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Published online on August 21, 2002, 10.1073/pnas.182234399
PNAS | September 3, 2002 | vol. 99 | no. 18 | 11934-11939


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Neurobiology
 Salvinorin A: A potent naturally occurring nonnitrogenous kappa  opioid selective agonist

Bryan L. Roth*,dagger ,Dagger ,§,, Karen Baner*, Richard Westkaemper||, Daniel Siebert**, Kenner C. Ricedagger dagger , SeAnna Steinberg*, Paul Ernsberger*,Dagger Dagger , and Richard B. Rothman§§

* National Institute of Mental Health Psychoactive Drug Screening Program, and Departments of dagger  Biochemistry, Dagger  Psychiatry, § Neurosciences, and Dagger Dagger  Pharmacology and Nutrition, Case Western Reserve University Medical School, Cleveland, OH 44106; §§ Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; || Department of Medicinal Chemistry, Medical College of Virginia, Richmond, VA 23298; ** The Salvia divinorum Research and Information Center, Malibu, CA 90263; and dagger dagger  Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Edited by Erminio Costa, University of Illinois, Chicago, IL, and approved July 9, 2002 (received for review April 18, 2002)

Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited 3H-bremazocine binding to cloned kappa  opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent kappa  opioid agonist at cloned kappa  opioid receptors expressed in human embryonic kidney-293 cells and at native kappa  opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for kappa  opioid receptors, kappa  opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that kappa  opioid receptors play a prominent role in the modulation of human perception.

To whom reprint requests should be addressed. E-mail: roth{at}biocserver.cwru.edu.

www.pnas.org/cgi/doi/10.1073/pnas.182234399
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