Salvinorin A

Template:Short description Template:Cs1 config Template:Infobox drug

Salvinorin A is the main active psychotropic molecule in Salvia divinorum. Salvinorin A is considered a dissociative hallucinogen.<ref name="fp">Template:Cite journal</ref><ref name="NCBI">Template:Cite journal</ref>

It is structurally distinct from other naturally occurring hallucinogens (such as DMT, psilocybin, and mescaline) because it contains no nitrogen atoms; hence, it is not an alkaloid (and cannot be rendered as a salt), but rather is a terpenoid.<ref name=fp/> It also differs in subjective experience, compared to other hallucinogens, and has been described as dissociative.<ref name="NCBI" />

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.<ref name=Roth2002/>

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.<ref name=Roth2002/>

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.<ref name=Ortega1982/> Around the same time, Leander Julián Valdés III independently isolated the molecule as part of his PhD research, published in 1983.<ref name=Valdes1983/> 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.<ref name=Valdes1984/> Valdés later isolated salvinorin C.<ref name=Valdes2001/>

Pharmacology

Salvinorin A is a trans-neoclerodane diterpenoid with the chemical formula C₂₃H₂₈O₈.<ref name=Prisinzano2005/> Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid, as it does not contain a basic nitrogen atom.<ref name=fp/><ref name=Harding2006/> Salvinorin A has no action at the 5-HT_2A serotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as LSD and mescaline.<ref name=Roth2002/><ref name=Harding2006/> Salvinorin A has also been shown to have effect on cannabinoid CB1 receptors.<ref>Template:Cite web</ref> It significantly increases prolactin and inconsistently increases cortisol.<ref>Template:Cite journal</ref> It causes dysphoria by stopping release of dopamine in the striatum.<ref name="pmc4188751">Template:Cite journal</ref> Salvinorin A increases activity of DAT while decreasing activity of SERT.<ref name="pmc4188751" />

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.<ref>Template:Cite journal</ref> It has a half-life of around 8 minutes in non-human primates.<ref>Template:Cite journal</ref>

Potency and selectivity

Salvinorin A is active at doses as low as 200 μg.<ref name=Prisinzano2005/><ref name=Imanshahidi2006/><ref name="Marushia2002p11"> Template:Cite journal</ref> Synthetic chemicals, such as LSD (active at 20–30 μg doses), can be more potent.<ref name=Greiner1958/> Research has shown that salvinorin A is a potent κ-opioid receptor (KOR) agonist (K_i = 2.4 nM, EC₅₀ = 1.8 nM).<ref name=Prisinzano2005/> It has a high affinity for the receptor, indicated by the low dissociation constant of 1.0 nanomolar (nM).<ref name=Lee2005b/> 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.<ref name=Seeman2009/> This suggests that the D₂ receptor may also play an important role in its effects.<ref name=Seeman2009/>

Salvinorin A shows atypical properties as an agonist of the KOR relative to other KOR agonists.<ref name="Dwoskin2014">Template:Cite book</ref>

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.<ref name=Capasso2006/> 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.<ref name=Capasso2007/>

Solubility

Salvinorin A is soluble in organic solvents such as ethanol and acetone, but not especially so in water.<ref>Template:Cite web</ref>

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.<ref name=Pichini2005/>

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.<ref name="NCBI"/> Like most other agonists of kappa opioid receptors, salvinorin A produces sedation, psychotomimesis, dysphoria, anhedonia, and depression.<ref name=fp/><ref name="Mott2011">Template:Cite book</ref><ref name="Biller2008">Template:Cite book</ref> Salvinorin A has been screened for its possible use as a structural "scaffold" in medicinal chemistry in developing new drugs for treating psychiatric diseases<ref name=fp/><ref>Template:Cite journal</ref> such as cocaine dependence.<ref>Template:Cite book</ref>

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, consistent with the common plastidial localization of diterpenoid metabolism.<ref name=Kutrzeba2007/>

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.

File:Synthesis of IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate Pathway.png

Synthesis of IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate pathway

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<ref name=SdCPS2>Template:Cite web</ref>), 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.<ref>Template:Cite journal</ref> 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.<ref name=SdCPS2/>

File:Biosynthesis of Salvinorin A.png

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.<ref name=Siebert2004/><ref name="urlKunkel2007"/>

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,<ref name=Scheerer2007/> then revised using 24 steps to yield salvinorin A in 0.15% yield.<ref name=Nozawa2008/> An approach to the trans-decalin ring system of salvinorin A used an intramolecular Diels-Alder reaction/Tsuji allylation strategy,<ref name=Burns2008/> and a total synthesis of salvinorin A was achieved using the intramolecular Diels-Alder / Tsuji allylation approach, combined with an asymmetric late-stage addition of the furan moiety.<ref>Template:Cite journal</ref>

Associated compounds

Template:Main

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.<ref name=Munro2003/> Salvinorin A can be synthesized from salvinorin B by acetylation, and de-acetylated salvinorin A becomes analog to salvinorin B.<ref name="lee2005a">Template:Cite journal</ref>

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.<ref name=Munro2008/><ref name=Holden2007/><ref name=Lee2006/><ref name=Beguin2006/>

The synthetic derivative RB-64 is notable because of its functional selectivity and potency.<ref name="pmid25320048">Template:Cite journal</ref> Salvinorin B methoxymethyl ether is seven times more potent than salvinorin A at KOPr in GTP-γS assays.<ref>Template:Cite journal</ref>

Natural occurrence

Salvinorin A occurs naturally in several Salvia species:

S. divinorum (0.89 mg/g to 3.70 mg/g).<ref>Template:Cite journal</ref>
S. recognita (212.9 μg/g).<ref name=":0" />
S. cryptantha (51.5 μg/g).<ref name=":0" />
S. glutinosa (38.9 μg/g).<ref name=":0">Template:Cite journal</ref>

Salvinorin B has been detected in S. potentillifolia and S. adenocaulon, however these species do not contain a measureable amount of salvinorin A.<ref name=":0" />

Legal status

Template:See also

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

United States

Template:See also Salvinorin A is not scheduled at the federal level in the United States.<ref name="Part 1308 — Schedules of Controlled Substances - 1308.11 Schedule I">Template:Cite web</ref> 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.Template:Citation needed

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."<ref name="Florida Statutes - Chapter 893 - Drug Abuse Prevention and Control">Template:Cite web</ref>

Australia

Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).<ref name="Poisons Standard">Template:Cite web</ref> 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.<ref name="Poisons Standard" />

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.<ref>Template:Cite web</ref>

References

Template:Reflist