Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist.
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 (3)H-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-HT(2A) 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.
Roth
Bryan L
BL
National Institute of Mental Health Psychoactive Drug Screening Program and Department of Biochemistry, Case Western Reserve University Medical School, Cleveland, OH 44106, USA. roth@biocserver.cwru.edu
Baner
Karen
K
Westkaemper
Richard
R
Siebert
Daniel
D
Rice
Kenner C
KC
Steinberg
SeAnna
S
Ernsberger
Paul
P
Rothman
Richard B
RB
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D006168:Guinea Pigs; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D027544:Salvia / Q000737:chemistry
D004224:Diterpenes; D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; D011994:Recombinant Proteins; C090499:salvinorin A