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What is the effect of removing the ether linkage in morphine?
What is the effect of removing the ether linkage in morphine?
What is the effect of acetylating the phenol group in morphine?
What is the effect of acetylating the phenol group in morphine?
Why is 6-acetylmorphine banned in many countries?
Why is 6-acetylmorphine banned in many countries?
What is the effect of adding a methyl group to the nitrogen in morphine?
What is the effect of adding a methyl group to the nitrogen in morphine?
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Why does heroin cross the blood-brain barrier more quickly than morphine?
Why does heroin cross the blood-brain barrier more quickly than morphine?
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What is the effect of changing the stereochemistry of morphine?
What is the effect of changing the stereochemistry of morphine?
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What is the significance of the hydroxyl (-OH) group in the phenolic ring of morphinans?
What is the significance of the hydroxyl (-OH) group in the phenolic ring of morphinans?
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Why is morphine metabolized to normorphine in the liver?
Why is morphine metabolized to normorphine in the liver?
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What is the primary use of Naltrexone?
What is the primary use of Naltrexone?
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What is the effect of adding a double bond at 7,8 in morphine?
What is the effect of adding a double bond at 7,8 in morphine?
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What is the effect of changing the hydroxyl (-OH) group to a methoxy (-OCH3) group in morphinans?
What is the effect of changing the hydroxyl (-OH) group to a methoxy (-OCH3) group in morphinans?
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Why is codeine used for mild pain and coughs?
Why is codeine used for mild pain and coughs?
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What is the significance of the nitrogen atom in morphinans?
What is the significance of the nitrogen atom in morphinans?
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What is the result of removing excess functional groups and ring D from opioid analogues?
What is the result of removing excess functional groups and ring D from opioid analogues?
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What is the importance of the nitrogen in morphine?
What is the importance of the nitrogen in morphine?
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What is the characteristic of Nalbuphine?
What is the characteristic of Nalbuphine?
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What is the effect of removing other rings from morphinans?
What is the effect of removing other rings from morphinans?
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What is the effect of changing the functional groups of morphinans?
What is the effect of changing the functional groups of morphinans?
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How many chiral centers are present in morphinans?
How many chiral centers are present in morphinans?
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What is the effect of replacing the hydroxyl (-OH) group with a hydrogen atom in morphinans?
What is the effect of replacing the hydroxyl (-OH) group with a hydrogen atom in morphinans?
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What is the characteristic of Levorphanol?
What is the characteristic of Levorphanol?
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What is the property of simplified opioid analogues?
What is the property of simplified opioid analogues?
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What is the characteristic of Butorphanol?
What is the characteristic of Butorphanol?
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What is the comparison between morphinans and their morphine counterparts?
What is the comparison between morphinans and their morphine counterparts?
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Study Notes
Removal of Ether Linkage
- Removal of the ether linkage produces compounds called morphinans, which has increased activity.
- Levorphanol (10X potent than morphine) is an example of a morphinan with increased activity.
Codeine
- Codeine is metabolized in the liver to morphine, and the observed activity is due to morphine.
- Codeine is used for mild pain and coughs, and it is a weaker analgesic with weaker side effects.
- Masking the phenol group decreases activity.
3-Acetylmorphine
- 3-Acetylmorphine has decreased activity due to the acetyl group masking the polar phenol group.
- The acetyl group is hydrolyzed in the brain to form morphine, which allows the compound to cross the blood-brain barrier more easily.
6-Position Substitution
- Substitution at the 6-position can increase activity, as seen in heterocodeine (5x activity).
- The 6-alcohol group is not important for binding, and masking it with an acetyl group can increase activity (4x) and make the compound more lipid-soluble.
Heroin
- Heroin has increased activity (2x) due to its increased lipid solubility, allowing it to cross the blood-brain barrier more quickly.
- The acetyl groups are hydrolyzed in the brain to generate morphine, producing fast onset and intense euphoric effects.
Double Bond at 7,8
- The double bond at 7,8 is not important for binding, as seen in dihydromorphine, which has increased activity.
Nitrogen Substitution
- Nitrogen is essential for binding, and substitution with a methyl group (NMe) can reduce activity (25%).
- Ionized molecules cannot cross the blood-brain barrier and are inactive.
- Stereochemistry affects activity, with the mirror image of morphine having 10% activity.
Stereochemistry of Morphine
- Morphine has 5 chiral centers and exists naturally as a single stereoisomer.
- The synthesized form is a racemic mixture, which binds to receptors but fails to activate them.
- Changing the stereochemistry is detrimental to activity.
Antagonists
- Naltrexone is a potent antagonist, 8x more active than naloxone.
- Nalorphine is an antagonist that can be used to treat morphine overdose and has weak agonist activity.
- Nalbuphine has similar activity to morphine, low addiction liability, and no psychotomimetic effect.
Simplification Strategies
- Simplification strategies involve removing non-essential functional groups, excess rings, and excess asymmetric centers.
- Simplified analogues have easier, quicker, and cheaper synthesis, and may increase or decrease activity, interact differently with the receptor, and have different side effects.
Morphinans
- Morphinans are more potent and longer acting than their morphine counterparts, but have higher toxicity and comparable dependence characteristics.
- The OH group in the phenolic ring and basic nitrogen is needed for activity and seen in all potent µ agonists.
- Activity can be preserved or enhanced by removing other rings.
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Description
This quiz covers the modification of opioid compounds, including the removal of ether linkage, and the effects on activity. It also discusses the properties of specific opioids, such as codeine and levorphanol.
