Advanced Opium and Morphine SAR for undergraduate and postgraduate students

Detailed lecture note on Opium and Morphine structural activity relationship (SAR) for undergraduate and postgraduate students and researchers

1. Chapter 24

2. YE OLDE OPIUM REMEDIES – 18YE OLDE OPIUM REMEDIES – 18
thth
Century Century
CHRONIC HEADACHECHRONIC HEADACHE
VERTIGOVERTIGO
EPILEPSYEPILEPSY
ASTHMAASTHMA
COLICCOLIC
FEVERSFEVERS
DROPSIESDROPSIES
LEPROSIESLEPROSIES
MELANCHOLYMELANCHOLY
‘‘TROUBLES TO WHICH WOMEN ARE TROUBLES TO WHICH WOMEN ARE
SUBJECT’SUBJECT’

3. GODFREY’S CORDIALGODFREY’S CORDIAL
INGREDIENTSINGREDIENTS
OPIUMOPIUM
MOLASSESMOLASSES
SASSAFRASSASSAFRAS
USESUSES
TEETHING AIDTEETHING AID
RHEUMATIC PAINSRHEUMATIC PAINS
DIARRHOEADIARRHOEA

4. Source of MorphineSource 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
HO
O
NMe
HO
HO O
NMe
HO
HO
O
NMe
HO
HO

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

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

7. Side EffectsSide Effects
RespirationRespiration
Nausea Nausea
Pupil constrictionPupil constriction
ConstipationConstipation
EuphoriaEuphoria
ToleranceTolerance
DependenceDependence

8. Structure DeterminationStructure Determination
Current methodsCurrent methods
Identify the atoms presentIdentify the atoms present
Measure the molecular weightMeasure the molecular weight
Infra red spectroscopyInfra red spectroscopy
X-ray crystallographyX-ray crystallography
Nuclear magnetic resonance spectroscopyNuclear magnetic resonance spectroscopy

9. Structure DeterminationStructure Determination
Methods availableMethods available
Identify the atoms presentIdentify the atoms present
Measure the molecular weightMeasure the molecular weight

10. Structure DeterminationStructure Determination
Methods availableMethods available
Identify the atoms presentIdentify the atoms present
Measure the molecular weightMeasure the molecular weight
‘‘Destroy’ morphine to simpler moleculesDestroy’ morphine to simpler molecules
‘‘Jigsaw puzzles’Jigsaw puzzles’
Propose a structurePropose a structure
Synthesise proposed structureSynthesise proposed structure

11. 19231923
MORPHINEO
NMe
HO
HO
StructureStructure

12. MORPHINEO
NMe
HO
HO
StructureStructure
19231923

13. MORPHINEO
NMe
HO
HO
StructureStructure
19231923

14. StructureStructure

15. StructureStructure

16. StructureStructure

17. StructureStructure

18. StructureStructure
T-Shaped moleculeT-Shaped molecule

19. Potential Binding GroupsPotential Binding Groups
Functional groupsFunctional groups
Carbon skeletonCarbon skeleton

20. PhenolPhenol
EtherEther
AlcoholAlcohol
AmineAmine
O
NMe
HO
HO
Potential Binding Potential Binding
GroupsGroups

21. PhenolPhenol
EtherEther
AlcoholAlcohol
AromaticAromatic
ringring
AlkeneAlkene
AmineAmine
O
NMe
HO
HO
Potential Binding Potential Binding
GroupsGroups

22. Structure Activity RelationshipsStructure 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 STRUCTURE ACTIVITY
RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
HO

24. STRUCTURE ACTIVITY STRUCTURE ACTIVITY
RELATIONSHIPSRELATIONSHIPS
O
NMe
HO

25. STRUCTURE ACTIVITY STRUCTURE ACTIVITY
RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
HO

26. STRUCTURE ACTIVITY STRUCTURE ACTIVITY
RELATIONSHIPSRELATIONSHIPS
O
NMe
HO

27. STRUCTURE ACTIVITY STRUCTURE ACTIVITY
RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
HO

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

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

30. SAR - The phenol moietySAR - The phenol moiety
R=Ac 3-AcetylmorphineR=Ac 3-Acetylmorphine
Decreased activityDecreased activity
•Acetyl masks the polar phenol group Acetyl 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
RO
HO
H
H

31. SAR - The 6-alcoholSAR - The 6-alcohol
R=Me HeterocodeineR=Me Heterocodeine
5 x activity5 x activity
NMe
O
HO
RO
H
H

32. SAR - The 6-alcoholSAR - 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
HO
HO
NMe
O
HO
O
NMe
O
HO

33. SAR - The 6-alcoholSAR - The 6-alcohol
R=Ac 6-AcetylmorphineR=Ac 6-Acetylmorphine
Increased activity (4x)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 high Dependence is very high
•6-Acetylmorphine is banned in many countries6-Acetylmorphine is banned in many countries
NMe
O
HO
RO
H
H

34. SAR - The 6-alcohol and phenolSAR - The 6-alcohol and phenol
R=Ac HeroinR=Ac Heroin
Increased activity (2x)Increased activity (2x)
•Increased lipid solubility Increased 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
RO
RO
H
H

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

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

37. SAR - Methyl group on nitrogenSAR - Methyl group on nitrogen
NR= NH NormorphineNR= NH Normorphine
Reduced activity (25%)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 activityNo activity
NR= NNR= N
++
MeMe
22
No activityNo activity
NR
O
HO
HO
H
H
OO
NR= NMeNR= NMe
++
--

38. SAR - StereochemistrySAR - Stereochemistry
Mirror image of morphineMirror image of morphine
No activityNo activity
10% activity10% activity
Changing the stereochemistry is detrimental to activityChanging the stereochemistry is detrimental to activity
NR
O
HO
HO
H
H
NR
O
HO
HO
H
H

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

40. PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic

41. PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic

42. PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic

43. 7.1987.198
4.6414.641
2.8002.800
PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic

44. 4.6414.641
2.8002.800
149.3149.3
oo
11.311.3
oo
1919
oo
PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic
7.1987.198

47. 23.523.5
oo

48. 23.523.5
oo

49. 23.523.5
oo
23.523.5
oo