The Journal of pharmacology and experimental therapeutics
March 1, 2004
Charles Chavkin, Sumit Sud, Wenzhen Jin et al.
212 citations
Salvinorin A, a diterpene from Salvia divinorum, is a high-affinity and selective full agonist at human kappa-opioid receptors. In human embryonic kidney-293 cells, salvinorin A fully inhibited forskolin-stimulated cAMP production, while derivatives like 2-propionate and 2-heptanoate were partial agonists. Further tests using chimeric G proteins confirmed its potency and efficacy. In Xenopus oocytes with minimal receptor reserve, salvinorin A acted as a full agonist, more efficacious than standard agonists U50488 and U69593, and similar to dynorphin A. The 2-position substituent is critical for receptor binding and activation. Salvinorin A is the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.
Biochemistry
June 21, 2005
Feng Yan, Philip D Mosier, Richard B Westkaemper et al.
91 citations
Salvinorin A, a hallucinogenic compound from the plant Salvia divinorum, selectively and potently activates kappa-opioid receptors (KORs), making it the only known lipid-like molecule to do so and the only non-nitrogenous opioid receptor agonist. Key residues in KORs responsible for its high binding affinity and agonist efficacy were identified: interactions with tyrosine residues in helix 7 (Tyr313 and Tyr320) and helix 2 (Tyr119) stabilize salvinorin A in the binding pocket, while activation requires interactions with helix 7 tyrosines Tyr312, Tyr313, and Tyr320 and with Tyr139 in helix 3.
Biochemistry
July 28, 2009
Feng Yan, Ruslan V Bikbulatov, Viorel Mocanu et al.
81 citations
Salvinorin A, the most potent naturally occurring hallucinogen, targets the kappa-opioid receptor (KOR). Researchers designed and synthesized novel irreversible salvinorin A-derived ligands, RB-64 and RB-48, as active state probes of KOR. Based on molecular modeling, they targeted cysteine residue C315(7.38) for covalent binding. Both compounds were extraordinarily potent and selective KOR agonists in vitro and in vivo. RB-64 showed wash-resistant inhibition of binding requiring a free cysteine near the binding pocket. Mass spectrometry confirmed C315(7.38) as the anchoring residue and suggested a biochemical mechanism for covalent binding. These findings provide direct evidence of a free cysteine in the agonist-bound KOR state and insights into salvinorin A's binding and activation mechanism.
Journal of molecular medicine (Berlin, Germany)
September 1, 2011
Gabriella Aviello, Francesca Borrelli, Francesca Guida et al.
70 citations
Salvinorin A, a hallucinogenic compound, reduces inflammation in immune cells and in animal models of inflammation. At extremely low concentrations (0.1-10 pM), it lowers levels of inflammatory markers nitrite, TNF-α, and IL-10 (but not IL-1β) and reduces expression of iNOS (but not COX-2) in stimulated macrophages. These effects are blocked by antagonists of both κ-opioid receptors (KOR) and cannabinoid CB1 receptors, and salvinorin A prevents the overproduction of these receptors induced by inflammation. In living animals, salvinorin A reduces paw swelling caused by LPS or carrageenan and pain from formalin injection, with these effects also blocked by KOR and CB1 antagonists. The compound acts through both KOR and CB1 receptors to produce potent anti-inflammatory actions on macrophages and moderate anti-inflammatory effects in vivo.
Phytochemistry
July 1, 2007
Lukasz Kutrzeba, Franck E Dayan, J'Lynn Howell et al.
45 citations
Salvinorin A, a potent kappa-opioid receptor agonist from the hallucinogenic plant Salvia divinorum, is biosynthesized via the 1-deoxy-D-xylulose-5-phosphate (DXP) pathway, not the classic mevalonic acid pathway. This was determined by feeding microshoots with isotopically labeled precursors and analyzing the resulting salvinorin A (2.7 mg from 200 microshoots) using NMR and HR-ESI-MS. Incorporation of labeled glucose and 1-deoxy-D-xylulose confirmed the DXP pathway, while labeled methionine showed that methylation of the C-4 carboxyl group is catalyzed by a type III S-adenosyl-L-methionine-dependent O-methyltransferase.
European journal of medicinal chemistry
October 6, 2014
Prabhakar R Polepally, Krzysztof Huben, Eyal Vardy et al.
