Salvinorin A

Salvinorin A
Systematic (IUPAC) name
methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxododecahydro-2H-benzo[f]isochromene-7-carboxylate
Identifiers
CAS number 83729-01-5
ATC code None
PubChem CID 128563
IUPHAR ligand 1666
ChemSpider 113947
Chemical data
Formula C23H28O8 
Mol. mass 432.46 g/mol
SMILES eMolecules & PubChem
Physical data
Melt. point 242-244–238-240 °C (-165–-162 °F)
Boiling point 760.2 °C (1400 °F)
Therapeutic considerations
Pregnancy cat.  ?
Legal status Uncontrolled (though Salvia divinorum is controlled in some parts of the world, such as in certain states in the US)
Routes Buccal/Sublingual, Smoked

Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans. Salvinorin A is a hallucinogenic compound with psychedelic/dissociative effects.

It is structurally distinct from other naturally-occurring hallucinogens (such as DMT, psilocybin, and mescaline), from semisynthetic hallucinogens (like LSD) and from synthetic hallucinogens, (like 2C-B), because it contains no nitrogen atoms, hence it is not an alkaloid.

Salvinorin A is one of the most potent naturally occurring psychoactive drugs known to date, with an effective dose in humans in the 200–1,000 μg range when smoked. In that way Salvinorin A's quantitative potency may be compared with a somewhat smaller dosage of LSD where 50–100 μg is usually considered an effective psychedelic dosage), although it is important to note that the effect profile is significantly different than that of LSD and similar drugs, and has a different mechanism of action.

Salvinorin A can produce psychoactive experiences in humans with a typical duration of action being several minutes to an hour or so, depending on the method of ingestion.[1]

Salvinorin A is found with several other structurally-related salvinorins. Salvinorin is a trans-neoclerodane diterpenoid. It acts as a kappa opioid receptor agonist and is the first known compound acting on this receptor that is not an alkaloid. Salvinorin A was isolated in 1982 by Alfredo Ortega in Mexico. Its pharmacological mechanism was elucidated in the laboratory of Bryan L. Roth, et al.

Contents

Pharmacology

Salvinorin A is a trans-neoclerodane diterpenoid, chemical formula C23H28O8.[2] Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid — it does not contain a basic nitrogen atom.[3] Salvinorin A has no action at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as LSD and mescaline.[3]

Potency and selectivity

Salvinorin A is a potent naturally-occurring psychedelic. It is active at doses as low as 200 µg.[2][4][5] Research has shown that salvinorin A is a potent κ-opioid receptor agonist.[2] It has been reported that the effects of salvinorin A in mice are blocked by κ-opioid receptor antagonists.[6] This makes it unlikely that another mechanism contributes independently to the compound’s observed effects in mice. However, salvinorin A has recently been found to act as an even more potent D2 receptor partial agonist, with an affinity of 5-10 nM, an intrinsic activity of 40-60%, and an EC50 of 50-90 nM, which is several-fold higher than its EC50 of 235 nM for the κ-opioid receptor.[7] This suggests that the D2 receptor may also play an important role in its effects.[7]

Salvinorin A is unique in that it is the only known naturally-occurring substance known to induce a visionary state via this mode of action; there are synthetic kappa-opioid agonists, (e.g. enadoline, ketazocine, pentazocine and relatives), which show similar hallucinatory and dissociative effects.

Salvinorin A's potency shouldn't be confused with toxicity. Mice chronically given dosages "many times that of what humans are exposed to"[8] did not show signs of organ damage. However, "further studies should be done on blood pressure effects" and "Pulse pressure did appear to increase with salvinorin A exposure twenty and forty minutes after exposure, however, this increase was not statistically significant" (note that the data shows an increase in Pulse Pressure that was roughly 1.5–2 times the control group's).[9]

Effect on intestinal motility

Salvinorin A is capable of inhibiting excess intestinal motility (e.g. diarrhea), through a combination of k-opioid and cannabinoid (mainly CB1 receptor) receptors in inflamed but not normal gut in vivo[10]. 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[11]. 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[12].

