Week 12 -CNS Discovery Analysis

Question 1

What is a challenge occuring at BBB

Answer 1

Establishing a conc. gradient (from blood across BBB)

• Blood conc. is limited
  
  • can ↑ GI tract drug conc. by ↑ drug intake
  • BUT when drug diffuses from GIT to blood the conc. is ↓ due to constant blood flow (taking drug away)
• DUE to LOW CONC. in BLOOD = gradient from blood to brain is LIMITED
  - even if BBB was permeable movement across BBB is limited
  - can NOT force drug out of blood + across BBB down conc. gradient

Question 2

List the 3 ways to overcome drug movement challenges at BBB

Answer 2

1. Improve DIFUSSION
2. Get TRANSPORTED in
3. Get LOCKED in

Question 3

How can we “improve diffusion”

Answer 3

By altering the following properties:
- logP: 2 – 4
- logD: 2 – 3
- MW: < 450 Da
- pKa: 6 – 10.5
- HBD: < 3
- PSA: < 90 Å2
NOTE: aim for results around these or better

pKa near physiological pH (= will have enough of neutral form to diffuse through and enough of ionised form to remain solid)
- REMEMEBR ONLY NEUTRAL form can DIFFUSE across membrane

HBD - OH and NH groups
- want to reduce the amount of these groups on molecule

Question 4

How can we get drug “transported in”

Answer 4

Design drugs that looks SIMILAR to natural nutrients the brain needs e.g. amino acids, glucose etc.

• Drug will be transported across BBB into CNS via transporters
  
  • e.g. L-dopa looks like an amino acid (tyrosine/phenylalanine) = hence why its transported into CNS

Question 5

How can we get drug “locked in”

Answer 5

Give prodrug that can cross BBB BUT when drug enters brain its metabolised into a molecule that can’t diffuse out of brain

e.g. Temozolomide (TMZ)
- prodrug used in brain tumour treatment

Question 6

Challenegs with measuring drug conc. in brain

Answer 6

Can NOT measure conc. non-destructively (i.e. measuring from brain requires brain to be extracted)

Example:
- Animal (rat) is dosed, killed then brain is extracted
- Brain is homeogenised then added to solution (buffer)
- Solution is mixed + centrifuged
- After centrifuge, solid bits sink to bottom AND we measure the conc. of the supernatant (liquid on top)
= UNETHICAL