28 citations
Salvinorin A, a compound from the plant Salvia divinorum, binds strongly and selectively to the κ-opioid receptor (KOR). A new series of salvinorin A derivatives with reactive Michael acceptor groups at C-2 was created to explore how the compound interacts with the receptor. Most of these derivatives retained high affinity for KOR, and some also bound to the μ-opioid receptor (MOR). None showed wash-resistant irreversible binding. Using the KOR crystal structure, mutagenesis data, and other methods, the researchers identified possible ways the new compounds interact with both KOR and MOR.
Bioorganic & medicinal chemistry letters
May 15, 2013
Prabhakar R Polepally, Kate White, Eyal Vardy et al.
24 citations
Salvinorin A, the active ingredient in the hallucinogenic plant Salvia divinorum, is nature's most potent hallucinogen and selectively activates the κ-opioid receptor. To explore how these compounds bind to specific receptors, researchers synthesized a series of dicarboxylic ester derivatives of salvinorin A and tested their binding affinity at κ-, δ-, and μ-opioid receptors. Most of the new compounds showed high affinity for the κ-opioid receptor. The methyl malonyl derivative 4 had the strongest binding, with a Ki of 2 nM, while analogues 5, 7, and 14 also exhibited significant affinity, with Ki values of 21, 36, and 39 nM respectively. These findings provide insights into brain chemistry and ligand-receptor interactions.
Journal of natural products
April 23, 2010
Lukasz M Kutrzeba, Xing-Cong Li, Yuanqing Ding et al.
23 citations
Fresh Salvia divinorum leaves yielded salvinorins E and D, which may be natural precursors to salvinorin A, a potent hallucinogen. During HPLC purification, salvinorin E spontaneously converted into a mixture with its regioisomer salvinorin D in a 3:5 ratio, observable by NMR. This isomerization occurs through a dynamic intramolecular transacetylation process.
Frontiers in psychiatry
January 1, 2019
Jordan K Zjawiony, Antônio S Machado, Ricardo Menegatti et al.
18 citations
Pain reduces quality of life, health, and economic well-being. Opioids are effective analgesics but cause side effects and have contributed to an overuse crisis, prompting the search for new pain treatments. This review examines salvinorin A and its analogs, focusing on their structural and pharmacological profiles as a basis for developing safer analgesics. Ethnopharmacological reports and preclinical data show antinociceptive effects of salvinorin A and some analogs. Analogs modified at the C-2 position dominate the literature. Binding affinity correlates with chemical structure and in vivo effects. Salvinorin A's susceptibility to chemical modification makes it a valuable tool for probing cellular mechanisms and developing promising analgesic analogs, though more research is needed to confirm therapeutic potential.
Journal of natural medicines
January 1, 2014
Anna P Kowalczuk, Vijayasankar Raman, Ahmed M Galal et al.
13 citations
Salvia divinorum, a species traditionally cultivated in Oaxaca, Mexico, has hallucinogenic properties and is legally controlled in many countries. Proper identification of the plant in fresh and dried forms is important for crime prevention. This paper provides a thorough anatomical description of leaves, petioles, and stems, with detailed investigation and illustration of foliar trichomes. Chromatographic analyses, including TLC and HPLC, were applied to fresh and dried plant material alongside the standard reference salvinorin A. A comprehensive identification method based on anatomical examination combined with chemical analysis is proposed for proper plant recognition.
Fitoterapia
June 1, 2023
Caroline V L Moreira, Ana Luiza G Faria, Daiany P B Silva et al.
2 citations
A new compound called P-3l, an analogue of salvinorin A, reduces pain and anxiety-like behaviors in mice after oral administration at doses of 1, 3, 10, and 30 mg/kg. It lessened acetic acid-induced writhing, formalin-induced paw licking, hotplate responses, and aversion in elevated plus-maze, open field, and light-dark box tests. P-3l also boosted the effects of morphine and diazepam at low doses without causing changes in organ weight or blood parameters. The pain and anxiety relief were blocked by naloxone, naloxonazine, nor-binaltorphimine, and flumazenil, indicating involvement of opioid receptors and the benzodiazepine site. These findings suggest P-3l may have clinical potential for pain and anxiety treatment.