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BIOSYNTHESIS, TOTAL SYNTHESIS AND BINDING AFFINITY OF SALVINORIN A

BIOSYNTHESIS, TOTAL SYNTHESIS AND BINDING AFFINITY OF SALVINORIN A. Jacqueline Tokarew. SALVIA DIVINORUM. Species: Salvia divinorum. Genus: Salvia. Family: Labiatae. Entheogen :   any substance, such as a plant or drug, taken to bring on a spiritual experience.

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BIOSYNTHESIS, TOTAL SYNTHESIS AND BINDING AFFINITY OF SALVINORIN A

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  1. BIOSYNTHESIS, TOTAL SYNTHESIS AND BINDING AFFINITY OF SALVINORIN A Jacqueline Tokarew

  2. SALVIA DIVINORUM Species: Salvia divinorum Genus: Salvia Family: Labiatae Entheogen:   any substance, such as a plant or drug, taken to bring on a spiritual experience Used to treat diarrhea, relieve headache and rheumatism Introduced to United States by R. Gordon Wasson in 1962 Imanshahidi, et. al. Phytotherapy Research, 2006, 20, 427-437

  3. SALVINORIN A Neoclerodanediterpene isolated by Valdès (1983) and Ortega (1982) Active compound found in the leaves (0.245%w/w) Highly oxygenated tricyclic naturally occuring compound First highly selective naturally occurring κ-opioid receptor agonist First non-alkaloid and highly potent psychoactive substance with analgesic properties Ortega, J. Chem. Soc. Perkin Trans. I, 1982, 2505-2508 Valdes, J. Org. Chem. 1984, 49, 4716-4720

  4. HALLUCINOGENIC PROPERTIES Effective dose: 200μg - 500μg (Salvinorin A smoked) Effects (variable): Becoming objects Revisiting places from the past Outer body or loss of identity Various sensations of motion Uncontrollable hysterical laughter Overlapping realities Side Effects: Reports of lingering depression Still legal in Canada and a few US states although many countries are beginning to regulate its recreational use Prisinzano, et. al. Life Sciences, 2005, 78, 527-531. Griffin, et. al. J. of Psychoactive Drugs,2008, 40,183-191. Ingestion: smoking (30min duration) or masticating leaves (up to 60min duration) Siebert, J. Ethnopharmacology, 1994,43, 53-56.

  5. OPIOID RECEPTORS Class of 7-transmembrane G-protein coupled receptors (GPCRs) Mediate analgesia (pain cessation) Agonismof the three well known subtypes causes: μ opioid receptor: analgesia, sedation, respiratory depression, euphoria, constipation and dependence δopioid receptor: analgesia and dependence κopioid receptor: analgesia, sedation, changes in mood and psychomimetic properties Opioid receptors are regulated by opiates: • -endogenous (endorphins, enkephalins, dynorphins ) -exogenous (synthetic and natural compounds) Kieffer, et. al. P. in Neurobiology 2002, 66, 285-306. Walsh, et. al. Psychopharmacology 2001, 157, 151–162.

  6. OPIOID RECEPTORS FUNCTION Pain Sensing Neuron at Resting State - - - - - Na+ channels are closed - - - - - Intracellular Resting Negative Charge (-70meV) - - - - - - - - - - - K+ channels are closed - - - G= G protein Simmons, et. al. Molecular Pharmacology,1996, 50, 80-85

  7. OPIOID RECEPTORS FUNCTION Pain Sensing Neuron Excited State (Pain Stimulation) - - - - - Na+ channels are open - - - - - Action Potential Propagation - - - - - - - + + - - N - - - - K+ channels are open - - - - - G= G protein N N = Neutransmitter N N Simmons, et. al. Molecular Pharmacology,1996, 50, 80-85

  8. OPIOID RECEPTORS FUNCTION Pain Sensing Neuron Inhibited State (Analgesia) - - - - - Na+ channels are closed - - - - - Hyperpolarization Larger Intracellular Negative Charge - - - - - N - - S - - - - K+ channels are open - - - G= G protein N S= Salvinorin A N K+ N S Simmons, et. al. Molecular Pharmacology,1996, 50, 80-85

  9. ANALGESICS AND HALLUCINOGENS First Non-Nitrogenous Opioid Agonist Opioid agonists and antagonists κ-opioid agonist -hallucinogenic Common non-opiate hallucinogens Feinberg, et. al. Proc. Natl. Acad. Sci. USA,1976, 73, 4215-4219 . Roth, et. al. Proc. Natl. Acad. Sci. USA,2002, 99, 11934 .

