Opioid analgesics

Question 1

Where have opioid analgesics originated from?

Answer 1

It all starts with an alkaloid isolated from the opium poppy.

Question 2

What is the principle of opium?

Answer 2

MORPHINE- it is a natural product with a very complex structure, and a lot of chiral centres.

Question 3

How do opioid analgesics work in the brain?

Answer 3

They work by elevating the pain threshold for better tolerance, therefore decreasing pain awareness in the brain.

Question 4

What are the side effects of morphine?

Answer 4

Depression of the respiratory centre in the brain
Constipation
Excitation and Euphoria
Nausea
Pupil constriction
Tolerance and Dependance - addiction

Question 5

Why have synthetic analouges of morphine been formed?

Answer 5

Due to the dangerous side effects, synthetic analouges have been formed for improved therapeutic effects.

Question 6

What are the SEMISYNTHETIC derivatives?

Answer 6

The functional groups have changed but the original morphine structure is the same

Question 7

What are SYNTHETIC derivatives?

Answer 7

They still have the morphine structure but have been modified more than semi-synthetic

Question 8

What is codeine?

Answer 8

It is a pro-drug of morphine, and a semi-synthetic derivative. It is a mild analgesic, and a cough sedative.

Question 9

What is Diacetylmorphine?

Answer 9

It is heroin, with fewer side effects, but higher dependancy. It is a semi-synthetic derivative.

Question 10

What is Methadone?

Answer 10

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.

Question 11

What is the first structure change approach to form derivatives?

Answer 11

The first approach is PERIPHERAL MODIFICATION.

Question 12

What is peripheral modification?

Answer 12

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.

Question 13

What are the two possible reactions morphine could undergo?

Answer 13

Glucuronidation or Methylation

Question 14

What causes the difference in pharmacodynamic properties of the derivatives?

Answer 14

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.

Question 15

What has many analogues including Dihydromorphine shown about analgesic activity?

Answer 15

They have shown that the double bond in the structure of morphine is NOT required for activity.

Question 16

What is the effect of the N-methyl group in morphine?

Answer 16

This group has a profound effect on activity because it interacts with analgesic receptors in the brain.

Question 17

What happens if the N-methyl group is removed or becomes ionised?

Answer 17

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.

Question 18

Are the aromatic rings in the structures essential?

Answer 18

Yes the aromatic rings are essential for activity whoch is why they are the base of all morphine derivatives’ structure.

Question 19

What about morphine’s stereochemistry?

Answer 19

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.

Question 20

What are the three important interactions of morphine for its activity?

Answer 20

Phenol group, Aromatic rings, Tertiary amine group are all essential for binding to receptors.

Question 21

What happens to binding in the ‘unatural form’ of morphine?

Answer 21

The benzene interaction still occurs, but the Tertiary amine and the Phenol group do not bind so there is NO activity.

Question 22

What are the different bonds involved in the binding at receptors?

Answer 22

Benzene ring: pi stacking Van der walls
Phenol group: Hydrogen bonding
N-methyl group: Ionic bonding.

Question 23

What is the second structure change approach to form morphine derivatives?

Answer 23

Drug extension

Question 24

What is Drug extension:

Answer 24

The molecule is extended by the addition of an extra binding group which is a probe for extra binding sites.

Question 25

Why would Drug extension be a good choice?

Answer 25

Because extra binding sites may improve analgesic activity

Question 26

Where in the structure of morphine does drug extension often occur?

Answer 26

On the N-methyl group, and the lower aromatic ring (not the top phenol ring)

Question 27

What is Naloxane and what structure was modified??

Answer 27

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

Question 28

What is Nalorphine and what structure was modified?

Answer 28

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.

Question 29

What does the 3rd receptor that Nalorphine does activate called?

Answer 29

A partial agonist

Question 30

What is the newer derivative that represents progress towards the ideal non-addictive powerful analgesic called and why is it so powerful?

Answer 30

Butorphanol: it is an extremely safe drug, with no respiratory depression. It is also more potent than morphine.