-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 κ-opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for κ-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 κ-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for κ-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at κ-opioid receptors. The American Society for Pharmacology and Experimental Therapeutics