title: Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations.
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.
authors.affiliation: Department of Biochemistry;, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Chavkin
authors.forename: Sumit
authors.initials: S
authors.lastname: Sud
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Jin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stewart
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Siebert
authors.forename: Beth Ann
authors.initials: BA
authors.lastname: Toth
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hufeisen
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D002460:Cell Line; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D004594:Electrophysiology; D006213:Hallucinogens / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology; D027544:Salvia / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D004224:Diterpenes; D045785:Diterpenes, Clerodane; D006213:Hallucinogens; D017473:Receptors, Opioid, kappa; C090499:salvinorin A