Salvinorin A
Jomana Amro, Philipp Becker, Conny Büchner, Nad¨zaD¨zindo Contents
1 General Information 2
2 Historical Background 4
3 Synthesis 4
4 Eects 5 4.1 Working Principle ...... 5 4.2 Importance in Experimental Research ...... 5 4.3 Potential Medical Eects ...... 6
5 References 7
1 1 General Information1 Salvinorin A (SA) is a psychoactive neoclerodane diterpenoid isolated from the plant Salvia Divinorum, a member of the mint family that has historically been used in ethnomedical practices in Mexico2 and which has gained increased popularity as a recreational drug3.
Characteristics of Salvinorin A Salvinorin A dierentiates to common hallucinogens in two ways. A common target of hallucinogens such as lysergic acid diethylamide (LSD) is the 5-HT2A serotonin receptor. However, Salvinorin A has no a nity at 5-HT2A. The other dierence is structural. Classic hallucinogens are nitrogen compounds which Salvinorin A is not.
IUPAC-Name methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-9-acetyloxy-2- (furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a- octahydro-1H-benzo[f] isochromene-7-carboxylate Chemical(Trivial) Names Salvinorin A Diviorin A 2H-Naphtho(2,1-c)pyran-7-carboxylic acid, 9-(acetyloxy)- 2-(3- furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-, methyl ester, (2S-(2alpha,4aalpha,6abeta,7beta,9beta, 10aalpha,10bbeta))-
Molecular Formula C23H28O8 Molecular Weight 432.469 g/mol Melting Point 238-240°C Solubility in water 12.1 mg/L at 25°C Hydrogen Bond Donor Count 0 Hydrogen Bond Acceptor Count 8 Isotope Atom Count 0 De ned Atom Stereocentre Count 7
Speci c optional rotation -45.3 deg at 22 deg C/D ( c = 8.530 CHCl3) Hazard statements H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral] Precautionary statements P264: Wash ... thoroughly after handling. P270: Do not eat, drink or smoke when using this product. P301+P312: If swallowed: Call a poison center or doctor/... if you feel unwell. P330: Rinse mouth.
1 https://pubchem.ncbi.nlm.nih.gov/compound/128563, 11.6.2019 2 Siebert 1994; Ott 1995; Ott 1996; Valdes et al. 2001 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208627/), 11.6.2019 3 Wu et al., 2011; Perron et al., 2012 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208627/), 11.6.2019
2 Salvia Divinorum Salvia Divinorum is also known as Diviner's Sage. There are about 900 dierent Salvia species including many ornamental garden sages and Salvia o cinalis, the common cooking sage. The plant has a charac- teristic weak 'mousy-but-minty' aroma. It originates from the south of Mexico, in the Sierra mazateca region in the mexican federal state Oaxaca.4 It is used by mazatec shamans and healers for rituals until today. In a low dose it is used for the therapy of physical in rmity and in a higher dose for visionary intoxication. The manners of consumption are very dierent: Mostly it is chewed, smoked or drunk as tea. It is used to get intoxicated around the world since the 1980`s. Nowadays Salvia Divinorum is illegal in many countries of the world.
Salvinorin A Salvinorin A is found in the resin secreted by special, hairy epidermal cells (trichomes), which the leaves are especially abundant in. However, the actual Salvinorin A concentration of Salvia Divinorum products is generally unknown. Pure, crystalline Salvinorin A does not appear to be oered on markets (neither online or in smartshops) but illustrated procedures for its isolation are available on the Internet.5
Structure6 Salvinorin is a trans-neoclerodane diterpenoid and it is structurally distinct from other naturally occur- ring hallucinogens (such as DMT, psilocybin, and mescaline) because it contains no nitrogen therefore it is not an alkaloid and cannot be rendered as a salt. Salvinorin A has eight hydrogen-bond acceptor sites, all oxygen atoms, and no hydrogen-bond donor groups. It would thus appear likely that its crystal lattice should comprise only weak non-bonded inter- actions between adjacent molecules and a resultant diminished lattice energy re ected in a low melting point.
