Flashcards in Ulcer Therapy: Development of the H2 receptor antagonist Deck (29):
What is a peptic ulcer?
It is an inflamed break in the lining of the stomach or the duodenum, typically between 10 and 20 millimetres across
Where is a peptic ulcer more common and least common?
Most common is Duodenum 1 in 10
Least common is Stomach 1 in 30
What are the cells that release the substance that causes peptic ulcers and what is this substance?
Gastric acid (HCl) is released from the Parietal cells in the lining of the stomach and duodenum.
What are the three substances that stimulate gastic acid release?
Acetyl Choline, Histamine, Gastrin
Describe the series of events that cause the release of Gastric acid:
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.
What are the three possible ways to inhibit gastric acid release?
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.
Developing the antihistamine drug: What is required in the structure?
2 carbon chains with a terminal alpha-amino grouo attached to an imidazole ring. The structure will exist as two tautomeric forms.
When is histamine normally released, and what is it normally associated with?
Histamine is released when a cell is damaged, and it is normally associated with allergic reactions like hayfever.
What dies histamine do?
Histamine stimulated dilation and increased permeability of the small blood vessels. White blood cells are then released to combat any infection
What are the Two histamone receptors and their function?
H1 receptor: allergic and hyper-sensitive reactions, treated with antihistamines
H2 receptor: gastric acid release, will not be inhibited by antihistamines.
Searching for a lead compound: Where do we start?
Start with the ligand: Histamine. We know that histamine is recognided by H2 receptor
After finding the starting material, what is the next step in the development of a drug blocking histamine induced gastric acid release?
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
What are the essential requirement for H1 binding?
A positive charged N atom with at least one proton in the side chain.
What are the essential requirements for H2 binding?
A flexible chain between the cation and the imidazole ring and must contain the amidine unit: HN-CH-N (forming the imidazole ring.)
What was the first breakthrough strategy in forming a drug against the histamine induced gastric acid release?
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.
What must be present in the structure to have an antagonistic effect?
An imidazole ring.
It was discovered that N-alpha-guanylhistamine was a weak antagonist, but what else was it found to be?
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.
Where can the charge of the guanidine group be spread around in the histamine analogue N-alpha-guanylhistamine?
It can be spread around 3 Nitrogens and can be potentially further away from the imidazole ring than in histamine.
What are the two possible binding sites of N-alpha-guanylhistamine?
An antagonist binding site and an agonist binding site therefore it is a PARTIAL AGONIST
What possibilities does the N-alpha-guanylhistamine have that histamine doesn't?
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.
After this initial lead of N-alpha-guanylhistamine that was a partial agonist, what was the next step?
Finding an analogue that would only bind to antagonist site to prevent any Gastric acid production.
How many strategies were there?
What was stratergy 1?
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.
Did stratergy 1 work?
Isothiourea showed increased antagonistic activity, but it was still a PARTIAL AGONIST
What was stratergy 2?
One terminal amino group was replaced by either a methylthio or a methyl group
Did stratergy 2 work?
No- both were still partial agonist, with lower antagonist activity than the original N-alpha-guanylhistamine.
What was stratergy 3?
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.
Was stratergy 3 successful?
There was increased Antagonist activity when adding NH, but decreased antagonist activity when adding S.