Flashcards in Opioid analgesics Deck (30):
Where have opioid analgesics originated from?
It all starts with an alkaloid isolated from the opium poppy.
What is the principle of opium?
MORPHINE- it is a natural product with a very complex structure, and a lot of chiral centres.
How do opioid analgesics work in the brain?
They work by elevating the pain threshold for better tolerance, therefore decreasing pain awareness in the brain.
What are the side effects of morphine?
Depression of the respiratory centre in the brain
Excitation and Euphoria
Tolerance and Dependance - addiction
Why have synthetic analouges of morphine been formed?
Due to the dangerous side effects, synthetic analouges have been formed for improved therapeutic effects.
What are the SEMISYNTHETIC derivatives?
The functional groups have changed but the original morphine structure is the same
What are SYNTHETIC derivatives?
They still have the morphine structure but have been modified more than semi-synthetic
What is codeine?
It is a pro-drug of morphine, and a semi-synthetic derivative. It is a mild analgesic, and a cough sedative.
What is Diacetylmorphine?
It is heroin, with fewer side effects, but higher dependancy. It is a semi-synthetic derivative.
What is Methadone?
It is a SYNTHETIC derivative used as an alternative for Heroin. It doesn't have the side effects associated with heroin (as much dependancy), but there is still some euphoria.
What is the first structure change approach to form derivatives?
The first approach is PERIPHERAL MODIFICATION.
What is peripheral modification?
This is switching the functional groups of ONE of the phenolic groups. Doing this results in a drop in activity, meaning that a free phenolic group is essential for activity.
What are the two possible reactions morphine could undergo?
Glucuronidation or Methylation
What causes the difference in pharmacodynamic properties of the derivatives?
The pharmacodynamic properties of the drug, and not their affinity to the analgesic receptor. An increase uptake into the brain makes the drug more potent with greater side effects, and more tolerance and dependance characteristics.
What has many analogues including Dihydromorphine shown about analgesic activity?
They have shown that the double bond in the structure of morphine is NOT required for activity.
What is the effect of the N-methyl group in morphine?
This group has a profound effect on activity because it interacts with analgesic receptors in the brain.
What happens if the N-methyl group is removed or becomes ionised?
There will be no analgesic effect if the N-group becomes ionised because the molecule will not be able to cross the blood brain barrier. If analogues that had ionised N-group were injected straight to the brain then they would have the same effect as morphine bu this is not practical.
Are the aromatic rings in the structures essential?
Yes the aromatic rings are essential for activity whoch is why they are the base of all morphine derivatives' structure.
What about morphine's stereochemistry?
Morphine is an asymmetric molecule (not identical both sides) containing several chiral centres and will exist naturally as a single enantiomer. The 'unatural form' i.e. the other enantiomer will have no activity.
What are the three important interactions of morphine for its activity?
Phenol group, Aromatic rings, Tertiary amine group are all essential for binding to receptors.
What happens to binding in the 'unatural form' of morphine?
The benzene interaction still occurs, but the Tertiary amine and the Phenol group do not bind so there is NO activity.
What are the different bonds involved in the binding at receptors?
Benzene ring: pi stacking Van der walls
Phenol group: Hydrogen bonding
N-methyl group: Ionic bonding.
What is the second structure change approach to form morphine derivatives?
What is Drug extension:
The molecule is extended by the addition of an extra binding group which is a probe for extra binding sites.
Why would Drug extension be a good choice?
Because extra binding sites may improve analgesic activity
Where in the structure of morphine does drug extension often occur?
On the N-methyl group, and the lower aromatic ring (not the top phenol ring)
What is Naloxane and what structure was modified??
It is a pure narcotic antagonist with no side effects of respiratory depression, nausea, hypotension, but also NO analgesic effect. It is used to treat and reverse overdose.
The structure modified was the N-alkyl group by drug extension
What is Nalorphine and what structure was modified?
It is an antagonist so shouldn't show analgesic activity, but some is still seen. This is because it does not switch on 2 receptors so is an antagonist at these, but will switch on 1 receptor which is why we see some analgesic activity. It is free from side effects.
What does the 3rd receptor that Nalorphine does activate called?
A partial agonist