Proceedings of the National Academy of Sciences of the United States of America
September 3, 2002
Bryan L Roth, Karen Baner, Richard Westkaemper et al.
782 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, potently and selectively activates kappa opioid receptors while having no effect on the serotonin 5-HT(2A) receptor targeted by classical hallucinogens like LSD. This makes it the first known naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A produces perceptual distortions, the findings suggest that kappa opioid receptors play a key role in modulating human perception and that kappa opioid-selective antagonists could be developed as novel treatments for disorders involving perceptual distortions, such as schizophrenia, dementia, and bipolar disorders.
Pharmacological reviews
June 1, 2011
Christopher W Cunningham, Richard B Rothman, Thomas E Prisinzano
109 citations
Salvinorin A, the psychoactive compound in the Salvia divinorum plant, activates kappa-opioid receptors (KOP) to produce its intense hallucinogenic effects, making it the first known non-nitrogenous opioid receptor agonist. Unlike classic hallucinogens such as LSD and mescaline, its effects do not involve the 5-HT(2A) receptor. Research into its structure has yielded receptor probes and tools to study its psychological effects. Salvinorin A shows therapeutic potential for treating pain, mood disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloid compounds can serve as scaffolds for developing drugs targeting aminergic G-protein coupled receptors.
The Journal of pharmacology and experimental therapeutics
August 1, 2006
Michael A Ansonoff, Jiwen Zhang, Traci Czyzyk et al.
101 citations
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, produces pain relief (antinociception) and lowers body temperature in mice by activating the kappa-opioid receptor. These effects were observed after injection of salvinorin A or a similar compound, salvinorinyl-2-propionate, into the brain of normal mice, but not in mice genetically lacking the kappa-opioid receptor. Salvinorin A showed high affinity specifically for the kappa-1 subclass of opioid receptors. In contrast, salvinorin B, an inactive derivative, had no effect on pain or body temperature. The findings confirm that salvinorin A acts through the kappa-opioid receptor to produce its behavioral effects.
Psychopharmacology
October 1, 2014
Bruce E Blough, Antonio Landavazo, Ann M Decker et al.
99 citations
Synthetic hallucinogenic tryptamines, including those originally described by Alexander Shulgin, are abused in the USA. While all psychoactive tryptamines act as agonists at serotonin 2A (5-HT₂A) receptors, their varied subjective effects suggest additional neurochemical mechanisms. This work evaluated 21 tryptamines for interactions with serotonin receptor subtypes and neurotransmitter transporters. Eight compounds released serotonin, thirteen inhibited serotonin uptake or were inactive. All were 5-HT₂A agonists with varying potencies; few activated 5-HT₁A receptors. Most recruited β-arrestin via 5-HT₂A. Serotonin transporter (SERT) activity may contribute significantly to some compounds' pharmacology. Releasers tended to be structurally smaller compounds. Two tertiary amines acted as selective SERT substrates, challenging the view that releasing activity requires primary or secondary amines.
The Journal of pharmacology and experimental therapeutics
February 1, 2007
Richard B Rothman, Daniel L Murphy, Heng Xu et al.
75 citations
Salvinorin A, a hallucinogenic compound that activates kappa-opioid receptors, also partially inhibits mu-opioid receptor binding through an allosteric mechanism. In cells expressing human mu-opioid receptors, salvinorin A reduced binding of two different radioligands (DAMGO and diprenorphine) in a dose-dependent, nonlinear way, altering both the number of binding sites and their affinity. It also slowed the dissociation of these ligands from the receptor and acted as an uncompetitive inhibitor of receptor signaling. Similar effects were observed in rat brain tissue. Together, these findings indicate that salvinorin A modulates the mu-opioid receptor allosterically, not by binding at the same site as typical opioids.
Journal of natural products
January 1, 2006
Wayne W Harding, Matthew Schmidt, Kevin Tidgewell et al.
