1. Chapter 24

2. YE OLDE OPIUM REMEDIES – 18 th Century CHRONIC HEADACHE VERTIGOEPILEPSYASTHMACOLICFEVERSDROPSIESLEPROSIESMELANCHOLY ‘TROUBLES TO WHICH WOMEN ARE SUBJECT’

3. GODFREY’S CORDIAL INGREDIENTSOPIUMMOLASSESSASSAFRASUSES TEETHING AID RHEUMATIC PAINS DIARRHOEA

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

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 Identify the atoms present Measure the molecular weight Measure the molecular weight Infra red spectroscopy Infra red spectroscopy X-ray crystallography X-ray crystallography Nuclear magnetic resonance spectroscopy Nuclear magnetic resonance spectroscopy

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

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

11. 1923 MORPHINE O NMe HO Structure

12. MORPHINE O NMe HO Structure 1923

13. MORPHINE O NMe HO Structure 1923

14. Structure

15. Structure

16. Structure

17. Structure

18. Structure T-Shaped molecule

19. Potential Binding Groups Functional groups Carbon skeleton

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

21. PhenolEther Alcohol Aromaticring Alkene Amine O NMe HO 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. STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

24. STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

25. STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

26. STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

27. STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

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

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. SAR - The phenol moiety R=Ac 3-Acetylmorphine Decreased activity Acetyl masks the polar phenol groupAcetyl masks the polar phenol group Compound crosses the blood brain barrier more easilyCompound crosses the blood brain barrier more easily Acetyl group is hydrolysed in the brain to form morphineAcetyl group is hydrolysed in the brain to form morphine NMe O RORO HOHO H H

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

32. SAR - The 6-alcohol Activity increases due to reduced polarityActivity increases due to reduced polarity Compounds cross the blood brain barrier more easilyCompounds cross the blood brain barrier more easily 6-OH is not important for binding6-OH is not important for binding NMe O HOHO HOHO O HOHO O O HOHO

33. SAR - The 6-alcohol R=Ac 6-Acetylmorphine Increased activity (4x) Acetyl masks a polar alcohol group making it easier to cross BBBAcetyl masks a polar alcohol group making it easier to cross BBB Phenol group is free and molecule can bind immediatelyPhenol group is free and molecule can bind immediately Dependence is very highDependence is very high 6-Acetylmorphine is banned in many countries6-Acetylmorphine is banned in many countries NMe O HOHO RORO H H

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

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

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

37. SAR - Methyl group on nitrogen NR= NH Normorphine Reduced activity (25%) Normorphine is more polar and crosses the BBB slowlyNormorphine is more polar and crosses the BBB slowly Ionized molecules cannot cross the BBB and are inactiveIonized molecules cannot cross the BBB and are inactive Ionized structures are active if injected directly into brainIonized structures are active if injected directly into brain R affects whether the analogue is an agonist or an antagonistR affects whether the analogue is an agonist or an antagonist No activity NR= N + Me 2 No activity NRNR O HOHO HOHO H H O NR= NMe +-

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

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

40. PHARMACOPHORE HBD/HBAVDWIonic

41. PHARMACOPHORE HBD/HBAVDWIonic

42. PHARMACOPHORE HBD/HBAVDWIonic

43. 7.198 4.641 2.800 PHARMACOPHORE HBD/HBAVDWIonic

44. 4.641 2.800 149.3 o 11.3 o 19 o PHARMACOPHORE HBD/HBAVDWIonic 7.198

47. 23.5 o