Week 9 - Chemistry of Parkinson's Disease Medicines and Prodrugs

Question 1

What properties are required for a drug to be able to cross BBB

Answer 1

• In SOLUTION (soluble)
  - not highly / fully ionised
  - need to have a % of neutral molecules that can cross membrane = form equilibrium / gradient
• SMALL (molecular weight)
• MORE LIPOPHILIC = more likely to penetrate membrane
• LESS hydrogen BOND DONORS (<3)
• HIGH LogP

CANT CROSS IF / not permeable:
- have high polarity
- ionised / charged

Question 2

Why is it hard for drugs to cross the BBB

Answer 2

1. Efflux transporters
   - pump drug back out of the CNS into blood again
   - have high expression of these on BBB
2. Tight junctions
   - difficult for molecules to pass between cells = have to diffuse through / across them
3. Total conc. can achieven blood is lower than what can be achieved in GI tract
   = cant force drug out of blood + through BBB
   = cant achieve a good conc. gradient

Question 3

Why can L-dopa cross BBB and not dopamine

Answer 3

Dopamine:
- Too HYDROPHILLIC
- Has TOO many hydrogen BOND DONORS
- Is small BUT is too POLAR

L-Dopa:
- Is small BUT even MORE POLAR (than dopamine)
- Has MORE hydrogen BOND DONORS
- Highly IONISED
(seems worse BBB molecule than dopamine BUT can still enter CNS, WHY?)
- Does NOT passively diffuse across BBB
- instead ACTIVE TRANSPORT
- have amino acid transporters on BBB membrane that take up L-dopa as it looks similar naturally occuring amino acids our brain needs

Question 4

What is the structure of carbidopa

DDC inhibitor

Answer 4

Has similar structure to L-Dopa
BUT:
- has NH2 group (amine)
- has methyl group (improves affinity for DDC = better inihbiton of DDC enzyme)
= above is what distinguishes it from L-dopa = can NOT cross BBB (through transporters)

IT IS:
- hydrophillic
- basic (due to di-amine)
- anionic (at physiological pH)
-

Question 5

What is the structure of COMT inhibitors

Answer 5

Have similar structure to L-dopa
BUT:
- has NO2 group (nitro)
- electron withdrawing = polar
- allows compound to bind to COMT enzyme + block its activity

CAN enter CNS due their amino-acid like structure = cant enter through transporters
- small molecules
- have 2 HBD (= good)

Question 6

What are the pharmacological issues with L-Dopa

Answer 6

1. Rapid clearance due to short half-life
   = have to have frequent dosing
2. Can’t just increase dose (to increase duration of action) due to high Cmax = toxicity

Despite drawbacks L-dopa is one of the most effective PD treatments

Question 7

How was L-dopa metabolism improved

Answer 7

1. DDC inhibitors
   (inhibit DDC enzyme)
   - ↓ peripheral dopamine production
   - ↓ decarboxylation of L-dopa (into dopamine) = more l-dopa can cross BBB
   - Prolonged L-dopa activity (increase half life)
2. COMT inihibitors
   (inhibit COMT enzyme)
   - prevented methylation of L-dopa (peripheral and CNS)
   - prevented methylation of dopamine (CNS)
   - Prolonged exposure (increase L-dopa half life) + ↓ dopamine breakdown
3. Using MR formulations
   - get sustained release of drug
   - drug is released slowly into GI tract = absorption is prolonged = prolonged exposure to drug
   - reduces rate of metabolism
   - smoothes out peak to trough ratio
   - Increases efficacy AND doesnt increase toxicity
   - e.g. Stalevo (triple combo drug)
   - L-dopa, DDC-i (carbidopa) and COMT-i (encantopone)