H2RA's

Question 1

Peptic Ulcer formation (Duodenal and gastric ulcer)

Answer 1

1. Parietal cells release acid in stomach stimulating
   - Gastrin receptors
   - H2 receptors
   - Muscarinic receptors
   K+H+ATPase pump exchanges K+ for H+
2. Muscarinic and gastrin receptors also have an effect on ECL cells
   - Stimulates release of Histamine
   - which causes release of Gastrin

Question 2

H2RA

Answer 2

Treat Helocibacter pylorii infection and NSAID’s induced peptic ulcer

• Competitive inhibition
• Suppress basal and meal stimulated gastric acid secretion
• Highly selective (only effect H2)

Question 3

SAR for H2R

Answer 3

Three nitrogen atoms are required for H2R agonist effect

• Three binding regions proposed for receptor - 1 imidazole binding region and 2 polar binding regions
• 1 polar binding region accessed by agonist and other by an antagonist
• Antagonist polar binding region is further from imidazole binding region
• 5 membered aromatic ring
• Short chain with sulfur
• H bond donor
• Double bond with electron withdrawing group

Question 4

N-guanylhistamine

Answer 4

Binds as an agonist in one mode and as an antagonist in the other mode (partial agonist/partial antagonist)

Question 5

Cimetidine

Answer 5

• Imidazole ring binds to iron centre of haem of cyp450
• inhibits cyp450
• increases levels of other drugs
• Has more adverse effects (capable of crossing blood brain barrier through lipophilicity)
• side effects: hallucinations in elderly, sexual dysfunction and
• males develop gynaecomastia which is development of breast tissue

Question 6

Inverse agonist

Answer 6

CIMETIDINE

• Causes conformational change
• Brings activity right down (close to zero)
• Reduces acid release
• Dimmer rather than off

Question 7

2nd generation anti-histamine

Answer 7

CETIRIZINE

• Has COOH
• Prevents crossing of blood-brain barrier
• Makes it non-drowsy

Question 8

STAGE 1 IN DISCOVERY

Answer 8

N-guanylhistamine was discovered

- Prevents histamine from releasing HCl

Question 9

STAGE 2 IN DISCOVERY

Answer 9

Buremomide was discovered

• More active as an antagonist
• Established the existence of H2R
• Chain extension proved good activity as an antagonist and better overlap of thiourea group
• Activity too low for oral use ( had to be injected )

Question 10

STAGE 3 IN DISCOVERY

Answer 10

Metiamide was discovered

• Adding methyl at C4 proved effective as it makes N in position 3 protonated and N-1 becomes less basic (due to sulfur)
• led to 1 death (granulocytosis)

Question 11

STAGE 4 IN DISCOVERY

Answer 11

Cimetidine was discovered

• Replaced C=S with C=N behaving as
• Electron withdrawing effect of CN has an inductive effect most felt at neighbouring N so it is less likely to form a H bond

Question 12

Thiaburimamide

Answer 12

Sulfur is slightly electron withdrawing making it harder to protonate imidazole

• This keeps it the right tautomer (Ntal)
• N pi is inactive and has no antagonist effect
• Adding methyl in position