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Opium and Morphine

Chapter 24. Opium and Morphine. YE OLDE OPIUM REMEDIES – 18 th Century CHRONIC HEADACHE VERTIGO EPILEPSY ASTHMA COLIC FEVERS DROPSIES LEPROSIES MELANCHOLY ‘TROUBLES TO WHICH WOMEN ARE SUBJECT’. GODFREY’S CORDIAL INGREDIENTS OPIUM MOLASSES SASSAFRAS USES TEETHING AID

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Opium and Morphine

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  1. Chapter 24 Opium and Morphine

  2. YE OLDE OPIUM REMEDIES – 18th Century CHRONIC HEADACHE VERTIGO EPILEPSY ASTHMA COLIC FEVERS DROPSIES LEPROSIES MELANCHOLY ‘TROUBLES TO WHICH WOMEN ARE SUBJECT’

  3. GODFREY’S CORDIAL INGREDIENTS OPIUM MOLASSES SASSAFRAS USES TEETHING AID RHEUMATIC PAINS DIARRHOEA

  4. HO HO HO HO O O O O NMe NMe NMe NMe HO HO HO HO Source of Morphine • Seed capsule of poppy plants • Opium is the extract and herbal remedy • Morphine is the active principle • Morphine (16%) • Codeine (4%)

  5. Clinical Use • Morphine is poorly absorbed orally • Potential realized with the invention of the hypdermic syringe

  6. Clinical Use • Used as an analgesic in the American Civil War and the Franco-Prussian War • Dosing regimes and side effects poorly understood

  7. Side Effects • Respiration • Nausea • Pupil constriction • Constipation • Euphoria • Tolerance • Dependence

  8. Structure Determination • Current methods • Identify the atoms present • Measure the molecular weight • Infra red spectroscopy • X-ray crystallography • Nuclear magnetic resonance spectroscopy

  9. Structure Determination • Methods available • Identify the atoms present • Measure the molecular weight

  10. Structure Determination • Methods available • Identify the atoms present • Measure the molecular weight • ‘Destroy’ morphine to simpler molecules • ‘Jigsaw puzzles’ • Propose a structure • Synthesise proposed structure

  11. HO O NMe HO Structure 1923 MORPHINE

  12. HO O NMe HO Structure 1923 MORPHINE

  13. Structure 1923 HO MORPHINE O NMe HO

  14. Structure

  15. Structure

  16. Structure

  17. Structure

  18. Structure T-Shaped molecule

  19. Potential Binding Groups Functional groups Carbon skeleton

  20. HO O Phenol NMe HO Ether Alcohol Amine Potential Binding Groups

  21. HO O Phenol NMe HO Aromatic ring Ether Alkene Alcohol Amine Potential Binding Groups

  22. Structure Activity Relationships • Mask or remove a functional group • Test the analogue for activity • Determines the importance or other wise of a functional group for activity

  23. HO O NMe HO STRUCTURE ACTIVITY RELATIONSHIPS

  24. STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

  25. HO O NMe HO STRUCTURE ACTIVITY RELATIONSHIPS

  26. STRUCTURE ACTIVITY RELATIONSHIPS HO O NMe

  27. HO O NMe HO STRUCTURE ACTIVITY RELATIONSHIPS

  28. RO O NMe H H HO SAR - The phenol moiety R=H Morphine R=Me Codeine Codeine 20% active (injected peripherally) 0.1% active (injected into brain)

  29. SAR - The phenol moiety Notes Codeine is metabolised in the liver to morphine. The activity observed is due to morphine. Codeine is used for mild pain and coughs Weaker analgesic but weaker side effects. Conclusion Masking phenol is bad for activity

  30. RO O NMe H H HO SAR - The phenol moiety R=Ac 3-Acetylmorphine Decreased activity • Acetyl masks the polar phenol group • Compound crosses the blood brain barrier more easily • Acetyl group is hydrolysed in the brain to form morphine

  31. HO O NMe H H RO SAR - The 6-alcohol R=Me Heterocodeine 5 x activity

  32. HO O NMe HO HO HO O O NMe NMe O SAR - The 6-alcohol • Activity increases due to reduced polarity • Compounds cross the blood brain barrier more easily • 6-OH is not important for binding

  33. HO O NMe H H RO SAR - The 6-alcohol R=Ac 6-Acetylmorphine Increased activity (4x) • Acetyl masks a polar alcohol group making it easier to cross BBB • Phenol group is free and molecule can bind immediately • Dependence is very high • 6-Acetylmorphine is banned in many countries

  34. RO O NMe H H RO SAR - The 6-alcohol and phenol R=Ac Heroin Increased activity (2x) • Increased lipid solubility • Heroin crosses the blood brain barrier more quickly • Acetyl groups are hydrolysed in the brain to generate morphine • Fast onset and intense euphoric effects

  35. HO O NMe H H HO SAR - Double bond at 7,8 Dihydromorphine Increased activity The alkene group is not important to binding

  36. HO O CHMe H H HO SAR - Nitrogen No activity Nitrogen is essential to binding

  37. HO + NR= NMe O O - NR H H HO SAR - Methyl group on nitrogen NR= NH Normorphine Reduced activity (25%) No activity NR= N+Me2 No activity • Normorphine is more polar and crosses the BBB slowly • Ionized molecules cannot cross the BBB and are inactive • Ionized structures are active if injected directly into brain • R affects whether the analogue is an agonist or an antagonist

  38. HO HO O O NR NR H H H H HO HO SAR - Stereochemistry Mirror image of morphine No activity 10% activity Changing the stereochemistry is detrimental to activity

  39. HO O NMe H H HO SAR - Important binding interactions HBD or HBA van der Waals Ionic (N is protonated)

  40. VDW HBD/HBA Ionic PHARMACOPHORE

  41. VDW HBD/HBA Ionic PHARMACOPHORE

  42. VDW HBD/HBA Ionic PHARMACOPHORE

  43. VDW HBD/HBA Ionic PHARMACOPHORE 2.800 7.198 4.641

  44. VDW HBD/HBA Ionic PHARMACOPHORE 2.800 19o 149.3o 7.198 4.641 11.3o

  45. 23.5o

  46. 23.5o

  47. 23.5o 23.5o

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