NEURO 21: Serotonin Med Chem

1. Serotonin (5-HT) Synthesis & Metabolism

Serotonin = 5-hydroxytryptamine (5-HT), a neurotransmitter involved in mood, sleep, pain, and migraines.
🧪 How is serotonin made?
1⃣ Start with tryptophan (an amino acid from diet)
2⃣ Tryptophan hydroxylase adds an –OH → makes 5-hydroxytryptophan (5-HTP) (this is the rate-limiting step!)
3⃣ Aromatic L-amino acid decarboxylase removes CO₂ → makes serotonin (5-HT)

🧪 How is serotonin broken down?
1⃣ Monoamine oxidase (MAO-A) converts 5-HT into 5-hydroxyindoleacetaldehyde
2⃣ Aldehyde dehydrogenase converts it into 5-hydroxyindoleacetic acid (5-HIAA) → excreted in urine

💡 Why do we care?

• MAO inhibitors (MAOIs) prevent serotonin breakdown → more serotonin in the brain → used in antidepressants.

• High 5-HIAA in urine = excess serotonin activity (e.g., carcinoid syndrome).

2. 5-HT Receptor Classes & Secondary Messengers

Serotonin receptors = 5-HT₁ to 5-HT₇, each linked to different signaling pathways.

💡 Why do we care?

• 5-HT1 receptors = migraine treatment (triptans).

• 5-HT2 receptors = mood & psychosis (blocked by trazodone & mirtazapine).

• 5-HT3 receptors = nausea/vomiting (blocked by ondansetron).

3. Insomnia: How Trazodone & Mirtazapine Work

🔹 Trazodone (Aryl-piperazine class)

• Blocks 5-HT2A receptors → ↓ overactive serotonin signaling = sleepiness & antidepressant effects.

• Weak serotonin reuptake inhibitor (SRI) → increases serotonin slightly.

• Metabolized to m-chlorophenylpiperazine (mCPP) → acts on 5-HT2C (unknown effects, but may worsen anxiety in some).

🔹 Mirtazapine (Tetracyclic antidepressant, NaSSA = Noradrenergic & Specific Serotonergic Antidepressant)

• Blocks 5-HT2 & 5-HT3 receptors → helps with sleep, reduces nausea.

• Blocks presynaptic α2-receptors → increases norepinephrine & serotonin release.

• Potent histamine H1 antagonist → makes you sleepy.

💡 Why do we care?

• Trazodone = better for sleep, but more sedation.

• Mirtazapine = good for sleep & appetite, but causes weight gain.

4. Why Trazodone Can Cause Liver Toxicity (Idiosyncratic Hepatotoxicity)

Trazodone is broken down in the liver by CYP3A4, creating reactive metabolites (like iminoquinone & epoxides). These:

• Bind to glutathione (GSH) → depletes it.

• Attack liver proteins → triggers liver damage.

• Similar to acetaminophen toxicity (NAPQI), but unpredictable (idiosyncratic).

💡 Why do we care?

• Liver toxicity is RARE but serious.

• Avoid trazodone in patients with liver disease or those taking CYP3A4 inhibitors.

5. Migraine: 5-HT Receptors Involved in Treatment

The key receptors for migraine treatment are:
✔ 5-HT1B → causes vasoconstriction in cranial arteries (reduces migraine).
✔ 5-HT1D → inhibits pain transmission in the trigeminal nerve.
✔ 5-HT1F → blocks pain without vasoconstriction (new target!).

💡 Triptans (like sumatriptan) are 5-HT1B/1D agonists → stop migraines by constricting blood vessels & reducing nerve pain.

6. Triptan Pharmacophore & 5-HT Structure

🔹 What’s a pharmacophore? → The essential structural features needed for a drug to bind & activate its target.

Key Features of Triptans (5-HT1B/1D Agonists):
✔ Indole ring (like serotonin) → fits into the 5-HT1 receptor.
✔ Amine group (NH2) → necessary for binding.
✔ Side chains (R groups) → affect bioavailability & half-life.

💡 Why do we care?

• Sumatriptan = fast onset, short half-life (~2.5 hrs).

• Frovatriptan = long half-life (~26 hrs), good for long-lasting migraines.

• New drug: Lasmiditan → selective 5-HT1F agonist, avoids vasoconstriction (better for heart patients).

Quick Summary of Key Points

✔ Serotonin is made from tryptophan & broken down by MAO.
✔ 5-HT receptors control mood, sleep, nausea, & pain.
✔ Trazodone blocks 5-HT2A, while mirtazapine blocks 5-HT2 & 5-HT3 + boosts norepinephrine.
✔ Trazodone’s liver toxicity is due to reactive metabolites attacking proteins.
✔ Migraine drugs (triptans) work by activating 5-HT1B/1D to constrict blood vessels.
✔ Triptans mimic serotonin but have modifications for better drug properties.