Solubility

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

Detection in urine

Humans who smoked 580 micrograms of the pure drug had urine salvinorin A concentrations of 2.4–10.9 µg/L during the first hour, but the levels fell below the detection limit by 1.5 hours after smoking. Analytical measurements may be performed using gas or liquid chromatography-mass spectrometry.[13]

Associated compounds

Many other terpenoids have been isolated from Salvia divinorum, including other salvinorins and related compounds named divinatorins and salvinicins. None of these compounds have shown significant (sub-micromolar) affinity at the kappa-opioid receptor, and there is no evidence that they contribute to the plant's psychoactivity.[14][15]

Salvinorin A synthesis

High purity salvinorin extract isolated from dried Salvia divinorum foliage
Salvinorin A

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 typical for plant terpenoids.[16]

Similar to many plant-derived psychoactive compounds, Salvinorin A is excreted via peltate glandular trichomes, which reside external to the epidermis[17][18].

Chemical synthesis

A total asymmetric synthesis of salvinorin A, which relies on a transannular Michael reaction cascade to construct the ring system, was achieved in 2007 by Evans and co-workers in 4.5% overall yield over 30 steps.[19] More recently, a synthesis was published by a Japanese group, requiring 24 steps to yield salvinorin A in 0.15% yield.[20]

An approach to the trans-decalin ring system of salvinorin A has been described by Forsyth (et al.) utilizing an intramolecular Diels-Alder reaction/Tsuji allylation strategy.[21]

An attempt at the synthesis of salvinorin A has also been published by a group at RMIT University, adopting a convergent synthesis of a functionalized cyclohexanone with a α,β-unsaturated lactone.[22]

Salvinorins A - F, J

Salvinorin A is one of several structurally related salvinorins found in the Salvia divinorum plant. Salvinorin A can be synthesized from the inactive salvinorin B by acetylation. The des-acetylated analog salvinorin B is devoid of human activity. It was speculated that salvinorin C might be even more potent than salvinorin A, but human tests and receptor binding assays could not confirm this. Salvinorin A seems to be the only active naturally occurring salvinorin.[15]

Salvinorins A - F
Name Structure R1 R2 Activity
Salvinorin A Salvinorins AB.png -OCOCH3 − active
Salvinorin B -OH − inactive
Salvinorin C Salvinorins DEF.png -OCOCH3 -OCOCH3 unknown
Salvinorin D -OH -OCOCH3 inactive
Salvinorin E -OCOCH3 -OH inactive
Salvinorin F -H -OH unknown

The newly discovered salvinorin J is most closely related to salvinorin E in structure, with a C-17 secondary alcohol instead of an ketone group[23].

Semi-Synthetic Analogues

Research on salvinorin derivatives has produced a number of semi-synthetic compounds, several of which can be conveniently made from Salvinorin B. Most derivatives are selective kappa opioid agonists as with Salvinorin A, although some are even more potent, with the most potent compound 2-ethoxymethyl Salvinorin B being 10x stronger than Salvinorin A. A few derivatives such as herkinorin have reduced kappa opioid action and instead act as mu opioid agonists.[24][25][26][27][28][29][30][31]

