lesson 5

what causes ulcers in the stomach

gastric acid damaging the stomach lining

which cells release gastric acid

parietal cells

Which three substances stimulate gastric acid release?

Acetylcholine, gastrin, histamine.

Name three ways to inhibit gastric acid secretion.

• Block gastrin

• Block acetylcholine receptors

• Block histamine receptors (H₂)

What is the role of histamine in the body?

Released during cell damage → causes vasodilation and immune response.

Why is histamine problematic in allergies?

Causes excessive inflammatory response.

Examples of antihistamines for allergies?

Benadryl, Claritin, Allegra.

Why don’t standard antihistamines reduce gastric acid?

they target H₁ receptors, not H₂ receptors.

What do H₁ receptors control?

Inflammatory responses.

What do H₂ receptors control?

Gastric acid secretion.

Key structural features of histamine?

• Imidazole ring

• Two-carbon chain

• Terminal amino group○

  

What are histamine tautomers?

Forms where a proton shifts within the imidazole ring.

What is essential for H₁ and H₂ receptor binding?

• Positively charged nitrogen

• Flexible chain

• Heteroaromatic ring

Feature required for H₁ binding?

Nitrogen with lone pair (ortho position).

Feature required for H₂ binding?

Amidine-type group.

Why modify the terminal amino group in drug design?

To convert agonists into antagonists.- improves selectivity

What was the first breakthrough compound?

Nα-guanylhistamine.

What type of drug is Nα-guanylhistamine?

Partial agonist.

What was the purpose of isothiourea(when terminal group of histamine is alterted) modification?

Restrict charge(charge is spread over several atoms- so not gonna cause a receptor effect but will still bind) to improve antagonist binding.

Outcome of isothiourea analogue?

Increased antagonist activity but still partial agonist

Why extend the carbon chain?

To improve receptor binding interactions.

Effect of increasing chain length?

Allows additional hydrogen bonding → alters activity.

What determines agonist activity in histamine?

• Imidazole ring (H-bonding)

• Charged amine (ionic interaction)

What determines antagonist activity in an antihistamine?

Similar interactions but altered geometry → blocks receptor

What is a chelated interaction?

Binding involving multiple interactions between ligand and receptor

What type of chains allow chelation?

Two-carbon chains.

Similarities between thiourea and guanidine?

• Planar

• Similar size

• Hydrogen bonding capability

what is thiourea and guanidine

functional group replacement/changes to the terminal amine of histamine

Key differencein thiourea and guanidine?Why is this difference important?

Guanidine is basic; thiourea is neutral.

Affects biological activity and receptor binding.

What is burimamide?

First highly selective H₂ antagonist.

Why is burimamide important?

Confirmed existence of H₂ receptors.

What improvement did cimetidine bring?

Effective H₂ receptor antagonist for ulcers.

Major side effect of cimetidine?

Inhibits cytochrome P450 → drug interactions.

Examples of improved H₂ antagonists?

Ranitidine, famotidine, nizatidine.

Advantage of later drugs over cimetidine?

Fewer drug interaction side effects.

Why is ranitidine effective?

Retains hydrogen bonding but avoids CYP450 inhibition.

What type of drug design was used for H₂ antagonists?

Rational drug design.

Why was histamine used as a starting point?

Known natural ligand → easier to design analogues.

Main goal of H₂ antagonist design?

Remove agonist activity and create full antagonists.

Why are H₂ antagonists useful clinically?

Reduce gastric acid → treat ulcers.