PD MED CHEM
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16 Terms
What does the phosphate group on produodopa provide?
- Enhanced solubility
- Increased absorption
Why can dopamine not cross the BBB?
- The amine group of dopamine is protonated at physiological pH due to its high pKa (~9-10).
- This makes dopamine positively charged and polar, so it cannot cross the BBB.
Why can Levodopa cross the BBB?
- In L-DOPA, the carboxylic acid group lowers the pKa of the amine, preventing protonation at physiological pH.
- The carboxylic acid allows L-dopa to be taken up by LNAAs•
- This allows L-DOPA to actively cross the BBB.
What enzyme converts levodopa to dopamine?
- Dopa decarboxylase
- It removes the carboxylic acid group.
Why is Levodopa used instead of dopamine for Parkinson's treatment?
Levodopa can cross the blood-brain barrier via the LAT1 transporter, while dopamine cannot.
What is COMT?
An enzyme that methylates and inactivates catechol compounds like L-DOPA.
What percentage of levodopa can cross the BBB, and why is this?
- 1%
- Levodopa is broken down by dopa decarboxylase in the periphery into dopamine which cannot cross the BBB.
How can the amount of levodopa that can cross the BBB be increased?
- Coadministration of levodopa with a dopa decarboxylase inhibitor.
- This prevents breakdown of levodopa into dopamine in the periphery.
- This allows more levodopa to cross the BBB.
- They are too polar to cross the BBB so only act on dopa decarboxylase in the periphery
What is the role of COMT inhibitors in Parkinson's treatment?
- They prevent methylation of L-DOPA, increasing its availability for conversion to dopamine in the brain.
- They are too polar to cross the BBB so only act on COMT in the periphery
What functional group is responsible for the activity of dopa decarboxylase inhibitors how does it so this?
- The hydrazine group (-NH-NH₂)
- DOPA decarboxylase uses PLP (pyridoxal phosphate) as a cofactor. The hydrazine group on the inhibitor binds irreversibly to PLP, preventing the enzyme from using it, and therefore blocking DOPA decarboxylase's activity.
Show the mechanism for how dopa decarboxylase inhibitors inactivate dopa decarboxylase.
What is monoamine oxidase-B (MAO-B)?
- An enzyme which deactivates dopamine in the brain.
- Inhibition of MAO-B can increase dopamine levels in the brain which is useful for Parkinson's.
What are examples of MAO-B inhibitors?
- Selegeline
- Rasagiline
What functional group is essential for MAO-B inhibitors?
- The propargyl group (-C≡C-CH₃).
Why is the propargyl group essential for MAO-B inhibitors?
- Forms a covalent bond with the FAD cofactor in MAO-B.
- This irreversibly inactivates the enzyme, preventing it from breaking down dopamine.
Show the mechanism for MAO-B inhibitors.
