It is structurally distinct from other naturally occurringhallucinogens (such asDMT,psilocybin, andmescaline) because it contains nonitrogen atoms; hence, it is not analkaloid (and cannot be rendered as asalt), but rather is aterpenoid.[4] It also differs in subjective experience, compared to other hallucinogens, and has been described as having strongdissociative effects.[5]
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.[6]
Salvinorin A was first described and named in 1982 by Alfredo Ortega and colleagues in Mexico. They used a combination ofspectroscopy andx-ray crystallography to determine the chemical structure of the compound, which was shown to have abicyclicditerpene structure.[7] Around the same time, Leander Julián Valdés III independently isolated the molecule as part of his PhD research, published in 1983.[8] Valdés named the chemicaldivinorin, and also isolated ananalog that he named divinorin B. The naming was subsequently corrected to salvinorin A and B after the work was published in 1984.[9] Valdés later isolated salvinorin C.[10]
Salvinorin A is atrans-neoclerodanediterpenoid with thechemical formula C23H28O8.[11] Unlike other known opioid-receptor ligands, salvinorin A is not analkaloid, as it does not contain anitrogenatom.[4][12] Salvinorin A has no action at the5-HT2Aserotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such asLSD andmescaline.[6][12] Salvinorin A has also been shown to have effect on cannabinoid CB1 receptors.[13] It significantly increases prolactin and inconsistently increases cortisol.[14] It causes dysphoria by stopping release of dopamine in thestriatum.[15] Salvinorin A increases activity ofDAT while decreasing activity ofSERT.[15]
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.[16]It has a half-life of around 8 minutes in non-human primates.[17]
Salvinorin A is active at doses as low as 200 μg.[11][18][19] Synthetic chemicals, such asLSD (active at 20–30 μg doses), can be morepotent.[20] Research has shown that salvinorin A is a potentκ-opioid receptor (KOR)agonist (Ki = 2.4 nM, EC50 = 1.8 nM).[11] It has a high affinity for the receptor, indicated by the lowdissociation constant of 1.0 nanomolar (nM).[21] In addition, salvinorin A has been found to act as aD2 receptorpartial agonist, with anaffinity of 5–10 nM, anintrinsic activity of 40–60%, and anEC50 of 48 nM.[22] This suggests that the D2 receptor may also play an important role in its effects.[22]
Salvinorin A shows atypical properties as an agonist of the KOR relative to other KOR agonists.[23]
Salvinorin A is capable of inhibiting excessintestinal motility (e.g. diarrhea), through its potent κ-opioid-activating effects. The mechanism of action for salvinorin A onileal tissue has been described as 'prejunctional', as it was able to modify electrically induced contractions, but not those ofexogenousacetylcholine.[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]
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 thedetection limit by 1.5 hours after smoking.[27]
Terpenoids are biosynthesized from two 5-carbon precursors,isopentenyl diphosphate (IPP) anddimethylallyl 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 theent-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 viapeltate glandulartrichomes, which reside external to theepidermis.[35][36]
A totalasymmetric synthesis of salvinorin A, which relies on a transannularMichael reaction cascade to construct the ring system, was achieved as a 4.5% overall yield over 30 steps,[37] then revised using 24 steps to yield salvinorin A in 0.15% yield.[38] An approach to thetrans-decalin ring system of salvinorin A used an intramolecularDiels-Alder reaction/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]
Salvinorin A is one of several structurally related salvinorins found in theSalvia divinorum plant. Salvinorin A is the only naturally occurring salvinorin that is known to be psychoactive.[41] Salvinorin A can be synthesized from salvinorin B byacetylation, and de-acetylated salvinorin A becomes analog to salvinorin B.[42]
Research has produced a number ofsemi-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 asherkinorin, reduce kappa opioid action and instead act asmu opioid agonists.[43][44][45][46]
Salvinorin A is not scheduled at the federal level in theUnited States.[51] Its molecular structure is unlike any Schedule I or II drug, so possession or sales is unlikely to be prosecuted under theFederal Analogue Act.[citation needed]
"Salvinorin A" is a Schedule Icontrolled substance in the state ofFlorida 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]
Salvinorin A is considered a Schedule 9 prohibited substance in Australia under thePoisons 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]
Sveriges riksdags health ministryStatens folkhälsoinstitut classified salvinorin A (andSalvia divinorum) as "health hazard" under the actLagen om förbud mot vissa hälsofarliga varor (translatedAct 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]
^Ortega A, Blount JF, Manchard PD (1982). "Salvinorin, a newtrans-neoclerodane diterpene fromSalvia divinorum (Labiatae)".Journal of the Chemical Society, Perkin Transactions 1:2505–8.doi:10.1039/P19820002505.