Legality

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

See also

References

  1. ↑ Roth BL, Baner K, Westkaemper R, et al. (2002). "Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist". Proc. Natl. Acad. Sci. U.S.A. 99 (18): 11934–9. doi:10.1073/pnas.182234399. PMID 12192085. 
  2. ↑ 2.0 2.1 2.2 Prisinzano TE (2005). "Psychopharmacology of the hallucinogenic sage Salvia divinorum". Life Sci. 78 (5): 527–31. doi:10.1016/j.lfs.2005.09.008. PMID 16213533. 
  3. ↑ 3.0 3.1 Harding WW, Schmidt M, Tidgewell K, et al. (2006). "Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A". J. Nat. Prod. 69 (1): 107–12. doi:10.1021/np050398i. PMID 16441078. 
  4. ↑ Imanshahidi M, Hosseinzadeh H (2006). "The pharmacological effects of Salvia species on the central nervous system". Phytother Res 20 (6): 427–37. doi:10.1002/ptr.1898. PMID 16619340. 
  5. ↑ Marushia, Robin (2002). "Salvia divinorum: The Botany, Ethnobotany, Biochemistry and Future of a Mexican Mint" (– Scholar search). Ethnobotany. http://www.cyjack.com/Cognition/Salvia.pdf. Retrieved 2006-12-23 
  6. ↑ Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ (2005). "Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors". Psychopharmacology (Berl.) 179 (3): 551–8. doi:10.1007/s00213-004-2087-0. PMID 15682306. 
  7. ↑ 7.0 7.1 Seeman P, Guan HC, Hirbec H (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse (New York, N.Y.) 63 (8): 698–704. doi:10.1002/syn.20647. PMID 19391150. 
  8. ↑ Note: the Mowry et al. study used the following data: 1600 μg/kg (0.0016 mg/g) daily injections for 14 days on "Swiss-Webster mice, aged 4–6 months" of unknown weight (when purchasing mice, a estimated maximum mass is 25g). Given that the average weight for males in the United States is 190.9 lbs (according to Wikipedia), or 86,590.7834 g, and that a single gram mixture of plain leaf contains roughly 3 mg/g of Salvinorin A (according to Daniel Siebert). This translates to the mice receiving an effective dose of roughly 6,494,309 times more than a human (human doses range from minimal, 200 μg, to upwards of 24 mg, and body weight for both humans and mice vary tremendously).
  9. ↑ Mowry M, Mosher M, Briner W (2003). "Acute physiologic and chronic histologic changes in rats and mice exposed to the unique hallucinogen salvinorin A" (PDF). J Psychoactive Drugs 35 (3): 379–82. PMID 14621136. http://www.sagewisdom.org/mowryetal.pdf. 
  10. ↑ http://66.102.1.104/scholar?q=cache:rKp2XTIIzT4J:scholar.google.com/+salvia+divinorum+enteric+motility&hl=en
  11. ↑ PMID 16371085 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  12. ↑ PMID 17931335 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand
  13. ↑ Pichini, Simona; Abanades, Sergio; Farré, Magí; Pellegrini, Manuela; Marchei, Emilia; Pacifici, Roberta; de la Torre, Rafael; Zuccaro, Piergiorgio (June 30, 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" (fee required). Rapid Communications in Mass Spectrometry (Online: Wiley InterScience) 19 (12): 1649–1656. doi:10.1002/rcm.1970. ISSN 1097-0231. PMID 15915477. http://www3.interscience.wiley.com/cgi-bin/fulltext/110502413/PDFSTART. "Salvinorin A was not detected in urine samples collected from 1.5–9.5 h after smoking, probably because of a dilution effect, which yielded concentrations below the LOD obtainable with this methodology.". 
  14. ↑ Bigham AK, Munro TA, Rizzacasa MA, Robins-Browne RM (2003). "Divinatorins A-C, new neoclerodane diterpenoids from the controlled sage Salvia divinorum". J. Nat. Prod. 66 (9): 1242–4. doi:10.1021/np030313i. PMID 14510607. 
  15. ↑ 15.0 15.1 Munro TA, Rizzacasa MA (2003). "Salvinorins D-F, new neoclerodane diterpenoids from Salvia divinorum, and an improved method for the isolation of salvinorin A". J. Nat. Prod. 66 (5): 703–5. doi:10.1021/np0205699. PMID 12762813. 
