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NEUROPHARMACOLOGY

Salvinorin A, an Active Component of the Hallucinogenic Sage Salvia divinorum Is a Highly Efficacious -Opioid Receptor Agonist: Structural and Functional Considerations

Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington (C.C., S.S., W.J.); Salvia divinorum Research and Information Center, Los Angeles, California (D.S.); Department of Pharmacognosy, University of Mississippi, Oxford, Mississippi (J.S., J.K.Z.); and National Institute of Mental Health Psychoactive Drug Screening Program and Department of Biochemistry, Case Western Reserve University Medical School, Cleveland, Ohio (B.A.T., S.J.H., B.L.R.)

The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective -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 -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 -opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for -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 -opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for -opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at -opioid receptors.

Address correspondence to: Dr. Bryan Roth, Department of Biochemistry; Room RT500-9, Case Western Reserve University Medical School, 2109 Adelbert Rd., Cleveland, OH 44106. E-mail: roth{at}biocserver.cwru.edu

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