Salvinorin A

History

Salvinorin A was first described and named in 1982 by Alfredo Ortega and colleagues in Mexico. They used a combination of spectroscopy and x-ray crystallography to determine the chemical structure of the compound, which was shown to have a bicyclic diterpene structure. Around the same time, Leander Julián Valdés III independently isolated the molecule as part of his PhD research, published in 1983. Valdés named the chemical divinorin, and also isolated an analog that he named divinorin B. The naming was subsequently corrected to salvinorin A and B after the work was published in 1984. Valdés later isolated salvinorin C.

Pharmacology

Salvinorin A is a trans-neoclerodane diterpenoid with the chemical formula C23H28O8. It significantly increases prolactin and inconsistently increases cortisol. It causes dysphoria by stopping release of dopamine in the striatum. Salvinorin A increases activity of DAT while decreasing activity of SERT.

Pharmacokinetics

Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of administration must be used for better absorption. It is absorbed by oral mucosa. It has a half-life of around 8 minutes in non-human primates.

Potency and selectivity

Salvinorin A is active at doses as low as 200 μg. Synthetic chemicals, such as LSD (active at 20–30 μg doses), can be more potent. Research has shown that salvinorin A is a potent κ-opioid receptor (KOR) agonist (Ki = 2.4 nM, EC50 = 1.8 nM). It has a high affinity for the receptor, indicated by the low dissociation constant of 1.0 nanomolar (nM). In addition, salvinorin A has been found to act as a D2 receptor partial agonist, with an affinity of 5–10 nM, an intrinsic activity of 40–60%, and an EC50 of 48 nM. This suggests that the D2 receptor may also play an important role in its effects.

Salvinorin A shows atypical properties as an agonist of the KOR relative to other KOR agonists.

Effect on intestinal motility

Salvinorin A is capable of inhibiting excess intestinal motility (e.g. diarrhea), through its potent κ-opioid-activating effects. The mechanism of action for salvinorin A on ileal tissue has been described as 'prejunctional', as it was able to modify electrically induced contractions, but not those of exogenous acetylcholine. A pharmacologically important aspect of the contraction-reducing properties of ingested salvinorin A on gut tissue is that it is only pharmacologically active on inflamed and not normal tissue, thus reducing possible side-effects.

Solubility

Salvinorin A is soluble in organic solvents such as ethanol and acetone, but not especially so in water.

Detection in urine

Researchers found that humans who smoked 580 μg of the pure drug had urine salvinorin A concentrations of 2.4–10.9 μg/L during the first hour; the levels fell below the detection limit by 1.5 hours after smoking.

Research

Salvinorin A has only been administered to humans in a few studies, one showing that its effects peaked at about 2 minutes, that its subjective effects may overlap with those of serotonergic psychedelics, and that it temporarily impairs recall and recognition memory. Like most other agonists of KOR, salvinorin A produces sedation, psychotomimesis, dysphoria, anhedonia, and depression. Salvinorin A has been screened for its possible use as a structural "scaffold" in medicinal chemistry in developing new drugs for treating psychiatric diseases such as cocaine dependence.

Synthesis

Biosynthesis

The biogenic origin of salvinorin A synthesis has been elucidated using nuclear magnetic resonance and ESI-MS analysis of incorporated precursors labeled with stable isotopes of carbon (carbon-13 13C) and hydrogen (deuterium 2H). It "is biosynthesized via the 1-deoxy-d-xylulose-5-phosphate pathway", rather than the classic mevalonate pathway, consistent with the common plastidial localization of diterpenoid metabolism.

Terpenoids are biosynthesized from two 5-carbon precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The NMR and MS study by Zjawiony suggested that the biosynthesis of salvinorin A proceeds via the 1-deoxy-d-xylulose-5-phosphate pathway. In the deoxyxylulose phosphate pathway, D-glyceraldehyde 3-phosphate and pyruvate, the intermediates of the glycolysis, are converted into 1-deoxy-D-xylulose 5-phosphate via decarboxylation. Subsequent reduction with NADPH generates 2C-methyl-D-erythritol 2,4-cyclodiphosphate, via the intermediates 4-diphosphocytidyl-2-C-methyl-D-erythritol and 4-diphosphocytidyl-2c-methyl-d-erythritol-2-phosphate, which then lead to IPP and DMAPP.

