Salvinorin A

Source: Wikipedia, the free encyclopedia.
Salvinorin A
Sublingual, Smoked
ATC code
  • none
Legal status
Legal status
Identifiers
  • methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-dodecahydro-1H-naphtho[2,1-c]pyran-7-carboxylate
JSmol)
Specific rotation[α]D = -45.3° at 22 °C/ (c = 8.530 CHCl3); [α]D = -41° at 25 °C (c = 1 in CHCl3)
Melting point238 to 240 °C (460 to 464 °F) (also reported 242–244 °C)[2]
Boiling point760.2 °C (1,400.4 °F)
Solubility in water25.07 mg/L at 25 °C (water, est) mg/mL (20 °C)
  • O=C(OC)[C@H]2[C@@]3(CC[C@H]4C(=O)O[C@H](c1ccoc1)C[C@@]4([C@H]3C(=O)[C@@H](OC(=O)C)C2)C)C
  • InChI=1S/C23H28O8/c1-12(24)30-16-9-15(20(26)28-4)22(2)7-5-14-21(27)31-17(13-6-8-29-11-13)10-23(14,3)19(22)18(16)25/h6,8,11,14-17,19H,5,7,9-10H2,1-4H3/t14-,15-,16-,17-,19-,22-,23-/m0/s1 checkY
  • Key:OBSYBRPAKCASQB-AGQYDFLVSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Salvinorin A is the main active

psychotropic molecule in Salvia divinorum. Salvinorin A is considered a dissociative hallucinogen.[3][4]

It is structurally distinct from other naturally occurring

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

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.[5]

Salvinorin A is found with several other structurally related

kappa opioid receptor agonist and is the first known compound acting on this receptor that is not an alkaloid.[5]

History

Salvinorin A was first described and named in 1982 by Alfredo Ortega and colleagues in Mexico. They used a combination of

bicyclic diterpene structure.[6] Around the same time, Leander Julián Valdés III independently isolated the molecule as part of his PhD research, published in 1983.[7] 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.[8] Valdés later isolated salvinorin C.[9]

Pharmacology

Salvinorin A is a trans-neoclerodane

serotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as LSD and mescaline.[5][11] Salvinorin A has also been shown to have effect on cannabinoid CB1 receptors.[12] It significantly increases prolactin and inconsistently increases cortisol.[13] It causes dysphoria by stopping release of dopamine in the striatum.[14] Salvinorin A increases activity of DAT while decreasing activity of SERT.[14]

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.[15] It has a half-life of around 8 minutes in non-human primates.[16]

Potency and selectivity

Salvinorin A is active at doses as low as 200 

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

exogenous acetylcholine.[24] 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.[25]

Solubility

Salvinorin A is soluble in

organic solvents such as ethanol and acetone, but not especially so in water.[26]

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.[27]

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

psychotomimesis, dysphoria, anhedonia, and depression.[3][28][29] Salvinorin A has been screened for its possible use as a structural "scaffold" in medicinal chemistry in developing new drugs for treating psychiatric diseases[3][30] such as cocaine dependence.[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

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]

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[33]), 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.[34] 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.[33]

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.[35][36]

Chemical synthesis

A total

Tsuji allylation strategy,[39] 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.[40]

Associated compounds

Main article: Salvinorin

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.

acetylated salvinorin A becomes analog to salvinorin B.[42]

Research has produced a number of

mu opioid agonists.[43][44][45][46]

The synthetic derivative RB-64 is notable because of its functional selectivity and potency.[47] Salvinorin B methoxymethyl ether is seven times more potent than salvinorin A at KOPr in GTP-γS assays.[48]

Natural occurrence

Salvinorin A occurs naturally in several Salvia species:

Salvinorin B has been detected in S. potentillifolia and S. adenocaulon, however these species do not contain a measureable amount of salvinorin A.[50]

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

See also: Legal status of Salvia divinorum in the United States

Salvinorin A is not scheduled at the federal level in the United States.[51] 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.[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."[52]

Australia

Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[53] 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.[53]

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.[54]

See also

References

  1. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
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  54. ^ "Förordning om ändring i förordningen (1999:58) om förbud mot vissa hälsofarliga varor" [Ordinance amending the ordinance (1999: 58) on the prohibition of certain dangerous goods] (PDF) (in Swedish). Svensk författningssamling. 2006. Archived from the original (PDF) on 2013-09-29. Retrieved 2013-09-25.

Further reading

  • Baselt RC (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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