Figure 1: Structure
4 http://www.sagewisdom.org/faq.html, 11.6.2019 5 http://www.emcdda.europa.eu/publications/drug-pro les/salvia, 11.6.2019 6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208627/, 11.6.2019
3 2 Historical Background7 The rst recorded mention of Salvia Divinorum was made in 1938 by Jean B. Johnson, who heard of Mazatecs making a tea from the leaves of hierba Maria, which induced visions in users. R. Gordon Wasson and Albert Hofmann acquired the rst specimen of Salvia Divinorum from the Mazatecs in 1962. They described it as a less desirable substitute for hallucinogenic mushrooms. Salvinorin A was rst named in 1982 by Alfredo Ortega and colleagues in Mexico. They used a combi- nation of spectroscopy and x-ray crystallography to determine the chemical structure of the compound, which was shown to have a bicyclic diterpene structure. Around the same time Leander Julián Valdés III independently isolated the molecule as part of his PhD research which was published in 1983. Valdés named the compound Divinorin and also isolated an analogue that he named Divinorin B. The naming was subsequently corrected to Salvinorin A and B after the work was published in 1984. Valdés later isolated Salvinorin C as well.
3 Synthesis8 Chemical Synthesis The synthesis of Salvinorin A is asymmetric and contains over 30 steps. It includes a transannular Michael reaction cascade and an intramolceluar Diels-Alder reaction/Tsuji allylation.
Biosynthesis There are dierent theories on how Salvinorin A is biosynthesized. The most probable pathway is the 1-deoxy-d-xylulose-5-phosphate pathway, where D-glyceraldehyde 3-phosphate and pyruvate are transformed into D-xylulose 5-phosphate. After reduction it turns to 2C-methyl-D-erythritol 2,4- cyclodiphosphate, which then leads to the two base bodies isopentenyl diphosphate (IPP) and dimethy- lallyl diphosphate (DMAPP). Three IPPs are added to one DMAPP, which creates geranylgeranyl diphospate (GGPP). SdCPS2 catalyzes the next steps, where ent-clerodienyl diphosphate intermedi- ate is created. After oxygenation, acylation and methylation, the biosynthesis is completed.
Figure 2: Biosynthesis of Salvinorin A
7 http://www.cesar.umd.edu/cesar/drugs/salvia.asp, 11.6.2019 8 Salvinorin A - Wikipedia, https://en.wikipedia.org/wiki/Salvinorin_A, 16.06.2019
4 4 Eects
It was not until August 2002 that researchers discovered that Salvia Divinorum acts at the kappa opioid receptor (KOR) site, where much of human perception is regulated. This puts Salvia Divinorum in a class of drugs known as KOR agonists, which are thought to play psychotherapeutic roles in perception altering diseases such as schizophrenia and Alzheimer's disease.
4.1 Working Principle9
The kappa-opioid receptor is one of 3 G-protein linked opioid receptors which are often found in the nervous sytem. Opioid receptors consist of seven transmembrane comprehensive alpha helices proteins which are linked to inhibitory G-Proteins (guanosine triphosphate binding protein).10 An example for a natural agonist of KOR is dynorphine, while naloxone and naltrexone are examples for natural antagonists.11 In general a stimulation of KOR leads to analgesia (pain relief), dysphoria (trouble of emotions), miosis (contraction of the pupil) and sedation (reduction of the CNS funktion).12 G-proteins are linked loosly with the cytoplasmatic site of the membrane. If linked to GTP (guanosine triphosphate) they are activated and inactivated if they are linked to GDP (guanosine diphosphate). KOR is linked to an inactive G-protein.13 When KOR gets activated by signal molecules it changes its steric conformation. An inactivated, with GDP loaded G-protein links to KOR. This causes a substitution from GDP to GTP. The G-protein is now activated and dissociates from the receptor. It dissociates along the membrane and links to the eector protein adenylate cyclase. Thereby the eector changes its activity and stops catalyzing the formation of the second messenger cAMP (cyclic AMP) from ATP. This leads to an inhibition of the voltage controlled calcium channels whereby the calcium in ux is reduced. Simultaneously potassium channels are opened. Potassium pours out of the cell. This leads to a hyperpolarisation. Thereby the neuronal signal transmission is inhibited.14
4.2 Importance in Experimental Research
