Salvinorin A

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Salvinorin A
Salvinorin A2DCSDS.svg
Clinical data
Routes of
administration Buccal/Sublingual, Smoked
ATC code
none
Legal status
Legal status
AU: S9 (Prohibited substance)
CA: Schedule IV
Uncontrolled (though Salvia divinorum is controlled in some parts of the world,
such as in certain states in the US)
Identifiers
IUPAC name
CAS Number
83729-01-5 ☒
PubChem CID
128563
IUPHAR/BPS
1666
ChemSpider
113947 check
UNII
T56W91NG6J
KEGG
C20196 ☒
ChEBI
CHEBI:67900 ☒
ChEMBL
ChEMBL445332 check
CompTox Dashboard (EPA)
DTXSID80232584 Edit this at Wikidata
ECHA InfoCard 100.215.796 Edit this at Wikidata
Chemical and physical data
Formula C23H28O8
Molar mass 432.469 g·mol−1
3D model (JSmol)
Interactive image
Specific rotation -45.3 °C at 22 deg C/D (c = 8.530 CHCl3); -41 °C at 25°C/D (c = 1
in CHCl3)
Melting point 238 to 240 °C (460 to 464 °F) (also reported 242–244 °C)[1]
Boiling point 760.2 °C (1,400.4 °F)
Solubility in water 25.07 mg/L at 25 °C (water, est) mg/mL (20 °C)
SMILES
InChI
☒check (what is this?) (verify)
Salvinorin A is the main active psychotropic molecule in Salvia divinorum.
Salvinorin A is considered a dissociative hallucinogen.[2][3]

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.[2]
It also differs in subjective experience, compared to other hallucinogens, and has
been described as dissociative.[3]
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.[4]

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.[4]

Contents
1 History
2 Pharmacology
2.1 Pharmacokinetic
2.2 Effects and research
2.3 Potency and selectivity
2.4 Effect on intestinal motility
2.5 Solubility
2.6 Detection in urine
3 Synthesis
3.1 Biosynthesis
3.2 Chemical synthesis
4 Associated compounds
5 Legal status
5.1 United States
5.1.1 Florida
5.2 Australia
5.3 Sweden
6 See also
7 References
8 Further reading
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.[5] Around the same time, Leander Julián Valdés III
independently isolated the molecule as part of his PhD research, published in 1983.
[6] 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.[7] Valdés later isolated salvinorin C.[8]

Pharmacology
Salvinorin A is a trans-neoclerodane diterpenoid with the chemical formula
C23H28O8.[9] Unlike other known opioid-receptor ligands, salvinorin A is not an
alkaloid, as it does not contain a basic nitrogen atom.[2][10] 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.[4][10]
Salvinorin A has also been shown to have effect on cannabinoid CB1 receptors.[11]
It significantly increases prolactin and inconsistently increases cortisol.[12] It
causes dysphoria by stopping release of dopamine in the striatum.[13] Salvinorin A
increases activity of DAT while decreasing activity of SERT.[13]

Pharmacokinetic
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.[14] It has a half-life of around 8 minutes in non-human
primates.[15]
Effects and 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.[16] Like most other agonists of kappa opioid receptors,
salvinorin A produces sedation, psychotomimesis, dysphoria, anhedonia, and
depression.[2][17][18] Salvinorin A is under preliminary research for its possible
use as a scaffold in medicinal chemistry to develop new drugs for treating
psychiatric diseases,[2][19] such as addiction from cocaine dependence.[20]

Potency and selectivity

Salvinorin A is active at doses as low as 200 µg.[9][21][22] Synthetic chemicals,
such as LSD (active at 20–30 µg doses), can be more potent.[23] Research has shown
that salvinorin A is a potent κ-opioid receptor (KOR) agonist (Ki = 2.4 nM, EC50 =
1.8 nM).[9] It has a high affinity for the receptor, indicated by the low
dissociation constant of 1.0 nanomolar (nM).[24] It has been reported that the
effects of salvinorin A in mice are blocked by κ-opioid receptor antagonists.[25]
In addition, salvinorin A has recently 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.[26] This suggests that the D2 receptor may also play an important role in
its effects.[26] Salvinorin A shows atypical properties as an agonist of the KOR
relative to other KOR agonists.[27] For instance, it is 40-fold less potent in
promoting internalization (receptor downregulation) of the human KOR relative to
the prototypical KOR agonist U-50488.[citation needed]

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.[28] 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.[29]

Solubility
Salvinorin A is soluble in organic solvents such as ethanol and acetone, but not
especially so in water.[30]

Detection in urine
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, 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.[31]

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.[32]

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.

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), produces an Iabdanyl diphosphate carbocation, which
is subsequently rearranged through a sequence of 1,2-hydride and methyl shifts to
form the ent-clerodienyl diphosphate intermediate.[33] 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.

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.[34][35]

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,[36] then revised using 24 steps to yield salvinorin A
in 0.15% yield.[37] An approach to the trans-decalin ring system of salvinorin A
used an intramolecular Diels-Alder reaction/Tsuji allylation strategy,[38] 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.[39]

Associated compounds
Main article: Salvinorin
Salvinorin A is one of several structurally related salvinorins found in the Salvia
divinorum plant. Salvinorin A seems to be the only naturally occurring salvinorin
that is psychoactive.[40] Salvinorin A can be synthesized from salvinorin B by
acetylation, and de-acetylated salvinorin A becomes analog to salvinorin B.[41]

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.[42][43][44][45]

The derivative RB-64 is notable because of its functional selectivity and potency.
[46] Salvinorin B methoxymethyl ether is seven times more potent than Salvinorin A
at KOPr in GTP-γS assays.[47]

Legal status
See also: Legal status of Salvia divinorum
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.[48] 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."[49]

Australia
Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the
Poisons Standard (October 2015).[50] 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.[50]

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 Apr 1, 2006, in their regulation SFS 2006:167 listed as "salvinorin
A", making it illegal to sell or possess.[51]

See also
Psychoactive drug
List of entheogens
Nalfurafine
Difelikefalin
Enadoline
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Wang, Y.; Chen, Y.; Xu, W.; Lee, D.; Ma, Z; Rawls, S.; Cowan, A.; Liu-Chen, L.
(2008). "2-methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist
with longer lasting action in vivo than salvinorin A." Journal of Pharmacology and
Experimental Therapeutics. 324 (3): 1073–1083. doi:10.1124/jpet.107.132142. PMC
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21 CFR — Schedules of Controlled Substances §1308.11 Schedule I.
Florida Statutes - Chapter 893 - Drug Abuse Prevention and Control
Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534
"Förordning om ändring i förordningen (1999:58) om förbud mot vissa hälsofarliga
varor (Swedish)" (PDF). Svensk författningssamling. 2006.
Further reading
Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th
ed.). Foster City, CA: Biomedical Publications. pp. 1405–6. ISBN 978-0-9626523-7-0.
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Categories: Drugs not assigned an ATC codeDissociative drugsEntheogensKappa
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