Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

TLDR

Salvia divinorum, containing the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant traditionally used by the Mazatecs and now widely employed in the U.S. as a legal hallucinogen. The study proposes that κ‑opioid‑selective antagonists derived from Salvinorin A could serve as novel psychotherapeutic agents for disorders involving perceptual distortions such as schizophrenia, dementia, and bipolar disorder. Binding assays and functional studies in recombinant and native κ‑opioid receptors demonstrated Salvinorin A’s potent, selective agonism.

Abstract

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 κ 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 κ opioid agonist at cloned κ opioid receptors expressed in human embryonic kidney-293 cells and at native κ 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 κ opioid receptors, κ 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 κ opioid receptors play a prominent role in the modulation of human perception.