Unit 4 - Receptors as Drug targets

Question 1

Where are most receptors found?

Answer 1

Embedded within the cell membrane with part of their structure exposed on the outer surface and part exposed on the inner surface

Question 2

What do receptors interact with?

Answer 2

Chemical messengers outside the cell

- transmit their message to the inside of the cell

Question 3

What are the two categories of chemical messengers?

Answer 3

Neurotransmitters
- released from nerve cells
- neurones
Hormones
- released from glands

Question 4

What is an endogenous ligand?

Answer 4

Natural chemical messenger which binds to a specific protein receptor which recognises that particular messenger

Question 5

What is signal transduction?

Answer 5

The endogenous ligand bind in a binding domain that is exposed on the outer surface of the cell, causing a change in shape which triggers a series of further events affecting other proteins within the cell membrane and the cell cytoplasm

Question 6

What happens to the binding domain once the message has been received?

Answer 6

The endogenous ligand leaves the binding domain unchanged and the protein returns to its inactive conformation or shape

Question 7

What effect does a full agonist have?

Answer 7

Produces maximal biological response
Has maximal positive intrinsic activity
- efficacy

Question 8

What effect does a partial agonist have?

Answer 8

Produces partial maximal biological response compared with full agonist
Has lower efficacy

Question 9

What effect does an inverse agonist have?

Answer 9

Produces opposite biological response of the endogenous ligand
Negative efficacy

Question 10

What is a competitive receptor antagonist?

Answer 10

Binds to a receptor at the same site as an endogenous or pharmacological agonist
- blocking agonist binding
- blocking receptor activation
Do not affect agonist activity
- maximal response
Do decrease affinity and potency
Can be reversed by increasing the amount of agonist

Question 11

What is a non-competitive receptor antagonist?

Answer 11

Bind to the same site as the agonist
Generally irreversible owing to formation of a covalent bond between antagonist and receptor
Reduce the number of receptors available to the agonist

Question 12

What are allosteric non-competitive receptor antagonists?

Answer 12

Drug binds to an allosteric site on the receptor
- different from where an agonist binds
- primary site
Binding to the allosteric site modifies the conformation of the primary sit
- altered conformation is less responsive to the agonist

Question 13

What methods are used to help design agonist and antagonists?

Answer 13

X-ray structure of protein-ligand complex
Ligand Based Drug Design
- LBDD
Structure Based Drug Design
- SBDD
Computer Aided Drug Design
- CADD

Question 14

What is Ligand Based Drug Design?

Answer 14

Don’t know receptor structure

Know ligands

Question 15

What is Structure Based Drug Design?

Answer 15

Know receptor structure

Don’t know ligands

Question 16

Give examples of non-polar aliphatic amino acids

Answer 16

Glycine
Alanine
Valine
Proline
Leucine
Methionine
Isoleucine

Question 17

What type of interactions do non-polar aliphatic amino acids form?

Answer 17

Van de Waals

Hydrophobic interactions

Question 18

Give examples of non-polar aromatic amino acids

Answer 18

Phenylalanine
Tyrosine
Tryptophan

Question 19

What type of interactions do non-polar aromatic amino acids form?

Answer 19

Van de Waals
Hydrophobic interactions
pi-pi stacking

Question 20

Give examples of polar, uncharged amino acids

Answer 20

Serine
Threonine
Cysteine
Aspargine
Glutamine

Question 21

What interactions do polar, uncharged amino acids form?

Answer 21

Hydrogen bonding
Disulphide bonds
- cysteine

Question 22

Give examples of positively charged (basic) amino acids

Answer 22

Lysine
Arginine
Histidine

Question 23

What interactions do positively charged (basic) amino acids form?

Answer 23

Ionic interactions

Hydrogen bonds

Question 24

Give examples of negatively charged (acidic) amino acids

Answer 24

Aspartate
- aspartic acid
Glutamate
- glutamic acid

Question 25

What interactions do negatively charged (acidic) amino acids form?

Answer 25

Ionic interactions

Hydrogen bonds

Question 26

What is the active principle of opium?

Answer 26

Morphine

Question 27

How does morphine work as an effective painkiller?

Answer 27

Acts in the brain

• appears to elevate the pain threshold
• decreasing the brain’s awareness of pain

Question 28

Give examples of semisynthetic derivatives of morphine

Answer 28

Codeine
Diacetylmorphine
- heroin
Dihydromorphine

Question 29

What are the uses of codeine?

Answer 29

Mild analgesic

Cough sedative

Question 30

Why is diacetylmorphine (heroin) addictive?

Answer 30

Fewer side effects so dependence more easily acquired

- don’t suffer the bad parts!

Question 31

What is dihydromorphine used for?

Answer 31

Relief of mild to moderate pain

Question 32

Give some examples of synthetic derivatives of morphine

Answer 32

Meperidine
- pethidine
Methadone

Question 33

How does naloxone work?

Answer 33

Pure narcotic antagonist

• removes
• respiratory depression
• nausea
• hypotension
• analgesia

Does not relieve pain
No potential for addiction

Question 34

What is naloxone used for?

Answer 34

Used to rapidly reverse effects of opiate overdose

• inhaler
• autoinjector

Question 35

What is nalorphine?

Answer 35

Antagonist
- should not have any analgesic activity BUT weak activity observed
Free from side effects
Unable to switch on 2 receptors
- true antagonist at these receptors
- but gives some activity so must be another receptor
- nalorphine activates a third receptor
- weak or partial agonist

Question 36

What led to the synthesis of related compounds of naloxone?

Answer 36

Naloxone was almost totally free from side effects