  10. SALVINORIN A’S BIOLOGICAL TARGET 90% Binding for κ-opioid receptor First naturally occurring κopioid selective ligand % Receptor Binding Only 30% Binding for κ-opioid receptor Opioids Dopamine Serotonin Various G-protein coupled receptors Roth, et. al. Proc. Natl. Acad. Sci. USA,2002, 99, 11934 .

  11. SALVINORIN A NATURAL ANALOGUES Lee, et. al. Bioorg. Med. Chem.2005, 13, 5635–5639 Harding, et. al. W. Org. Lett. 2005, 7, 3017-3020. Kutrzeba, et. al. J. Nat. Prod. 2009, 72,1361–1363

  12. TERPENOID BIOSYNTHESIC PATHWAY BIOSYNTHESIS Kutrzeba, et. al. Phytochemistry2007, 68,1872-1881

  13. ELUCIDATION OF COMMON ISOPRENE BIOSYNTHETIC PATHWAY Glycolysis Glycolysis pyruvate and glyceraldehyde 3-phosphate AcetylCoA Mevalonic Acid Pathway Deoxy-xylulose Phosphate Pathway Kutrzeba, et. al. Phytochemistry2007, 68,1872-1881

  14. MEVALONIC ACID PATHWAY BIOSYNTHESIS Rohmer, et. al. Nat. Prod. Rep. 1999,16,565-574

  15. DEOXY-XYLULOSE PHOSPHATE PATHWAY BIOSYNTHESIS Rohmer, et. al. Nat. Prod. Rep. 1999,16,565-574

  16. 13C NMR SUGGESTS DEOXY-XYLULOSE PHOSPHATE PATHWAY BIOSYNTHESIS A- 13C of salvinorin A isolated from control B- 13C of salvinorin A isolated from 13C glucose incubated plants Kutrzeba, et. al. Phytochemistry2007, 68,1872-1881

  17. First Asymmetric Total Synthesis Retrosynthetic Analysis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  18. Asymmetric Total Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969 Aldehyde Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2005,127, 10507.

  19. Asymmetric Total Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969 Aldehyde Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2005,127, 10507.

  20. Asymmetric Total Synthesis Pollet, et. al. Synthesis 1978,142-143 Aldehyde Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  21. Asymmetric Total Synthesis Cahiez, et. al. Synthesis 1998, 1199-1205 Aldehyde Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  22. Asymmetric Total Synthesis Nagao, et. al. J. Org. Chem. 1986, 51, 2391-2393 Aldehyde Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  23. Asymmetric Total Synthesis Frantz, et. al. J. Am. Chem. Soc. 2000,122, 1806-1807 Aldehyde Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  24. Asymmetric Total Synthesis Aldehyde Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  25. Asymmetric Total Synthesis Corey, et. al. Angew. Chem. Int. Ed. 1998,37, 1986-2012 Vinyl Iodide Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  26. Asymmetric Total Synthesis Brown, et. al. J. Am. Chem. Soc.1975, 97, 891-893 Negishi, et. al. Synthesis 1979,79,501-502 Vinyl Iodide Fragment Synthesis Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  27. Asymmetric Total Synthesis Assembly of Fragments Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  28. Asymmetric Total Synthesis Transannular Cyclization forms 3 stereocenters (C5, C 9and C10) Shiina, et. al. Tet. Lett. 2002,43, 7535-7539 Assembly of Fragments Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  29. Asymmetric Total Synthesis TransannularCyclization Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  30. Asymmetric Total Synthesis Conversion to Salvinorin A Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  31. Asymmetric Total Synthesis Conversion to Salvinorin A Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  32. Asymmetric Total Synthesis Fully Asymmetric Synthesis from 6g of 3-furaldehyde and 6g of thiazolidinethione Key Cyclization Step Involves TransannularCyclization Michael Addition Cascade or exo Diels-Alder Total number of steps= 29 Total number of asymmetric reactions= 8 Total overall yield= 1.06% Produced 2.5mg of product Confirmed the assigned absolute stereochemistry Evans, et. al. J. Am. Chem. Soc. 2007,129, 8968-8969

