Salvinorin A

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Salvinorin A
Salvinorin-A structure.png
Salvinorin A-sticks.png
Identifiers
CAS number 83729-01-5
PubChem 128563
MeSH Salvinorin+A
SMILES
InChI
Properties
Molecular formula C23H28O8
Molar mass 432.464
Melting point

238-240°C[1]
242-244°C[2]
Boiling point

760.2 °C (estimation by the Joback method)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

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 dissociative effects.

It is structurally distinct from other naturally-occurring hallucinogens (such as N,N-dimethyltryptamine, psilocybin, and mescaline), and from synthetic hallucinogens, (e.g. lysergic acid diethylamide (LSD), 2C-B), because it contains no nitrogen (or tryptamine moiety), 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 LSD, 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.[3]

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.

Contents

[edit] Pharmacology

Salvinorin A is a trans-neoclerodane diterpenoid, chemical formula C23H28O8.[4] Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid — it does not contain a basic nitrogen atom.[5] 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.[5]

[edit] Potency and selectivity

By weight, Salvinorin A is the most potent naturally-occurring psychoactive compound known.[6][7] It is active at doses as low as 200 µg.[4][7][8] Research has shown that salvinorin A is a potent and selective κ (kappa) opioid receptor agonist.[4] It has been reported that the effects of salvinorin A in mice are blocked by kappa opioid receptor antagonists.[9] This makes it unlikely that another mechanism contributes independently to the compound’s observed effects in mice[original research?].

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. Rodents chronically exposed to dosages many times greater than those to which humans are exposed did not show signs of organ damage.[10]

[edit] 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[11]. 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[12]. 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[13].

[edit] Solubility

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

[edit] 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]

[edit] Salvinorin A synthesis

[edit] 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).[16] It is synthesized via the deoxyxylulose phosphate pathway, rather than the classic mevalonate pathway typical for plant terpenoids.

Similar to many plant-derived psychoactive compounds, Salvinorin A is excreted via peltate glandular trichomes located just beneath the cuticle (subcuticular) layer[17][18].

[edit] Chemical synthesis

A total asymmetric synthesis of salvinorin A was achieved by Evans and co-workers in 4.5% overall yield over 30 steps,[19] and 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]

[edit] 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].

[edit] 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]

[edit] See also

[edit] References

  1. ^ Ortega A, Blount JF, Manchand PS (1982). "Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum(Labiatae)". J. Chem. Soc., Perkin Trans. 1: 2505–8. doi:10.1039/P19820002505. 
  2. ^ Valdes LJ, Butler WM, Hatfield GM, Paul AG, Koreeda M (November 1984). "Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum(Labiatae)". J. Org. Chem. 49 (24): 4716–8. doi:10.1021/jo00198a026. 
  3. ^ 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. 
  4. ^ a b c 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. 
  5. ^ a b 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. 
  6. ^ http://totallysynthetic.com/blog/?p=692
  7. ^ a b 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. 
  8. ^ Marushia, Robin (2002), "Salvia divinorum: The Botany, Ethnobotany, Biochemistry and Future of a Mexican Mint" ([dead link] – Scholar search), Ethnobotany, http://www.cyjack.com/Cognition/Salvia.pdf, retrieved 2006-12-23 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ http://66.102.1.104/scholar?q=cache:rKp2XTIIzT4J:scholar.google.com/+salvia+divinorum+enteric+motility&hl=en
  12. ^ Capasso, R.; Borrelli, F.; Capasso, F.; Siebert, D. J.; Stewart, D. J.; Zjawiony, J. K.; Izzo, A. A. (2006). "The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin a inhibit enteric cholinergic transmission in the guinea-pig ileum". Neurogastroenterology and Motility 18 (1): 69. doi:10.1111/j.1365-2982.2005.00725.x. PMID 16371085.  edit
  13. ^ Capasso, R.; Borrelli, F.; Zjawiony, J.; Kutrzeba, L.; Aviello, G.; Sarnelli, G.; Capasso, F.; Izzo, A. A. (2007). "The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin a reduce inflammation-induced hypermotility in mice". Neurogastroenterology & Motility 0: 070907093643003. doi:10.1111/j.1365-2982.2007.00994.x.  edit
  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. ^ a b 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. ^ Siebert, D. J. (2004). "Localization of Salvinorin a and Related Compounds in Glandular Trichomes of the Psychoactive Sage, Salvia divinorum". Annals of Botany 93 (6): 763. doi:10.1093/aob/mch089. PMID 15087301.  edit
  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/ol7025069. 
  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. ISSN 10.1021/np900181q DOI: 10.1021/np900181q. 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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