^Valdés III LJ (1983).The pharmacognosy ofSalvia divinorum (Epling and Jativa-M): An Investigation of Ska Maria Pastora (Mexico) (PhD thesis). University of Michigan.ProQuest303280881.
^Valdés III LJ, Butler WM, Hatfield GM, Paul AG, Koreeda M (1984). "Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mintSalvia divinorum".Journal of Organic Chemistry.49 (24):4716–20.doi:10.1021/jo00198a026.
^Valdés LJ, Chang HM, Visger DC, Koreeda M (November 2001). "Salvinorin C, a new neoclerodane diterpene from a bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum".Organic Letters.3 (24):3935–3937.doi:10.1021/ol016820d.PMID11720573.
^abcPrisinzano TE (December 2005). "Psychopharmacology of the hallucinogenic sage Salvia divinorum".Life Sciences.78 (5):527–531.doi:10.1016/j.lfs.2005.09.008.PMID16213533.
^Siebert DJ (June 1994). "Salvia divinorum and salvinorin A: new pharmacologic findings".Journal of Ethnopharmacology.43 (1):53–56.doi:10.1016/0378-8741(94)90116-3.PMID7526076.
^Imanshahidi M, Hosseinzadeh H (June 2006). "The pharmacological effects of Salvia species on the central nervous system".Phytotherapy Research.20 (6):427–437.doi:10.1002/ptr.1898.PMID16619340.S2CID35676076.However, when smoked (in a manner similar to free base cocaine), the compound is effective in doses of 200–500 μg and produces visions that last from 30 minutes to an hour or two, while doses over 2 mg are effective for much longer. At doses greater than 500 μg the subject is often no longer aware of their surroundings and may enter an uncontrollable delirium. This compound is the most potent naturally occurring hallucinogen thus far isolated.
^Greiner T, Burch NR, Edelberg R (February 1958). "Psychopathology and psychophysiology of minimal LSD-25 dosage; a preliminary dosage-response spectrum".A.M.A. Archives of Neurology and Psychiatry.79 (2):208–210.doi:10.1001/archneurpsyc.1958.02340020088016.PMID13497365.
^Lee DY, Ma Z, Liu-Chen LY, Wang Y, Chen Y, Carlezon WA, Cohen B (October 2005). "New neoclerodane diterpenoids isolated from the leaves of Salvia divinorum and their binding affinities for human kappa opioid receptors".Bioorganic & Medicinal Chemistry.13 (19):5635–5639.doi:10.1016/j.bmc.2005.05.054.PMID16084728.
^abSeeman P, Guan HC, Hirbec H (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil".Synapse.63 (8):698–704.doi:10.1002/syn.20647.PMID19391150.S2CID17758902.
^Capasso R, Borrelli F, Capasso F, Siebert DJ, Stewart DJ, Zjawiony JK, Izzo AA (January 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):69–75.doi:10.1111/j.1365-2982.2005.00725.x.PMID16371085.S2CID4498185.