Subsequent addition of three 5-carbon IPP units to a single 5-carbon DMAPP unit generates the 20-carbon central precursor, geranylgeranyl diphosphate (GGPP). Bicyclization of GGPP by the class II diterpene synthase, ent-clerodienyl diphosphate synthase (SdCPS2), produces a labdanyl diphosphate carbocation, which is subsequently rearranged through a sequence of 1,2-hydride and methyl shifts to form the ent-clerodienyl diphosphate intermediate. SdCPS2 catalyzes the first committed reaction in the biosynthesis of salvinorin A by producing its characteristic clerodane scaffold. A series of oxygenation, acylation and methylation reactions is then required to complete the biosynthesis of salvinorin A.

Similar to many plant-derived psychoactive compounds, salvinorin A is excreted via peltate glandular trichomes, which reside external to the epidermis.

Chemical synthesis

A total asymmetric synthesis of salvinorin A, which relies on a transannular Michael reaction cascade to construct the ring system, was achieved as a 4.5% overall yield over 30 steps,

Associated compounds

Main article: Salvinorin

Salvinorin A is one of several structurally related salvinorins found in the Salvia divinorum plant. Salvinorin A is the only naturally occurring salvinorin that is known to be psychoactive.

Research has produced a number of semi-synthetic compounds. Most derivatives are selective kappa opioid agonists as with salvinorin A, although some are even more potent, with the most potent compound salvinorin B ethoxymethyl ether being ten times stronger than salvinorin A. Some derivatives, such as herkinorin, reduce kappa opioid action and instead act as mu opioid agonists.

The synthetic derivative RB-64 is notable because of its functional selectivity and potency. Salvinorin B methoxymethyl ether is seven times more potent than salvinorin A at KOPr in GTP-γS assays.

Natural occurrence

Salvinorin A occurs naturally in several Salvia species:

• S. divinorum (0.89 mg/g to 3.70 mg/g).
• S. recognita (212.9 μg/g).
• S. cryptantha (51.5 μg/g).
• S. glutinosa (38.9 μg/g).

Salvinorin B has been detected in S. potentillifolia and S. adenocaulon, however these species do not contain a measureable amount of salvinorin A.

Legal status

Salvinorin A is sometimes regulated together with its host, Salvia divinorum, due to its psychoactive and analgesic effects.

United States

Salvinorin A is not scheduled at the federal level in the United States. Its molecular structure is unlike any Schedule I or II drug, so possession or sales is unlikely to be prosecuted under the Federal Analogue Act.

Florida

"Salvinorin A" is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida. There is an exception however for "any drug product approved by the United States Food and Drug Administration which contains salvinorin A or its isomers, esters, ethers, salts, and salts of isomers, esters, and ethers, if the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation."

Australia

Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.

Sweden

Sveriges riksdags health ministry Statens folkhälsoinstitut classified salvinorin A (and Salvia divinorum) as "health hazard" under the act Lagen om förbud mot vissa hälsofarliga varor (translated Act on the Prohibition of Certain Goods Dangerous to Health) as of April 1, 2006, in their regulation SFS 2006:167 listed as "salvinorin A", making it illegal to sell or possess.

