The development of Burimamide

Question 1

Why did this need to be developed?

Answer 1

The partial agonist needed to be changed to an antagonist with no agonist activity.

Question 2

What does the histamine’s agonist activity depend on?

Answer 2

The imidazole group (H bonding) and the charged amino function (ionic bonding)

Question 3

What does the antagonist activity of the Histamine analogue depend on?

Answer 3

The imidazole ring (H bonding) and the guanidine group (ionic bonding and charge is spread over 3 Nitrogens)

Question 4

How can we distinct between both charged groups of the amino functiona and the guanidine?

Answer 4

The compounds which show antagonist activity (the guanidine) are ALL capable of forming a CHELATED BONDING STRUCTURE

Question 5

What is a chelated bonding structure?

Answer 5

The interaction involves 2 H-bonds between two charged species. (hydrogen bonding)

Question 6

Is an ionic (charged group) necessary for chelating?

Answer 6

No- a charged group (guanidine) is not necessary- a neutral group can also chelate to the antagonist site by Hydrogen boding.

Question 7

Because chelating does not require charge, what does this mean?

Answer 7

We can use this to distinct between the agonist and antagonist site as ionic bonding IS necessary for the agonist site

Question 8

What neutral group is found to be able to chelate with antagonists binding sites and how does it work?

Answer 8

Thiourea group is a neutral group that can form 2 hydrogen bond interations with the antagonist site and it is a full antagonist (no agonist effect so no gastric acid production)

Question 9

What are the similarities between Thiourea and Guanidine groups?

Answer 9

Both are planar, similar in size and can take part in Hydrogen Bonding.

Question 10

What are the differences in Thiourea and Guanidine groups?

Answer 10

The thiourea group is neutral - no charge and also non-basic.

Question 11

What does the differences between Thiourea and Guanidine groups result in?

Answer 11

We can say that the difference in biological activity is attributed to the differences in bacicity and charge of the two groups.

Question 12

What does further extension and an addition of an N-methyl group cause?

Answer 12

The formation of Burimamide with enhanced antagonistic activity.

Question 13

What does the addition of the N-methyl group cause?

Answer 13

Increased hydrophobicity

Question 14

What does an increased chain length cause?

Answer 14

Chain extension moves the thiourea group closer to the antagonist binding site.

Question 15

What is Burimamide?

Answer 15

A highly specific competitive antagonist of histamine at the H2 receptor, which is 100 times more potent thatn N-alpha-guanylhistamine.

Question 16

What was developed after Burimamide?

Answer 16

Cimetidine

Question 17

What is different between Cimetidine and Burimamide?

Answer 17

The thiourea group has been replaced b a cyanoguanidine group that is still neutral. but it was metabolised by P450 so had unwanted side effects

Question 18

What is the newest analogue used today?

Answer 18

Ranitidine x10 more active than Cimetidine

Question 19

What is the big difference in the structure of Ranitidine?

Answer 19

It has NO IMIDAZOLE ring, instead it has a FURAN ring with a termianl tertiary amine. It still has the Hydrogen bonding groups at the end that bind to antagonist receptors.