Ulcer Therapy: Development of the H2 receptor antagonist

Question 1

What is a peptic ulcer?

Answer 1

It is an inflamed break in the lining of the stomach or the duodenum, typically between 10 and 20 millimetres across

Question 2

Where is a peptic ulcer more common and least common?

Answer 2

Most common is Duodenum 1 in 10

Least common is Stomach 1 in 30

Question 3

What are the cells that release the substance that causes peptic ulcers and what is this substance?

Answer 3

Gastric acid (HCl) is released from the Parietal cells in the lining of the stomach and duodenum.

Question 4

What are the three substances that stimulate gastic acid release?

Answer 4

Acetyl Choline, Histamine, Gastrin

Question 5

Describe the series of events that cause the release of Gastric acid:

Answer 5

1. Triggering of the autonomic nervous system will cause Acetylcholine to be released, which activates cholinergic receptors, stimulating the release of Gastric acid from Parietal cells
2. Autonomic nervous system also stimulates the nerve signals in the antrum (end of the stomach), causing the release of a hormone called GASTRIN which stimulates parietal cells to release Gastric Acid
3. Gastric acid release from the parietal cells is also stimulated by histamine.

Question 6

What are the three possible ways to inhibit gastric acid release?

Answer 6

1. An Anticholinergic drug that will block the acetylcholine receptor
2. A drug to block the hormone Gastrin
3. An antihistamine drug to inhibit the gastric release via histamine.

Question 7

Developing the antihistamine drug: What is required in the structure?

Answer 7

2 carbon chains with a terminal alpha-amino grouo attached to an imidazole ring. The structure will exist as two tautomeric forms.

Question 8

When is histamine normally released, and what is it normally associated with?

Answer 8

Histamine is released when a cell is damaged, and it is normally associated with allergic reactions like hayfever.

Question 9

What dies histamine do?

Answer 9

Histamine stimulated dilation and increased permeability of the small blood vessels. White blood cells are then released to combat any infection

Question 10

What are the Two histamone receptors and their function?

Answer 10

H1 receptor: allergic and hyper-sensitive reactions, treated with antihistamines
H2 receptor: gastric acid release, will not be inhibited by antihistamines.

Question 11

Searching for a lead compound: Where do we start?

Answer 11

Start with the ligand: Histamine. We know that histamine is recognided by H2 receptor

Question 12

After finding the starting material, what is the next step in the development of a drug blocking histamine induced gastric acid release?

Answer 12

Vary the structure of the ligand Histamine so that it is still recognised by the receptor, but will binf in such a way that it acts as an antagonist rather than an agonist i.e. not stimulate HCl release

Question 13

What are the essential requirement for H1 binding?

Answer 13

A positive charged N atom with at least one proton in the side chain.

Question 14

What are the essential requirements for H2 binding?

Answer 14

A flexible chain between the cation and the imidazole ring and must contain the amidine unit: HN-CH-N (forming the imidazole ring.)

Question 15

What was the first breakthrough strategy in forming a drug against the histamine induced gastric acid release?

Answer 15

Replacing the terminal amino group with different polar groups, which could bind to the same site on the receptor as the NH3+ , but altered the geometry of the bonding enough to produce an antagonist.

Question 16

What must be present in the structure to have an antagonistic effect?

Answer 16

An imidazole ring.

Question 17

It was discovered that N-alpha-guanylhistamine was a weak antagonist, but what else was it found to be?

Answer 17

A partial agonist: it still had some agonist effect, but much less than before the modification. It does activate the H2 receptor but to a lesser extent than histamine so there is less gastric acid released.

Question 18

Where can the charge of the guanidine group be spread around in the histamine analogue N-alpha-guanylhistamine?

Answer 18

It can be spread around 3 Nitrogens and can be potentially further away from the imidazole ring than in histamine.

Question 19

What are the two possible binding sites of N-alpha-guanylhistamine?

Answer 19

An antagonist binding site and an agonist binding site therefore it is a PARTIAL AGONIST

Question 20

What possibilities does the N-alpha-guanylhistamine have that histamine doesn’t?

Answer 20

N-alpha-guanylhistamine can interact with other sites that are ‘out of reach’ of histamine becuause the +ive charge on histamine isn’t spread over the 3 Nitrogens. So histamine can only bind agonist and not antagonist.

Question 21

After this initial lead of N-alpha-guanylhistamine that was a partial agonist, what was the next step?

Answer 21

Finding an analogue that would only bind to antagonist site to prevent any Gastric acid production.

Question 22

How many strategies were there?

Answer 22

3

Question 23

What was stratergy 1?

Answer 23

Isothiourea synthesis: adding a Sulphur group to the molecule, pushing the +ive charge further away from the imidazole ring, to the end of the chain, should bind more strongly with the antagonist binding site.

Question 24

Did stratergy 1 work?

Answer 24

Isothiourea showed increased antagonistic activity, but it was still a PARTIAL AGONIST

Question 25

What was stratergy 2?

Answer 25

One terminal amino group was replaced by either a methylthio or a methyl group

Question 26

Did stratergy 2 work?

Answer 26

No- both were still partial agonist, with lower antagonist activity than the original N-alpha-guanylhistamine.

Question 27

What was stratergy 3?

Answer 27

Extending the chain from 2C to 3C, again moving the +ive Nitrogen further from the imidazole group, by adding another carbon group, and also either NH or S to the chain.

Question 28

Was stratergy 3 successful?

Answer 28

There was increased Antagonist activity when adding NH, but decreased antagonist activity when adding S.

Question 29

What is the best analogue of N-alpha-guanylhistamine?

Answer 29

A 3C analogue with NH within the chain, and it has increased antagonist activity.