Lecture 9 & 10 - Opioids

Question 1

What are the CNS effects of morphine (2)

Answer 1

Elevates pain threshold, decreases brain awareness of pain

Question 2

What are some of the side effects or morphine? (6)

Answer 2

Depression of the respiratory centre, constipation, nausea, pupil constriction, euphoria, tolerance, dependence

Question 3

How many rings does morphine have and what shape are they in?

Answer 3

5 rings and T-shaped structure

Question 4

Is morphine acidic or basic?

Answer 4

A functionally weak base

Question 5

What does morphine exist as at physiological pH

Answer 5

Cation

Question 6

What are the four types of opioid receptors?

Answer 6

MOR, KOR, DOR and ORL1 (opioid-like receptors)

Question 7

Which receptor does morphine bind most strongly to?

Answer 7

MOR instead of DOR and KOR

Question 8

What type of receptor is the opioid receptor

Answer 8

GPCR

Question 9

Where does morphine bind to in the MOR?

Answer 9

A cavity at the extracellular edge of the receptor

Question 10

What is the difference between opium and morphine?

Answer 10

Opium is an extract obtained form the opium poppy and contained more than 20 alkaloids, morphine is the main active alkaloid in opium.

Question 11

Why can’t morphine poorly absorbed in the gut?

Answer 11

It is polar

Question 12

Why is octanol used to calculate the partition coefficient?

Answer 12

It has a long hydrocarbon tail so it mimics

the amphiphilic nature of lipid membranes

Question 13

What logP guarantees oral absorption?

Answer 13

2-5

Question 14

What percentage of morphine is unionised at pH 7.4

Answer 14

14%

Question 15

What is morphine’s pKA

Answer 15

8.2

Question 16

What is the difference between morphine and normorphine

Answer 16

Normorphine has a amine group added instead of the methyl so it has increase ionisation

Question 17

Which molecule has the highest lipophilicity?

Answer 17

Heroin

Question 18

Which molecule has the highest relative analgesic activity?

Answer 18

6-acetylmorphine (an active metabolite of heroin)

Question 19

Heroin is a prodrug true or false

Answer 19

True

Question 20

What groups have been replaced in morphine to make heroin?

Answer 20

The 3-6 hydroxyl groups have been replaced with acetyl groups

Question 21

What is codeine?

Answer 21

A 3-methylether of morphine

Question 22

Is codeine a prodrug

Answer 22

Yes

Question 23

Is codeine found in opium

Answer 23

Yes

Question 24

How is codeine metabolised in the liver?

Answer 24

O-demethylation

Question 25

What re the 3 conjugations of morphine in the liver?

Answer 25

Morphine 3-glucuronide Morphine 6-glucuronide Morphine 3,6-glucuronide

Question 26

Which of the glucuronide conjugations of morphine is active?

Answer 26

Morphine 6-glucuronide

Question 27

Which OH group is important for morphine activity

Answer 27

The 3 hydroxyl

Question 28

Which confirmation of the target does an agonist stabilise?

Answer 28

The active conformation

Question 29

What are the three key groups for morphine activity?

Answer 29

1. 3-hydroxyl forms hydrogen bonds 2. Benzene rings have Van der waals interactions 3. The N-methyl group can become charged and form ionic bonds

Question 30

What is the 'message' responsible for?

Answer 30

Pharmacological activity

Question 31

Which parts are responsible for the message in morphine?

Answer 31

The charged amine and phenolic group

Question 32

What is the 'address' responsible for?

Answer 32

Target selectivity (MOR vs KOR)

Question 33

What is responsible for the address portion of morphine?

Answer 33

The variable hydrophobic portion

Question 34

How is oxycodone generated?

Answer 34

An an extra OH group at position 14

Question 35

At which alkyl group does agonistic activity of morphine return?

Answer 35

Pentyl and hexyl

Question 36

What is one of the most potent N-alkylation substitutions?

Answer 36

Phenethylmorphine

Question 37

Why is naltrexone such an effective antagonist?

Answer 37

It has a cycylpropane group at the N-alkylation

Question 38

Which is more rapid, naloxone or naltrexone?

Answer 38

Naloxone

Question 39

Why are fentanyl and sufentanil more potent than morphine?

Answer 39

1. Both are highly lipophilic due to a phenylethyl on N | 2. Fentanyl has a phenetyl group attached to the nitrogen ring, sufentanil has a bioisosteric replacement with thiophene

Question 40

How is etorphine different from morphine and how does this influence potency?

Answer 40

Etorphine is synthesised from thebaine and is conformationall restricted

Question 41

Which rings have been removed in pethidine and norpethidine?

Answer 41

B, C and D

Question 42

What is the consequence of removing B, C and D

Answer 42

No 'address' concept, they bind in different manners

Question 43

What are met and leu enkphalins

Answer 43

Pentapeptides with a preference for MOR and DOR

Question 44

Dynorphin vs endorphine selectivity for receptors

Answer 44

KOR vs MOR and DOR

Question 45

Which groups are essential for the activity of met-enkephalin

Answer 45

Tyrosine phenol and amino groups

Question 46

How do you remove the activity of met-enkephalin (2)

Answer 46

Replace the tyrosine | Inactivate it using peptidase

Question 47

What provides the message in met-enkephalin?

Answer 47

The tyrosine

Question 48

Morphine vs enkephalin selectivity for for MOR, KOR and DOR

Answer 48

+++, ++, + vs +++, ___, +++