References

References

1. Anvisa. (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
2. "salvinorin A". PubChem.
3. (2020). "The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain". Scientific Reports.
4. (2015). "Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders". Frontiers in Pharmacology.
5. (March 2013). "Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects". Psychopharmacology.
6. "Salvinorin A".
7. (April 2016). "Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans". Journal of Psychopharmacology.
8. (November 2014). "Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism". Neuropharmacology.
9. (June 1994). "Salvia divinorum and salvinorin A: new pharmacologic findings". Journal of Ethnopharmacology.
10. (December 2015). "Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents, Monitored In Vivo with PET". Neuropsychopharmacology.
11. Linda P. Dwoskin. (29 January 2014). "Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse". Elsevier Science.
12. "Salvia divinorum". European Monitoring Centre for Drugs and Drug Addiction.
13. (2 December 2011). "A Literature Review on the Status and Effects of Salvia Divinorum on Cognitive, Affective, and Behavioral Functioning". Universal-Publishers.
14. (2008). "The Interface of Neurology & Internal Medicine". Lippincott Williams & Wilkins.
15. (2014). "Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse".
16. (December 11, 2016). "Salvia divinorum kolavenyl diphosphate synthase (CPS2) mRNA, complete cds".
17. (March 2017). "Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase". The Plant Journal.
18. (December 2016). "Total Synthesis of (-)-Salvinorin A". Chemistry: A European Journal.
19. (August 2005). "Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues". Bioorganic & Medicinal Chemistry Letters.
20. (January 2015). "The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo". The Journal of Pharmacology and Experimental Therapeutics.
21. (March 2008). "2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A". The Journal of Pharmacology and Experimental Therapeutics.
22. (February 2021). "Pharmacokinetics and Pharmacodynamics of Salvinorin A and ''Salvia divinorum'': Clinical and Forensic Aspects". Pharmaceuticals.
23. (November 2017). "Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species". Phytochemical Analysis.
24. "21 CFR — Schedules of Controlled Substances §1308.11 Schedule I.".
25. "Statutes & Constitution :View Statutes : Online Sunshine".
26. (October 2015). "Poisons Standard". The Australian Government.
27. (2006). "Förordning om ändring i förordningen (1999:58) om förbud mot vissa hälsofarliga varor". Svensk författningssamling.
28. (September 2006). "Synthesis and in vitro evaluation of salvinorin A analogues: effect of configuration at C(2) and substitution at C(18)". Bioorganic & Medicinal Chemistry Letters.
29. (September 2003). "Divinatorins A-C, new neoclerodane diterpenoids from the controlled sage Salvia divinorum". Journal of Natural Products.
30. (January 2008). "Intramolecular Diels-Alder/Tsuji allylation assembly of the functionalized trans-decalin of salvinorin A". Organic Letters.
31. (January 2006). "The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A inhibit enteric cholinergic transmission in the guinea-pig ileum". Neurogastroenterology and Motility.
32. (February 2008). "The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A reduce inflammation-induced hypermotility in mice". Neurogastroenterology and Motility.
33. (February 1958). "Psychopathology and psychophysiology of minimal LSD-25 dosage; a preliminary dosage-response spectrum". A.M.A. Archives of Neurology and Psychiatry.
34. (January 2006). "Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A". Journal of Natural Products.
35. (November 2007). "Synthetic studies of neoclerodane diterpenes from Salvia divinorum: exploration of the 1-position". Bioorganic & Medicinal Chemistry Letters.
36. (June 2006). "The pharmacological effects of Salvia species on the central nervous system". Phytotherapy Research.
37. (2007). "Leaf glandular trichome (''Salvia divinorum'')". Dennis Kunkel Microscopy, Inc.
38. (July 2007). "Biosynthesis of salvinorin A proceeds via the deoxyxylulose phosphate pathway". Phytochemistry.
39. (July 2009). "Salvinorins J from Salvia divinorum: mutarotation in the neoclerodane system". Journal of Natural Products.
40. (October 2005). "New neoclerodane diterpenoids isolated from the leaves of Salvia divinorum and their binding affinities for human kappa opioid receptors". Bioorganic & Medicinal Chemistry.
41. (November 2006). "Synthesis and in vitro pharmacological studies of new C(4)-modified salvinorin A analogues". Bioorganic & Medicinal Chemistry Letters.
42. (May 2003). "Salvinorins D-F, new neoclerodane diterpenoids from Salvia divinorum, and an improved method for the isolation of salvinorin A". Journal of Natural Products.
43. (February 2008). "Standard protecting groups create potent and selective kappa opioids: salvinorin B alkoxymethyl ethers". Bioorganic & Medicinal Chemistry.
44. (April 2008). "Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A". Organic Letters.
45. (1982). "Salvinorin, a new ''trans''-neoclerodane diterpene from ''Salvia divinorum'' (Labiatae)". Journal of the Chemical Society, Perkin Transactions 1.
46. (30 June 2005). "Quantification of the plant-derived hallucinogen Salvinorin A in conventional and non-conventional biological fluids by gas chromatography/mass spectrometry after Salvia divinorum smoking". Rapid Communications in Mass Spectrometry.
47. (December 2005). "Psychopharmacology of the hallucinogenic sage Salvia divinorum". Life Sciences.
48. (September 2002). "Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist". Proceedings of the National Academy of Sciences of the United States of America.
49. (July 2007). "Asymmetric synthesis of salvinorin A, a potent kappa opioid receptor agonist". Journal of the American Chemical Society.
50. (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse.
51. (June 2004). "Localization of salvinorin A and related compounds in glandular trichomes of the psychoactive sage, Salvia divinorum". Annals of Botany.
52. (1984). "Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint ''Salvia divinorum''". Journal of Organic Chemistry.
53. (November 2001). "Salvinorin C, a new neoclerodane diterpene from a bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum". Organic Letters.