The Medicinal Chemistry of Opioid Analgesics 1

Question 1

What are opioid alkaloids?

Answer 1

Centrally acting analgesics

Possess strong narcotic effect in terms of side effects

Question 2

What kind of narcotic side effects can come from opioid use?

Answer 2

Sedation and even loss of consiousness

Question 3

What are the indications of opioids?

Answer 3

Moderate to severe pain analgesia
Cough e.g. codeine, dihydrocodeine, ethylmorphine
Diarrhoea e.g. loperamide
Opioid dependence e.g. methadone and buprenorphine

Question 4

Common adverse reactions to opioids?

Answer 4

Respiratory depression
Nausea and vomiting
Drowsiness
Itching 
Dry Mouth 
Constipation 
Miosis

Question 5

Problems associated with opioids?

Answer 5

Tolerance
Physical Dependence
Addiction

Question 6

Where do delta (δ) opioid receptors exist and what is the agonist function?

Answer 6

CNS (brain) and ENS

Analgesia, antidepressant and physical dependence

Question 7

Where do kappa (k) opioid receptors exist and what is the agonist function?

Answer 7

CNS (brain, spinal cord) and ENS

Spinal analgesia, sedation, miosis, inhibition of ADH release (anti-diuretic hormone)

Question 8

Where do mu (μ) opioid receptors exist and what is the agonist function?

Answer 8

CNS (brain, spinal cord,) and ENS and GI 
μ1 Supraspinal (above spine) analgesia
Physical dependence 
μ2 Respiratory depression 
Miosis and reduced GI motility

Question 9

Agonist action at which opioid receptor causes respiratory depression and constipation?

Answer 9

μ2 opioid receptor

Question 10

Agonist action at which opioid receptor causes anti depressant effects?

Answer 10

δ opioid receptor

Question 11

Where are endorphins isolated from?

Answer 11

Pituitary glands

Question 12

What are the two most important enkephalins?

Answer 12

Leu-Enkephalin

Met-Enkephalin

Question 13

Which amino acid is found at the terminal of leu and met enkephalin?

Answer 13

Tyrosine

Question 14

What is the difference between phenol and alcohol group?

Answer 14

Phenol is more acidic, can ionise more readily and is more polarised, making it a better H bond donor

Question 15

What benefit do the rings in the morphine structure hold?

Answer 15

Rigidity which is good for receptor binding

Question 16

What happens if you change the phenol group on morphine structure 3rd carbon?

Answer 16

All modifications lead to reduced analgesic activity

Question 17

What is produced if you change the -OH phenol group on carbon 3 of morphine to an ether with a CH3 as the functional group?

Answer 17

Codeine

Question 18

What is produced if you change the -OH phenol group on carbon 3 of morphine to an ether with a Et (ethyl) as the functional group?

Answer 18

Ethylmorphine

Question 19

What is produced if you change the -OH phenol group on carbon 3 of morphine to an ether with an Acetyl as the functional group?

Answer 19

3-Acetylmorphine

Question 20

How does codeine act as a prodrug?

Answer 20

Codeine is metabolised in the liver into morphine which then has the analgesic effect

Question 21

What happens in liver metabolism of codeine to produce morphine?

Answer 21

Methyl group is cleaved

Question 22

What is produced if you change the -OH alcohol group on carbon 6 of morphine to a CH3 as the functional group?

Answer 22

Heterocodeine

Question 23

What is produced if you change the -OH alcohol group on carbon 6 of morphine to an Et (ethyl) as the functional group?

Answer 23

6-Ethlymorphine

Question 24

What is produced if you change the -OH alcohol group on carbon 6 of morphine to a Acetyl as the functional group?

Answer 24

6-Acetlymorphine

Question 25

What happens to the analgesic activity of moprhine when the phenol at carbon 3 is modified?

Answer 25

Reduced analgesic activity

Question 26

What happens to the analgesic activity of morphine when the -OH alcohol group at carbon 6 is modified?

Answer 26

4-5 fold increase in activity

Question 27

What is the nomenclature of diamorphine / heroin?

Answer 27

3,6 - diacetylmorphine

The phenol group and -OH group at carbon 3 and 6 are replaced by acetyl groups

Question 28

What is the ultimate resistance to CNS receptor access?

Answer 28

Blood Brain Barrier

Question 29

What kind of molecules enter the CNS across the BBB easily?

Answer 29

Highly lipophillic

Question 30

Examples of lipophillic opioid drugs that can cross the BBB?

Answer 30

6-acetylmorphine and heroin (3,6, diacetylmorphine)

Question 31

What form of drug is able to cross the blood brain barrier?

Answer 31

Lipophillic

Question 32

Why is morphine BBB penetration limited in the 20% not ionised?

Answer 32

The polarity contributed by -OH at carbon 3 and 6 means too polar to cross easily

Question 33

Why can more 6-acetylmorphine cross the BBB than morphine can?

Answer 33

The actely group at the 6th carbon masks the polarity of the -OH alcohol group that was there before and so makes the molecule less polar

Question 34

What are the benefits of 6-acetlymorphine structure regarding the BBB compared to morphine/diamorphine?

Answer 34

Higher concentration of active drug at the receptor

Question 35

Why is diamorphine / heroin able to cross the BBB easily?

Answer 35

3,6 diacetylmorphine is able to cross because highly lipophillic and reduced polarity by masking the phenolic and alcoholic -OH groups

Question 36

What is the main problem with analgesic effect in diamorphine once it has crossed the BBB?

Answer 36

The phenolic -OH group essential for binding to the receptor as an agonist is an acetyl group at carbon 6

Question 37

How is the diamorphine active form regiained?

Answer 37

Esterases that are abundant in brain tissue cells is able to break down the ester bond on the molecule to restore the phenolic -OH at the 3rd carbon (and can restore the 6th carbon -OH also)
Can now bind to the ester