medicinal chemistry Opium and Morphine SAR

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Slide 1: 

Chapter 24

Slide 2: 

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

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

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

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

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

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Side Effects Respiration Nausea Pupil constriction Constipation Euphoria Tolerance Dependence

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

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Structure Determination Methods available Identify the atoms present Measure the molecular weight

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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

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1923 MORPHINE Structure

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MORPHINE Structure 1923

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MORPHINE O NMe HO HO Structure 1923

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Structure

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Structure

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Structure

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Structure

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Structure T-Shaped molecule

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Potential Binding Groups Functional groups Carbon skeleton

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Potential Binding Groups

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Potential Binding Groups

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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

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STRUCTURE ACTIVITY RELATIONSHIPS

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STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

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STRUCTURE ACTIVITY RELATIONSHIPS

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STRUCTURE ACTIVITY RELATIONSHIPS O NMe HO

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STRUCTURE ACTIVITY RELATIONSHIPS

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SAR - The phenol moiety R=H Morphine R=Me Codeine Codeine 20% active (injected peripherally) 0.1% active (injected into brain)

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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

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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

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SAR - The 6-alcohol R=Me Heterocodeine 5 x activity

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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

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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

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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

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SAR - Double bond at 7,8 Dihydromorphine Increased activity The alkene group is not important to binding

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SAR - Nitrogen No activity Nitrogen is essential to binding

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SAR - Methyl group on nitrogen NR= NH Normorphine Reduced activity (25%) 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 No activity NR= N+Me2 No activity

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SAR - Stereochemistry Mirror image of morphine No activity 10% activity Changing the stereochemistry is detrimental to activity

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HBD or HBA Ionic (N is protonated) van der Waals SAR - Important binding interactions

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PHARMACOPHORE

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PHARMACOPHORE

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PHARMACOPHORE

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7.198 4.641 2.800 PHARMACOPHORE

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4.641 2.800 149.3o 11.3o 19o PHARMACOPHORE 7.198

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23.5o

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