P6 - Morphine and its Analogues

Question 1

Which features of morphine’s structure are essential for it’s activity?

Answer 1

Phenol
Aromatic ring (ring A)
Amine
Stereochemistry
Hydrophobicity to pass BBB

Question 2

Which features of morphine’s structure are not essential for it’s activity?

Answer 2

The alcohol in position 6 (6-OH)
The 7-8 double bond
The methyl group attached to the amine
The ether bridge

Question 3

What structural change is made to morphine to form codeine?

Answer 3

Capping the 3-OH with a methyl group
Forms a prodrug for morphine
Has to undergo O-demethylation by CYP2D6 in the liver
Has 20% of morphine’s biological activity

Question 4

What structural change is made to morphine to form diamorphine/heroin?

Answer 4

Capping both OH groups with an acetyl group

This improves hydrophobicity so a greater concentration enters the CNS and faster

Question 5

What 3 strategies have been used to successfully optimise the structure of morphine?

Answer 5

1. Drug extensions/addition of extra functional groups
2. Drug simplification/ring removal
3. Drug rigidification

Question 6

What functional groups have been added to morphine to optimise it? What was formed and what was the effect on activity?

Answer 6

Oxidise 6-OH into a ketone, and add another OH group forms Oxymorphine. 2.5x activity due to extra hydrogen bonding

Question 7

What was the effect of changing the group attached to the amine of morphine?

Answer 7

Adding longer alkyl chains decreases activity

Adding a phenethyl group creates N-phenethylmorphine with 14x activity. Due to extra hydrophobic binding region

Question 8

How can drug extensions be used to create antagonists of the opioid receptor, and how are these useful?

Answer 8

Oxidise 6-OH to a ketone and then add allyl or cyclopropylmethylene to the amine.
Forms Naloxone and Naltrexone.
Strong mu and delta antagonist, weak kappa agonist.
Prevents respiratory depression during morphine/heroin overdose. But can cause hallucinations/dysphoria.

Question 9

What happens to morphine when ring E is removed?

Answer 9

Loss of drug activity (due to amine being a pharmacophore)

Question 10

What happens to morphine when ring D is removed?

Answer 10

Creates morphinan. 5x more potent.
Removal of ring D AND addition of allyl creates 5x more potent antagonist.
Easier synthesis and good oral bioavailability.

Question 11

What happens to morphine when rings C and D are removed?

Answer 11

Forms benzomorphan.
Retains analgesia, easier synthesis, lower addiction risk and no respiratory depression.
Kappa agonist but antagonist of mu and delta.
Still causes hallucinations and dysphoria.

Question 12

What happens to morphine when rings B, C and D are removed?

Answer 12

Forms 4-phenylpiperidines, such as pethidine Retains analgesia, easier synthesis, rapid onset and short duration of action.
Used in childbirth ask lower risk of respiratory depression for child. Same side effects as morphine.
This structure can be used to synthesise fentanyl.

Question 13

What happens to morphine when rings B, C, D and E are removed?

Answer 13

Produces methadone.
Comparable activity to morphine but less side effects and withdrawal symptoms. Not as addictive. Used to wean addicts off heroin/morphine.

Question 14

What is the result of rigidification to the morphine structure? Name 3 of the compounds this forms

Answer 14

Forms the Oripavines

1. Etorphine
2. Diprenorphine
3. Buprenorphine

Question 15

What are the features of Etorphine?

Answer 15

1000x more potent than morphine
High lipophilicity
High affinity for all receptors
Used to immobilise elephants
Worse side effects than morphine

Question 16

What are the features of Diprenorphine?

Answer 16

Powerful opioid receptor antagonist

Reverses effects of etorphine (wake elephants up again)

Question 17

What are the features of Buprenorphine?

Answer 17

Partial agonist of mu, antagonist of delta and kappa
Analgesic effect
Low addiction risk
No respiratory depression
Used to wean off heroin addicts