  33. PRELIMINARY MODELING RECEPTOR BINDINGSTUDIES Roth, et. al. Proc. Natl. Acad. Sci. USA,2002, 99, 11934 .

  34. STRUCTURE ACTIVITY ASSAYS Munro, T. A. et. al. J. Med. Chem. 2005, 48, 345. Harding, W. et. al. J. Med. Chem. 2005,48, 4765-4771 Lee, D. Y. W. et. al. Bioorg. Med. Chem.Lett. 2005,15, 3744 Beguin, et. al. Bioorganic & Medicinal Chemistry , 2009, 17, 1370–1380

  35. IDENTIFYING THE PHARMACOPHORE Munro, T. A. et. Al. J. Med. Chem. 2005, 48, 345. Harding, W. et. al. J. Med. Chem. 2005,48, 4765-4771 Lee, D. Y. W. et. al. Bioorg. Med. Chem.Lett. 2005,15, 3744 Beguin, Bioorganic & Medicinal Chemistry , 2009, 17, 1370–1380

  36. REVIEWING PRELIMINARY MODELING RECEPTOR BINDINGSTUDIES C12 Furan ring necessary for binding. C2 Small alkyl chains increase binding= Small hydrophobic pocket C17 Carbonyl is not hydrogen bonding to tyrosine residue 139 C18 Reduced alcohol = poor affinity Carbonyl methoxy in small hydrophobic pocket C20 methyl group not yet explored Perlmutter, et.al., J. Org. Chem. 2009,74,2589–2591 Munro, T. A. et. al. J. Med. Chem. 2005, 48, 345. Harding, W. et. al. J. Med. Chem. 2005,48, 4765-4771 Lee, D. Y. W. et. al. Bioorg. Med. Chem.Lett. 2005,15, 3744 Beguin, et. al. Bioorganic & Medicinal Chemistry , 2009, 17, 1370–1380 Roth, et. al. Proc. Natl. Acad. Sci. USA,2002, 99, 11934 .

  37. 20-NORSALVINORIN A SYNTHESIS Key Intermediate Perlmutter, et.al., J. Org. Chem. 2009,74,2589–2591

  38. 20-NORSALVINORIN A SYNTHESIS Reported 6 steps with 19 % overall yield to target intermediate Racemic Synthesis Perlmutter, et.al., J. Org. Chem. 2009,74,2589–2591

  39. 20-NORSALVINORIN A SYNTHESIS Perlmutter, et.al., J. Org. Chem. 2009,74,2589–2591

  40. 20-NORSALVINORIN A SYNTHESIS Several steps ending with racemic mixture Perlmutter, et.al., J. Org. Chem. 2009,74,2589–2591

  41. CONCLUSIONS Salvinorin A is the first, highly selective and potent non alkaloid κ-opioid receptor agonist The κ-opioid receptor is responsible for analgesia and psychomimetic properties Salvia diterpenes share a common deoxyxylulose phosphate pathway Total Synthesis of Salvinorin A achieved by Evans’ group Key TransannularCyclizationin 99% yield and 95% diastereoselectivity The combination of natural scaffold + total synthesis + SAR studies provides greater insight into the pharmacophore of salvinorin A Synthesis of key intermediate of 20-Norsalvinorin A may provide faster route to Salvinorin A analogues

  42. THANKS! Dr. Robert Ben Roger Tam John Trant Jennifer Chaytor Mathieu Leclere ChantelleCapiccotti TazCheema Anna Balcerak Elisabeth Von Moos Former Ben Lab Members

  43. FUN FACTS The Salvia divinorum Research and Information Center The Salvia divinorum User's Guide. A basic educational manual. by Siebert The SALVIA Experiential Rating Scale Level - 1 “S" stands for SUBTLE effects. Level - 2 “A" stands for ALTERED perception. Level - 3 “L" stands for LIGHT visionary state. Level - 4 “V" stands for VIVID visionary state. Level - 5 “I" stands for IMMATERIAL existence. Level - 6 “A" stands for AMNESIC effects. “Our herbal product is most appealing to mature, higher-thinking individuals and our Salvia Divinorum is a tremendous value Buy Salvia Divinorum today!”- Online Salvia Supplier

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