H2 receptor Inverse Agonists

Question 1

What is a Bioisostere?

Answer 1

A replacement group (or molecule) that produces a similar biological effect to the orginial

Question 2

What is a Pharmacophore?

Answer 2

Optimum molecular features for biological activity

Question 3

What is a blockbuster drug?

Answer 3

A drug that earns at least $1b/year

Question 4

What is a Me-Too drug, and what are some of the benefits of one?

Answer 4

A drug chemically related to an earlier drug, which has an identical mechanism of action but little benefit over the original.
Additional therapeutic choice – some may have reactions to one kind of the drug or has interactions with another medicine they take.
Lowers drug price before patent expiry because of the competition on shelves.
Example: Cimetidine inhibits cytochrome P450 due to the imidazole ring binding to the iron – significant drug interactions; potentiates drug metabolised by oxidation, e.g., warfarin, phenytoin, theophylline; also, alcohol. Narrow therapeutic index
Whereas ranitidine has very little effect on cytochrome p450, famotidine and nizatidine have no effect on cytochrome p450.

Question 5

What is rational drug design?

Answer 5

Invention of drugs by using information concerning the structure of a receptor or its ligands

Question 6

What is a lead compound?

Answer 6

A molecule that shows promising biological activity but requires further structural modification before a drug can be obtained

Question 7

What is a structure-activity relationship?

Answer 7

The relationship between chemical structure and biological properties.

Question 8

Why was zantac withdrawn?

Answer 8

Because of a carcinogenic impurity found.

Question 9

How is acid released into the stomach?

Answer 9

Acid is secreted by parietal cells in the stomach lining.
Gastrin binding to the gastrin receptor, histamine binding to the H2R receptor, and the muscarinic N receptor is stimulated by the nervous system, which activates the parietal cells and causes them to release acid (protons) via a ATPase pump activated by cAMP.
This pump exchanges potassium in the stomach for protons, raising the pH.

Question 10

How do H2 receptor blockers work?

Answer 10

They bind to the H2R receptor on parietal cells to block the formation of acid

Question 11

What are the notable features of Cimetidine (Tagamet)?

Answer 11

Imidazole ring (lewis base)
Short chain sulphur (withdrawing group)
Guanidine group with a carbon that has a cyano bond (C=N) also bonded to a nitrogen, making this nitrogen non-basic as C=N is electron withdrawing.

Question 12

What are the doses of the H2R receptor drugs?

Answer 12

Cimetidine: 800mg
Ranitidine: 300mg
Famotidine: 40mg
Nizatidine: 300mg

Question 13

How does histamine work?

Answer 13

Imidazole ring with amine group binds to the H receptors and acts as an agonist

Question 14

How does Cimetidine work?

Answer 14

It relieves gastric ulcers by acting as an inverse agonist.

Question 15

How does cetirizine work?

Answer 15

Acts as inverse-agonist, 2 aromatic rings with short chain leading to nitrogen ring which is basic, if it is a second-generation anti-histamine it will have another short chain leading to a polar group (would be carboxylic acid group and oxygen atom) to prevent crossing through the BBB

Question 16

Name the general symptoms of the H2R receptor drugs

Answer 16

Diarrhoea and headache are a symptom that resonates between all these drugs, but Cimetidine also has somnolence, gynaecomastia, and sexual dysfunction as symptoms.

Question 17

What type of agonists are the H2-R drugs?

Answer 17

H2-R drugs are H2-inverse agonists as they bind and they decrease activity, they do not antagonise the receptor.
Agonist: binds to receptor to increase activity (>H+ release)
Antagonist: binds to receptor to stop activity but there will still be some inherent, low-level activity (H+ release)
Inverse agonist: binds to receptor to decrease activity (

Question 18

What are the drawbacks of random screening?

Answer 18

• Random screening and modification, even if successful, does not reveal why a compound is either active or inactive.
• Because the drug developers are working ‘blind’ this strategy is very slow and extremely expensive, with a tremendous failure rate.
• Typically, 20,000 compounds must be tested before 1 active molecule is found. The odds are getting worse as too few structurally diverse new compounds are available for screening.

Question 19

What are the principles of rational drug design?

Answer 19

• Understanding interactions between ligands and receptors generates a lead by studying the structure-activity relationships or computer modelling.
• The lead compound is improved to give a new lead. Otherwise, a new lead compound is proposed.
• The new lead is tested, and a better understanding of ligand-receptor interactions is achieved.

Question 20

What are other benefits of bioisosteres?

Answer 20

Bioisosteres can give better lipophilicity and metabolic stability.