7 - Antipsychotics

Question 1

Which subtypes of the 5-HT receptor are most pharmacotherapeutically important? What types of receptors are they?

Answer 1

• Subtypes 1, 2, 3, and 7

- All are GPCRs, except 5-HT3 is a ligand-gated ion channel

Question 2

5-HT receptors (subtypes 1, 2, and 4-7) have ____ transmembrane domains

Answer 2

7

Question 3

Where are 5-HT (subtype 1) receptor located? What are their functions?

Answer 3

• Located in CNS, CV, skin, and ileum

- Functions = behavioural, vasoconstriction, and vasodilation

Question 4

Where are 5-HT (subtype 2) receptor located? What are their functions?

Answer 4

• Located in CNS, CV, respiratory, urogenital, and blood platelets
• Functions = behavioural, muscle contraction, and platelet aggregation

Question 5

Where are 5-HT (subtype 3) receptor located? What are their functions?

Answer 5

• Located in CNS and PNS

- Functions = neuronal excitation, anxiety, and emesis

Question 6

Majority of 5-HT receptors are _____, except ____ which is _____

Answer 6

Majority are post-synaptic, except 5-HT1 which is pre- and post-synaptic

Question 7

Where is serotonin stored? When is it released into blood?

Answer 7

• Stored in platelets

- Released into blood when platelet activating factor concentration is less than 1 nM (too much vasodilation)

Question 8

What are the most commonly prescribed migraine tx?

Answer 8

“Triptans”, potent agonists of 5-HT1B and 5-HT1D receptors

Question 9

Why does agonism of 5-HT1B and 5-HT1D receptors cause migraine relief?

Answer 9

Causes constriction of cranial blood vessels and inhibition of pro-inflammatory mediators

Question 10

What is buspirone?

Answer 10

Long-chain arylpiperazine, which is a non-selective 5-HT1A receptor agonist

Question 11

What is chlorpromazine?

Answer 11

Typical antipsychotic

Question 12

What are common structural features of typical antipsychotics?

Answer 12

• Either tricyclic or bicyclic w/ EW groups

- Tethered to chain w/ terminal amine

Question 13

What are some side effects of second gen antipsychotics?

Answer 13

• Weight gain
• Movement effects (tremor, stiffness, agitation)
• Sedation
• Decreased sex drive and function

Question 14

What is “modelling the pharmacophore”?

Answer 14

Using the receptor and seeing which ligands fit into it, and looking at what is important to each molecule for agonist activity

Question 15

What are the 4 spheres for 5-HT3 receptor pharmacophores?

Answer 15

1) Hydrophobic group
2) Aromatic ring 1
3) Aromatic ring 2
4) Basic center (amine)

Question 16

What are the 3 components that a selective 5-HT reuptake inhibitor must have?

Answer 16

1) 2 aromatic rings that are almost perpendicular to each other
2) Basic center (amine) which is 6.6A and 4.1A distance form aromatic rings 1 and 2
3) Hydrophobic group as a substituent for 1 aromatic ring

Question 17

What are the 4 spheres for 5-HT transporter pharmacophores?

Answer 17

1) H bond acceptor
2) Aromatic ring
3) Basic center (amine)
4) Hydrophobic group