Dugga 3- opioid analgesics

Question 1

What does analgesic mean?

Answer 1

To relieve pain

Question 2

What are opioids?

Answer 2

Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia.

Question 3

What type of receptors are opioid receptors?

Answer 3

G protein coupled receptors

Question 4

What does morphine look like?

Answer 4

Four six membered rings (3 planar and one perpendicular to it), two OH groups, One NMe group and an oxygen bound by two six membered rings forming a five-membered ring

Question 5

Does opium contain morphine?

Answer 5

Yes

Question 6

What are the important groups in morphine?

Answer 6

OH group, aromatic ring and tertiary amine (protonated and ionised when drug interacts with binding site)

Question 7

Is morphine a chiral molecule?

Answer 7

Yes it contains several assymmetric centres

Question 8

What are the side effects of morphine?

Answer 8

Dependence, depression and tolerance

Question 9

What are the three types of analgesic or opioid receptors activated by morphine?

Answer 9

mu, kappa and delta receptors, all G protein coupled receptors

Question 10

Which functional groups are important and why?

Answer 10

the amine nitrogen is protonated and charged which means it forms ionic bonds,
the phenol acts as hydrogen bond donor,
the aromatic ring has a defined orientation allowing van der Waals interactions with a hydrophobic location in the binding site

Question 11

Where are the analgesic receptors located?

Answer 11

In the central nervous system (so morphine needs to cross BBB)

Question 12

How does a polar molecule such as morphine cross BBB?

Answer 12

The amine group is a weak base so morphine exists both as free base and ionised form and the free base can cross BBB and then be ionised to interact with opioid receptors

Question 13

What is another name for diamorphine?

Answer 13

Heroin

Question 14

Which prodrugs of morphine exist and why?

Answer 14

6-acetylmorphine (4x more active) and diamorphine (2x more active), the polar functional groups are masked and it is then possible to get increased levels of morphine in the brain

Question 15

Which receptor does morphine bind most strongly to?

Answer 15

The mu receptor (this is responsible for the serious side effects of morphine)

Question 16

Which receptor is responsible for analgesia and sedation (but has psychological side effects)

Answer 16

Kappa

Question 17

Which receptor is favoured by enkephalins?

Answer 17

The delta receptor

Question 18

Can opioids also be used to treat diarrhea?

Answer 18

Yes, because a side effect of them is constipation so morphine analogues have been developed that focus only on improving that side effect. Names of these drugs ae loperamide, imodium and diphenoxylate

Question 19

What is enkephalin?

Answer 19

An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body’s opioid receptors.

Question 20

What does an addition of a 14hydroxyl group or an N-phenethyl group do to morphine?

Answer 20

Increases activity as a result of interactions with extra binding regions

Question 21

How are N-alkylated analogues of morphine synthesised?

Answer 21

By demethylating morphine to normorphine and alkylating with alkyl halides

Question 22

What happens to morphine structures when suitable N-substituents are added?

Answer 22

Compounds act as antagonists or partial agonists

Question 23

Why can small changes in morphin analogues result in it being an agonist or antagonist?

Answer 23

It is proposed that there are two accessory hydrophobic regions and an agent will act as an agonist or antagonist depending on which region it reaches

Question 24

Which peptides act as the body’s natural painkillers?

Answer 24

Enkephalins, dynorphins, endomorphins and endorphines

Question 25

What is crucial to the activity of the peptides that act as the body’s own painkillers?

Answer 25

The N-terminal tyrosine

Question 26

How have analogues of enkephalin been made more stable?

Answer 26

More stable to peptidases by the inclusion of unnatural amino acids, D-amino acids or N-methylated peptide links

Question 27

Which concept has been used to design opioids that are selective for a particular type of opioid receptor?

Answer 27

Message-address concept.

Question 28

What are alkaloids?

Answer 28

Plant-derived nitrogen containing compounds (are bases/alkaline)

Question 29

Which strategies exist to make analoges?

Answer 29

Vary substituents
Extend structure
Simplify structure
Rigidify structure

Question 30

Do we need the SAR before making analogues?

Answer 30

Yes

Question 31

Extending stucture can improve binding in what way?

Answer 31

Extra binding groups

Question 32

Extending the structure can also lead to the formation of …

Answer 32

antagonists

Question 33

Which rings are essential in morphin?

Answer 33

Ring A and E

Question 34

What is fentanyl?

Answer 34

A morphin analogue 100x stronger than heroine, used in hospitals, given in very controlled amount

Question 35

What is the opioid epidemic?

Answer 35

People in US became dependent on opiate agonist called oxycontin

Question 36

Is ring E really essential for morphine?

Answer 36

No, can be mimicked by phenyl and methyl

Question 37

Give an example of a morphine analogue without ring E?

Answer 37

Metadon
Used to treat heroin addiction