Receptors as drug targets 2

Question 1

What are the properties of nalbuphine and naltrexone?

Answer 1

Good analgesic activity

Low abuse potential

Question 2

Describe butorphanol

Answer 2

Further structure variation led to butorphanol
- more potent than morphine and phenazocine
Extremely safe drug
- no respiratory depression
Butorphanol represents considerable progress towards the ideal non-addictive powerful analgesic

Question 3

What is the receptor theory of analgesics?

Answer 3

1. Must be a basic centre (nitrogen) which can be ionised at physiological pH to form positively charged group
   - analgesics must have pKa of 7.8-8.9 so equal chance of the amine being ionised or unionised at physiological pH
   - ionised to bind with receptor
   - unionised to cross blood brain barrier
2. The aromatic ring in morphine has to be properly orientated with respect to the nitrogen atom to allow a Van de Waals interaction
3. The phenol group is probably hydrogen bonded to a suitable residue at the receptor site
4. There might be a hollow for the ethylene bridge to fit
   - not a requirement

Question 4

What are the three analgesic receptors?

Answer 4

Mu
Kappa
Delta

Question 5

What is the mu receptor?

Answer 5

An analgesic receptor
Morphine binds strongest here
Receptor binding leads to undesired side effects
- respiratory depression
- euphoria
- addition

Question 6

What is the kappa receptor?

Answer 6

Morphine binds less strongly here
Biological response = analgesia with sedation
No hazardous side effects

Question 7

What is the delta receptor?

Answer 7

Brain’s natural painkillers interact here

• morphine can bind strongly here
• good thing!

Question 8

What are Lipinski’s rule for a CNS drug?

Answer 8

Two or fewer H-bond donors
- 40% have none
Six or fewer H-bond acceptors
MWt less than 400
- 90% less than
cLogP less than 5
- MLogP less than 4.15
Potent activity
- nano to sub nanomolar
Not a CYP3A4 inducer
Not a high affinity P-glycoprotein substrate
Not an acid
Neutral or basic with pKa between 7.5 - 10.5
Not a membrane stabiliser or destabiliser

Question 9

What are the three main ligands for the parietal cell in the stomach?

Answer 9

Acetylcholine
Gastrin
Histamine

Question 10

What are the three possible ways to inhibit gastric acid release?

Answer 10

Anticholinergic drug
- block the acetylcholine receptor
A drug to block the hormone gastrin
Antihistamine
- inhibit gastric acid release

Question 11

What is the role of histamine?

Answer 11

Released when a cell is damaged
Stimulates dilation and increased permeability of small blood vessels
- white blood cells released to combat infection
- beneficial!
Problem when allergic reaction
- histamine has adverse effect
- hay fever
- insect bites
- asthma

Question 12

How can histamine reactions be treated?

Answer 12

Antihistamines

• Benadryl
• Claritin
• Allegra

Question 13

How many histamine receptors are there?

Answer 13

Four
Histamine also stimulates gastric acid release
- but antihistamines have no effect on gastric acid release
- so at least two receptors
- H1 = inflammation
- H2 = gastric acid secretion

Question 14

What is histamine?

Answer 14

Two carbon chain with a terminal alpha-amino group attached to imidazole ring
Exists in two tautomeric forms

Question 15

What structure does histamine have for H1 binding?

Answer 15

N atom with lone pair of electrons ORTHO to the side chain

Question 16

What structure does histamine have for H2 binding?

Answer 16

Contain an amidine unit

- NH-CH-N:

Question 17

What is needed in histamine for H1 and H2 binding?

Answer 17

A positively charged N atom with at least one proton in the side chain

A flexible chain between the cation and heteroaromatic ring.

Question 18

What is chelated bonding structure ?

Answer 18

The interactions between the chelated structure involves TWO hydrogen bond between TWO charged species.