^Capasso R, Borrelli F, Zjawiony J, Kutrzeba L, Aviello G, Sarnelli G, et al. (February 2008). "The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A reduce inflammation-induced hypermotility in mice".Neurogastroenterology and Motility.20 (2):142–148.doi:10.1111/j.1365-2982.2007.00994.x.PMID17931335.S2CID25081755.
^"Salvia divinorum". European Monitoring Centre for Drugs and Drug Addiction. Retrieved4 September 2014.Salvinorin A is unstable in basic solutions and is soluble in conventional organic solvents, including acetone, acetonitrile, chloroform, dimethyl sulfoxide and methanol, but is essentially insoluble in hexane and water.
^Pichini S, Abanades S, Farré M, Pellegrini M, Marchei E, Pacifici R, et al. (30 June 2005). "Quantification of the plant-derived hallucinogen Salvinorin A in conventional and non-conventional biological fluids by gas chromatography/mass spectrometry after Salvia divinorum smoking".Rapid Communications in Mass Spectrometry.19 (12):1649–1656.Bibcode:2005RCMS...19.1649P.doi:10.1002/rcm.1970.PMID15915477.
^Kivell BM, Ewald AW, Prisinzano TE (2014). "Salvinorin a Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse".Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse. Advances in Pharmacology. Vol. 69. pp. 481–511.doi:10.1016/B978-0-12-420118-7.00012-3.ISBN9780124201187.PMC4128345.PMID24484985.
^Scheerer JR, Lawrence JF, Wang GC, Evans DA (July 2007). "Asymmetric synthesis of salvinorin A, a potent kappa opioid receptor agonist".Journal of the American Chemical Society.129 (29):8968–8969.Bibcode:2007JAChS.129.8968S.doi:10.1021/ja073590a.PMID17602636.
^Nozawa M, Suka Y, Hoshi T, Suzuki T, Hagiwara H (April 2008). "Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A".Organic Letters.10 (7):1365–1368.doi:10.1021/ol800101v.PMID18311991.
^Burns AC, Forsyth CJ (January 2008). "Intramolecular Diels-Alder/Tsuji allylation assembly of the functionalized trans-decalin of salvinorin A".Organic Letters.10 (1):97–100.doi:10.1021/ol7024058.PMID18062692.
^Line NJ, Burns AC, Butler SC, Casbohm J, Forsyth CJ (December 2016). "Total Synthesis of (-)-Salvinorin A".Chemistry: A European Journal.22 (50):17983–17986.doi:10.1002/chem.201604853.PMID27758012.
^Munro TA, Rizzacasa MA (May 2003). "Salvinorins D-F, new neoclerodane diterpenoids from Salvia divinorum, and an improved method for the isolation of salvinorin A".Journal of Natural Products.66 (5):703–705.doi:10.1021/np0205699.PMID12762813.
^Lee DY, Karnati VV, He M, Liu-Chen LY, Kondaveti L, Ma Z, et al. (August 2005). "Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues".Bioorganic & Medicinal Chemistry Letters.15 (16):3744–3747.doi:10.1016/j.bmcl.2005.05.048.PMID15993589.
^Lee DY, He M, Liu-Chen LY, Wang Y, Li JG, Xu W, et al. (November 2006). "Synthesis and in vitro pharmacological studies of new C(4)-modified salvinorin A analogues".Bioorganic & Medicinal Chemistry Letters.16 (21):5498–5502.doi:10.1016/j.bmcl.2006.08.051.PMID16945525.
^Béguin C, Richards MR, Li JG, Wang Y, Xu W, Liu-Chen LY, et al. (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):4679–4685.doi:10.1016/j.bmcl.2006.05.093.PMID16777411.
^abcdHatipoglu SD, Yalcinkaya B, Akgoz M, Ozturk T, Goren AC, Topcu G (November 2017). "Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species".Phytochemical Analysis.28 (6):541–549.Bibcode:2017PChAn..28..541H.doi:10.1002/pca.2703.PMID28722248.
Baselt RC (2008).Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1405–6.ISBN978-0-9626523-7-0.
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