59 citations
Salvinorin A, a hallucinogen from the plant Salvia divinorum, is unique as the first non-nitrogenous compound known to bind to opioid receptors. To understand why it selectively targets kappa opioid receptors, researchers systematically altered its structure and tested the effects on receptor binding and activity. This work describes chemical transformations of salvinorin A, including a semisynthesis of salvinicins A and B. It also identifies compound 10a as the first neoclerodane diterpene with delta opioid antagonist activity, providing new tools for studying opioid receptor interactions.
Journal of natural products
April 25, 2011
Anthony Lozama, Christopher W Cunningham, Michael J Caspers et al.
40 citations
New chemical methods using microwave heating enabled the first successful Diels-Alder cycloaddition reactions on the furan ring of salvinorin A, a neoclerodane diterpene natural product. This approach introduced electron-withdrawing groups and bulky aromatic rings at the C-12 position. Some of the resulting cycloadducts, specifically dimethyl- and diethylcarboxylate analogues, retained affinity and selectivity for kappa opioid receptors and acted as full agonists. However, converting these cycloadducts into planar phenyl ring systems reduced their receptor affinity. The work provides a novel strategy for rapidly exploring structure-activity relationships of furan-containing natural products.
PloS one
January 1, 2013
Tamara Antonio, Steven R Childers, Richard B Rothman et al.
36 citations
Iboga alkaloids, including ibogaine, its metabolite noribogaine, and the synthetic compound 18-methoxycoronaridine (18-MC), were tested for their ability to activate the μ-opioid receptor (MOR), a common target of opioid drugs. In rat thalamic membranes, all three compounds acted as antagonists, blocking the receptor rather than activating it, with functional Ke values ranging from 3 μM for ibogaine to 13 μM for noribogaine and 18-MC. None of the compounds stimulated MOR-related G protein activity in cells expressing human or rat MORs, and only limited partial agonist effects were seen in mouse MOR-expressing cells. The findings indicate that an opioid agonist mechanism does not explain these alkaloids' effects on opioid withdrawal, supporting a novel mechanism of action and justifying further search for alternative targets.
Bioorganic & medicinal chemistry
May 1, 2012
Kimberly M Lovell, Tamara Vasiljevik, Juan J Araya et al.
35 citations
A palladium-catalyzed cross-coupling reaction (Liebeskind-Srogl) applied to a modified natural product scaffold produces ketone analogs of salvinorin A at neutral pH and room temperature, expanding synthetic access to this class. A one-step microwave method converts salvinorin A to its 12-epimer, previously requiring multiple steps. Several new analogs (alkene 9 and aromatic compounds 12, 19, 23, 25, 26) retain affinity and selectivity for kappa opioid receptors (KOP), and the furan-2-yl analog (31) shows similar affinity to the parent compound. These results indicate that diverse aromatic groups attached to the decalin core may be tolerated by KOP receptors, potentially yielding additional ligands.
Tetrahedron
December 20, 2008
Gianfranco Fontana, Giuseppe Savona, Benjamín Rodríguez et al.
32 citations
Salvinorin A, a compound from the hallucinogenic mint Salvia divinorum, is the only known non-nitrogenous and specific kappa-opioid agonist. Several related compounds from Salvia splendens and a series of semisynthetic derivatives, including some with a pyrazoline structural moiety, were tested for their ability to bind to human mu, delta, and kappa opioid receptors. None of these compounds showed high-affinity binding to these receptors. However, one compound (10) showed modest affinity for kappa receptors, suggesting that other naturally occurring neoclerodanes from different Salvia species may have opioid affinity.
Tetrahedron
February 21, 2009
Gianfranco Fontana, Giuseppe Savona, Benjamín Rodríguez et al.
12 citations
Salvinorin A is a unique naturally occurring compound that activates κ-opioid receptors without containing nitrogen. Researchers modified the A ring of salvinorin A and related compounds from Salvia splendens and a non-natural derivative, producing new molecules. When tested for opioid receptor activity, none of these derivatives were active. The absence of activity may be due to the presence of a lactone group at specific positions in the molecular structure.