There is no approved medicinal use for Salvia Divinorum or Salvinorin A. However, there is intensive research to explore the therapeutic potential of structurally related KOR agonists or antagonists.15 Nonhuman research studies have characterized the pharmacological, behavioral, and discriminative ef- fects of S. divinorum and Salvinorin A17. There is interest in using Salvinorin A and related compounds to study kappa-opioid mechanisms in neurological disorders (e.g., Alzheimer's disease), psychiatric dis- orders, pain, and drug dependence18. Most information about the eects of Salvia Divinorum in humans has come from survey studies and qualitative interviews of Salvia Divinorum users. Survey respondents are in general agreement that the eects of Salvia Divinorum are intense and unique compared to other drugs or methods for inducing alterations in consciousness.19
9 https://www.spektrum.de/lexikon/neurowissenschaft/kappa-rezeptor/6390, 25.4.2019 10 http://geb.uni-giessen.de/geb/volltexte/2010/7621/pdf/DierkesBirgit_2010_04_28.pdf S.1-6, 2.5.2019 11 https://www.spektrum.de/lexikon/neurowissenschaft/opiatrezeptoren/9235, 25.4.2019 12 https://www.pharmacytimes.com/contributor/jerey-fudin/2018/01/opioid-agonists-partial-agonists-antagonists- oh-my, 30.4.2019 13 Biologie, Campbell, Reece; Pearson Studium; 8. aktualisierte Au age S. 280-285; 1127-1128 14 https://opus.bibliothek.uni-wuerzburg.de/opus4-wuerzburg/frontdoor/deliver/index/docId/5881/ le/ DissertationNFfoLebensl.pdf S.1-8, 2.5.2019 15 http://www.emcdda.europa.eu/publications/drug-pro les/salvia, 11.6.2019 17 Vortherms TA, Roth B:. Salvinorin A: from natural product to human therapeutics, 2011 18 Mello NK, Negus SS: Interactions between kappa opioid agonists and cocaine, 2000 19 Albertson DN, Grubbs LE: Subjective eects of Salvia divinorum: LSD- or marijuana-like? J Psychoactive Drugs, 2009
5 4.3 Potential Medical Eects Salvinorin A is a highly selective K-opioid receptor agonist20. These kappa receptors induce primarily analgesic eects in the human body. This applies for activation by Salvinorin A as well. But Salvinorin A generates a lot of dierent biological eects. In various studies it is demonstrated that Salvinorin A has potent anti-in ammatory eects21 which leads to the question how to use Salvinorin A in therapeutic manners. But as announced in the title Salvinorin A causes robust hallucinogenic eects. In many countries it is even used as a recreational drug. It is reported that this compound expresses itself in intense hallucinations and total loss of one's grip to reality22. The course of these eects is interesting as well. Immediate eects are reported. Within a time of about one minute Salvinorin A is noticeable and it reaches its peak after about two minutes and lasts then about 30 minutes. This was quanti ed by dierent studies in measuring the blood concentration in rhesus monkeys at speci c time rates23 as well as measuring the brain concentration with Positron emission tomography24. Because of these hallucinogenic eects and the relatively short duration researches about Salvinorin A have focused on discovering a similar compound that induces just analgesic and anti-in ammatory eects with a longer duration.
In uence of Salvinorin A on Cocaine Addiction25 Tests on rats have shown that Salvinorin A counteracts many cocaine-related behaviours. It reduces drug-seeking, triggered by cocaine, but does not initiate the eect of conditioned aversion. Many side eects such as promoting depression, sedation and dysphoria make a therapeutic use di cult.
20 Roth and colleagues; Salvinorin A: A potent naturally occurring nonnitrogenous K opioid selective agonist, 2001 21 Jakub Fichna, PhD, et al. Salvinorin A Has Antiin ammatory and Antinociceptive Eects in Experimental Models of Colitis in Mice Mediated by KOR and CB1 Receptors, 2012 22 Addy PH, Garcia-Romeu A, Metzger M, Wade J: The subjective experience of acute, experimentally-induced Salvia divinorum inebriation, 2015 23 Eduardo R. Butelman, et al. Unconditioned Behavioral Eects of the Powerful k -Opioid Hallucinogen Salvinorin A in Nonhuman Primates, 2008 24 Jacob M. Hooker, Youwen Xu, et al. Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of eects in humans, 2008 25 Morani: Single injection of novel kappa opioid receptor agonist salvinorin A attenuates expression of cocaine induced behavioral sensitization in rats, 2012
6 5 References Figures: Figure 1: https://de.wikipedia.org/wiki/Furanolactone, 23.06.2019 Figure 2: http:// ipper.di.org/app/items/5403, 23.06.2019
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