opium and morphine
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
Chapter 24
YE OLDE OPIUM REMEDIES – 18YE OLDE OPIUM REMEDIES – 18thth Century Century
CHRONIC HEADACHECHRONIC HEADACHEVERTIGOVERTIGOEPILEPSYEPILEPSYASTHMAASTHMACOLICCOLICFEVERSFEVERSDROPSIESDROPSIESLEPROSIESLEPROSIESMELANCHOLYMELANCHOLY‘‘TROUBLES TO WHICH WOMEN ARE TROUBLES TO WHICH WOMEN ARE SUBJECT’SUBJECT’
GODFREY’S CORDIALGODFREY’S CORDIAL
INGREDIENTSINGREDIENTSOPIUMOPIUMMOLASSESMOLASSESSASSAFRASSASSAFRAS
USESUSESTEETHING AIDTEETHING AIDRHEUMATIC PAINSRHEUMATIC PAINSDIARRHOEADIARRHOEA
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
Clinical UseClinical Use
Morphine is poorly absorbed orally Potential realized with the invention of the hypdermic syringe
Clinical UseClinical Use
Used as an analgesic in the American Civil War and the Franco-Prussian War
Dosing regimes and side effects poorly understood
Side EffectsSide Effects
RespirationRespiration Nausea Nausea Pupil constrictionPupil constriction ConstipationConstipation EuphoriaEuphoria ToleranceTolerance DependenceDependence
Structure DeterminationStructure Determination
Current methodsCurrent methodsIdentify the atoms presentIdentify the atoms presentMeasure the molecular weightMeasure the molecular weightInfra red spectroscopyInfra red spectroscopyX-ray crystallographyX-ray crystallographyNuclear magnetic resonance spectroscopyNuclear magnetic resonance spectroscopy
Structure DeterminationStructure Determination
Methods availableMethods availableIdentify the atoms presentIdentify the atoms presentMeasure the molecular weightMeasure the molecular weight
Structure DeterminationStructure Determination
Methods availableMethods availableIdentify the atoms presentIdentify the atoms presentMeasure the molecular weightMeasure the molecular weight‘‘Destroy’ morphine to simpler moleculesDestroy’ morphine to simpler molecules‘‘Jigsaw puzzles’Jigsaw puzzles’Propose a structurePropose a structureSynthesise proposed structureSynthesise proposed structure
19231923
MORPHINEO
NMe
HO
HO
StructureStructure
MORPHINEO
NMe
HO
HO
StructureStructure
19231923
MORPHINEO
NMe
HO
HO
StructureStructure
19231923
StructureStructure
StructureStructure
StructureStructure
StructureStructure
StructureStructure
T-Shaped moleculeT-Shaped molecule
Potential Binding Potential Binding GroupsGroups
Functional groupsFunctional groups
Carbon skeletonCarbon skeleton
PhenolPhenol
EtherEther
AlcoholAlcohol
AmineAmine
O
NMe
HO
HO
Potential Binding Potential Binding GroupsGroups
PhenolPhenol
EtherEther
AlcoholAlcohol
AromaticAromaticringring
AlkeneAlkene
AmineAmine
O
NMe
HO
HO
Potential Binding Potential Binding GroupsGroups
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
STRUCTURE ACTIVITY STRUCTURE ACTIVITY RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
HO
STRUCTURE ACTIVITY STRUCTURE ACTIVITY RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
STRUCTURE ACTIVITY STRUCTURE ACTIVITY RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
HO
STRUCTURE ACTIVITY STRUCTURE ACTIVITY RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
STRUCTURE ACTIVITY STRUCTURE ACTIVITY RELATIONSHIPSRELATIONSHIPS
O
NMe
HO
HO
SAR - The phenol moietySAR - The phenol moiety
R=H MorphineR=H MorphineR=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
HH
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
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
HH
SAR - The 6-alcoholSAR - The 6-alcohol
R=Me HeterocodeineR=Me Heterocodeine 5 x activity5 x activity
NMe
O
HO
RO
HH
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
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
HH
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
HH
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
HH
SAR - NitrogenSAR - Nitrogen
No activity No activity
Nitrogen is essential to bindingNitrogen is essential to binding
CHMe
O
HO
HO
HH
SAR - Methyl group on nitrogenSAR - Methyl group on nitrogen
NR= NH NormorphineNR= NH NormorphineReduced 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 activityNR= NNR= N++MeMe22
No activityNo activity
NR
O
HO
HO
HH
OO
NR= NMeNR= NMe++
--
SAR - StereochemistrySAR - Stereochemistry
Mirror image of morphineMirror image of morphineNo activityNo activity
10% activity10% activity
Changing the stereochemistry is detrimental to activityChanging the stereochemistry is detrimental to activity
NR
O
HO
HO
HHNR
O
HO
HO
HH
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
HH
PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic
PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic
PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic
7.1987.198
4.6414.641
2.8002.800
PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic
4.6414.641
2.8002.800
149.3149.3oo
11.311.3oo
1919oo
PHARMACOPHOREPHARMACOPHORE
HBD/HBAHBD/HBA
VDWVDW
IonicIonic
7.1987.198
23.523.5oo
23.523.5oo
23.523.5oo23.523.5oo