  16. ↑ Kutrzeba L, Dayan FE, Howell J, Feng J, Giner JL, Zjawiony JK (July 2007). "Biosynthesis of salvinorin A proceeds via the deoxyxylulose phosphate pathway". Phytochemistry 68 (14): 1872–81. doi:10.1016/j.phytochem.2007.04.034. PMID 17574635. 
  17. ↑ PMID 15087301 (PubMed)
    Citation will be completed automatically in a few minutes. Jump the queue or expand by hand "A peltate glandular trichome on the abaxial leaf surface", and "The fact that most of the salvinorin content of fresh leaves can be extracted into chloroform without the solvent penetrating the epidermis indicates that these compounds are secreted externally to the epidermis."
  18. ↑ http://www.denniskunkel.com/DK/Plants/24071B.html
  19. ↑ Scheerer, J.R.; Lawrence, J.F.; Wang, G.C.; Evans, D.A. (2007). "Asymmetric synthesis of salvinorin A, a potent kappa opioid receptor agonist". J. Am. Chem. Soc. 129 (29): 8968–9. doi:10.1021/ja073590a. PMID 17602636. 
  20. ↑ Nozawa M, Suka Y, Hoshi T, Suzuki T, Hagiwara H (April 2008). "Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A". Org. Lett. 10 (7): 1365–8. doi:10.1021/ol800101v. PMID 18311991. 
  21. ↑ Burns, A.C.; Forsyth, C.J. (2008). "Intramolecular Diels−Alder/Tsuji Allylation Assembly of the Functionalized trans-Decalin of Salvinorin A". Org. Lett. 10 (1): 97–100. doi:10.1021/ol7024058. 
  22. ↑ Lingham AR, Hügel HM, Rook TJ (2006). "Studies Towards the Synthesis of Salvinorin A". Aust. J. Chem. 59 (5): 340–348. doi:10.1071/CH05338. 
  23. ↑ Kutrzeba, Lukasz; Ferreira, Zjawiony (2009). "Salvinorins J from Salvia divinorum: Mutarotation in the Neoclerodane System". J. Nat. Prod. 72 (7): 1361–1363. doi:10.1021/np900181q. ISSN = 10.1021/np900181q doi = 10.1021/np900181q. PMID 19473009. http://pubs.acs.org/doi/abs/10.1021/np900181q. 
  24. ↑ Lee DY, Karnati VV, He M, Liu-Chen LY, Kondaveti L, Ma Z, Wang Y, Chen Y, Beguin C, Carlezon WA, Cohen B (August 2005). "Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues". Bioorganic & Medicinal Chemistry Letters 15 (16): 3744–7. doi:10.1016/j.bmcl.2005.05.048. PMID 15993589. 
  25. ↑ Munro TA, Duncan KK, Xu W, Wang Y, Liu-Chen LY, Carlezon WA, Cohen BM, Béguin C (February 2008). "Standard protecting groups create potent and selective kappa opioids: salvinorin B alkoxymethyl ethers". Bioorganic & Medicinal Chemistry 16 (3): 1279–86. doi:10.1016/j.bmc.2007.10.067. PMID 17981041. 
  26. ↑ [1] Harding WW, Tidgewell K, Byrd N, Cobb H, Dersch CM, Butelman ER, Rothman RB, Prisinzano TE. "Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands." Journal of Medicinal Chemistry. 2005 Jul 28;48(15):4765-71. PMID 16033256
  27. ↑ [2] Tidgewell K, Harding WW, Lozama A, Cobb H, Shah K, Kannan P, Dersch CM, Parrish D, Deschamps JR, Rothman RB, Prisinzano TE. "Synthesis of salvinorin A analogues as opioid receptor probes." Journal of Natural Products. 2006 Jun;69(6):914-8. PMID 16792410
  28. ↑ [3] Holden KG, Tidgewell K, Marquam A, Rothman RB, Navarro H, Prisinzano TE. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Exploration of the 1-position. Bioorganic and Medicinal Chemistry Letters. 2007 Nov 15;17(22):6111-5. PMID 17904842
  29. ↑ Lee DY, He M, Liu-Chen LY, Wang Y, Li JG, Xu W, Ma Z, Carlezon WA, Cohen B (November 2006). "Synthesis and in vitro pharmacological studies of new C(4)-modified salvinorin A analogues". Bioorganic & Medicinal Chemistry Letters 16 (21): 5498–502. doi:10.1016/j.bmcl.2006.08.051. PMID 16945525. 
  30. ↑ Béguin C, Richards MR, Li JG, Wang Y, Xu W, Liu-Chen LY, Carlezon WA, Cohen BM (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 16 (17): 4679–85. doi:10.1016/j.bmcl.2006.05.093. PMID 16777411. 
  31. ↑ Cecile Beguin, William A. Carlezon, Bruce M. Cohen, Minsheng He, David Yue-Wei Lee, Michele R. Richards, Lee-Yuan Liu-Chen. Salvinorin derivatives and uses thereof. US Patent Application 2007/0213394 A1

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