Salvinorin A, an Active Component of the Hallucinogenic Sage Salvia divinorum, is a Highly Efficacious Kappa Opioid Receptor Agonist: Structural and Functional Considerations antagonist in the treatment of opioid dependence
Chavkin C, Sud S, Jin W, Steward J, Zjawiony JK,
Siebert D, Toth BA, Hufeisen SJ, Roth BL.
University of Washington.
J Pharmacol Exp Ther. 2004 Jan 8
ABSTRACTThe 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 HEK-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 co-transfecting 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. Since 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 co-expressed in Xenopus oocytes-system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than U50488 or 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.Salvia divinorum
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