Salvinorin A

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 a much smaller dosage of LSD where 20-30 mcg 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.
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.
==Pharmacology==
Salvinorin A is a trans-neoclerodane diterpenoid, chemical formula C23H28O8. Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid — it does not contain a basic nitrogen atom. 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.
===Potency and selectivity===
Salvinorin A is a potent naturally-occurring psychedelic. It is active at doses as low as 200 µg.
 Research has shown that salvinorin A is a potent and selective κ (kappa) opioid receptor agonist. It has been reported that the effects of salvinorin A in mice are blocked by kappa opioid receptor antagonists. This makes it unlikely that another mechanism contributes independently to the compound's observed effects in mice.
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.
===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.http://66.102.1.104/scholar?q=cache:rKp2XTIIzT4J:scholar.google.com/+salvia+divinorum+enteric+motility&hl=en 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 is soluble in organic solvents such as ethanol and acetone, but not especially so in water.
==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.
==Salvinorin A 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 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.http://www.denniskunkel.com/DK/Plants/24071B.html
===Chemical synthesis===
A total asymmetric synthesis of salvinorin A was achieved by Evans and co-workers in 4.5% overall yield over 30 steps,
and more recently, a synthesis was published by a Japanese group, requiring 24 steps to yield salvinorin A in 0.15% yield.
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.
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.
==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.
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.
==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. 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 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 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 17904842Cecile 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
* 2-Ethoxymethyl Salvinorin B
* 2-Methoxymethyl Salvinorin B
* Herkinorin
==References==
===Further reading===
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==External links==
* The Salvia divinorum Research and Information Center (Daniel Siebert)
* Erowid Salvia divinorum vault
* Lycaeum Salvinorin A
* Tryptamind Salvinorin A Downloadable salvinorin extraction photos.
Category:Entheogens