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