Epilepsy Med Chem

What metabolises carbamazepine?

- CYP3A4 to the 10,11 epoxide (active compound)

- Further metabolism from epoxide inactivates it.

Why is carbamazepine an autoinducer?

- It induces CYP3A4 activity which metabolises carbamazepine.

- Therefore it induces its own metabolism which can lead to interactions.

Why is oxycarbazepine a safer alternative than carbamazepine?

- Contains a carboxyl group which prevents formation of a toxic epoxide group like in carbazmazepine.

- It is a CYP inducer but not an autoinducer.

- Cytosolic enzymes metabolises it to licabazepine which undergoes majority of its activity.

How is oxycarbazepine excreted?

Following glucuronidation

Describe eslicarbazepine.

- Available as the the pro-drug (eslicarbazepine acetate).

- Converted to licarbazepine when metabolsied, simirlary to oxycarbazepine however faster.

- (S) enantiomer is most active.

Describe the SAR of benzodiazepines.

- Aromatic A-ring is essential as it allows Pi-pi stacking with receptor.

- Double bond O/S/N hydrogen acceptor is essential for activity as it allows co-planar positioning with aromatic ring.

- Nitrogen at position 1 is not essential, can be anything.

- Nitrogen and double bond at position 4 is not required.

- C-ring is not essential however provides additional binding interactions.

- OH group ( 3 position B ring) increases speed of onset of action and allows rapid excretion via glucouronidation in liver

How can the A-ring be altered to affect selectivity to receptor?

- Small electronegative group at position 7 increases activity e.g., NO2, Cl, F.

- Addition of a group at any other position decreases activity.

- Can be a heteroaromatic ring however less active

Why is the double bonded O/S/N essential for benzodiazepine activity?

- Provides essential H-bond accepting.

- Double bond allows group to be co-planar with aromatic ring.

How can C-ring be altered to affect activity of benzodiazepeines?

- Substitution at the 4' position decreases activity by providing a steric effect.

- Halogen at the 2' position increases lipophilicity which enhances binding.

Describe the metabolism of diazepam.

- CYP450 mediated N-dealkylation leads to formation of an active metabolite (N-Desmethyldiazepam)

- CYP450 mediated hydroxylation then occurs producing oxazepam.

How is oxazepam excreted?

- Rapidly excreted via glucuronidation metabolism at its OH group.

- Allows it to be a short acting benzodiazepam which is safer compared to long acting diazepam.

Why does lorazepam have a short half-life?

- Extra hydroxyl group allows glucuronidation to occur.

Describe 1-2 annelation of benzodiazepines.

- Extends the ring system by fusing another ring to it e.g., imidazole or a triazole onto the benzo.

- This blocks metabolism at N-1 position via providing a steric block, increasing activity.

- This includes an electron rich ring (triazole or imidazole) which increases pi-pi interactions and therefore its activity.

What do the chlorine groups on lorazepam provide?

Increase lipophilicity of lorazepam allowing it to move across the BBB more efficiently increasing its activity.

Describe midazolam.

- pKa 6.2

- Effective aqueous and lipid solubility.

- Used as pre-medication for anesthesia due to rapid onset (1-2 mins) and recovery (20 mins)

What are examples of class B benzodiazepams?

- Triazolam

- Midazolam

Describe vigabatrin.

- Irreversible inhibitor of GABA transaminase.

- Increases brain GABA levels by blocking the breakdown of GABA.

• Exerts its effect only after binding to its target enzyme.

Why can midazolam be given IV?

- At low pH (~3), midazolam exists as a dihydrochloride salt, with protonated nitrogen atoms.

- This charged form is highly water-soluble, making it suitable for injectable or oral liquid formulations.

- When the drug enters the body (at pH ~7.4), it loses the extra protons and becomes neutral and lipophilic.

- The neutral form can cross the blood-brain barrier quickly, leading to fast onset of action.

- This pH-triggered shift allows midazolam to be both formulation-friendly and highly effective in the CNS.

Describe how GABA is synthesised and subsequently broken down to form succinic semialdehyde.

- Glutamate is converted to GABA by GAD, using PLP as a cofactor.

- GABA is broken down by GABA-AT into succinic semialdehyde, also using PLP.

- During GABA breakdown, PLP is temporarily converted to PMP.

How does vigabatrin affect GABA breakdown?

Vigabatrin inhibits GABA-AT which therefore prevents GABA being broken down into succinic semialdehyde.

How does vigabatrin irreversibly inhibit GABA transaminase (GABA-T)?

Vigabatrin mimics GABA and binds to PLP in GABA-T. This forms a stable, irreversible covalent bond with PLP, permanently inactivating the enzyme and increasing GABA levels in the brain.

Show the mechanism of vigabatrin inhibiting GABA breakdown.

Why can't GABA alone be used as a drug to increase GABA levels in the brain?

- At physiological pH, the amine on GABA is too polar and therefore cannot cross the BBB.

- The ethene (vinyl) group on vigabatrin is electron withdrawing which lowers the pKa of the amine increasing its lipophilicity.

- This allows it to cross the BBB.