AW 2

Question 0

Rule of five

Answer 0

Lipinski's Rule of Five does a good job of quantifying drug like properties. According to this rule a drug should have: 
• molecular weight < 500 
• a log P < 5 
• < 5 hydrogen bond donors 
• < 10 hydrogen bond acceptors

Question 1

Nogradys drug definition

Answer 1

A drug molecule possesses one or more functional groups positioned in three-dimensional space

on a structural framework that holds the functional groups in a defined position that enables the

molecule to bind specifically to a targeted biological macromolecule, the receptor

Question 2

Three properties of drug able targets

Answer 2

• usually protein (good target as we can alter their function)
• leads to biological response
• does not cause toxicity

Question 3

Food and smell of causes…

Answer 3

Acetylcholine activates cholinergic receptors of the parietal cells leading to the release of gastric acid into the stomach
• The hormone histamine also stimulates the release of gastric acid by specific receptor interaction – Receptor unknown!

Question 4

Hypothesis about histamine

Answer 4

Two receptors
H1 -conventional antihistamines
H2 - gastric acid

Question 5

Why did they think there were two histamine receptor

Answer 5

4-methyl histamine round to be selective agonist - produces gastric acid secretion , no other effects (because of conformation)

Question 6

Nα-guanylhistamine relevance

Answer 6

Found to be antagonist (and partial agonist of gastric acid secretion)
Put forth theory of agonist and antagonist regions

Question 7

Burinamide

Answer 7

Too weakly active for oral admin but was partial antagonist NO AGONIST ACTIVITY

Question 8

How was Burinamide optimised?

Answer 8

Found to be too basic. Protonated at physiological pH where as histine mostly unionised.
We added a sulfur EWG to pull electrons out of ring. And EDG Me at position 4.

Question 9

Why could we not used they amazing new optimised burimide?

Answer 9

Metiamide, although ten times more active, caused kidney problems

Question 10

Why is the optimisation of burinemide super cool?

Answer 10

Didn’t add pharmacophore. Just optimised pH

Question 11

Two reasons we don’t want the Thiourea in Metiamide?

Answer 11

Thiourea group in Metiamide uncommon in humans… Thiourea.

Also exhibited excessive confirmational isomerism so 75% is not used

Question 12

What was the thinking behind cemetedines group?

Answer 12

Guanadine has good tox but is too basic

Append with cyano group to attenuate basicicity

Question 13

Cemetedine acts on

Answer 13

Strong selective antagonist for h2

Question 14

Cimetidine was marketed as

Answer 14

Tagamet

Question 15

How is cimetidine metabolised

Answer 15

Me into OH (not longer EDG)
S becomes S=O
No longer have effects on basicity of ring

Question 16

Oxemetadaine was a

Answer 16

Conformationally-locked analogues of the cyano-guanidine group in cimetidine

Question 17

Ranitidine action comparison

Answer 17

Ten times more active
Fewer side effects
Lasts longer

Question 18

Ranitidine two structural changes from Cemetedine

Answer 18

Nitroketeneaminal instead of cyanogunidine

Furan ring instead of imidazole

Question 19

Famotidine and Nizatidine

Answer 19

Later produced patent busters very similar to Cemetedine

Question 20

H2 antag superseded by ?.. Which act on ….

Answer 20

H+\k+ATPase pump - enzyme pump that exports h

+

Question 21

Why are PPIs a better target?

Answer 21

Down streatm, operate in final stages of h release.

Where as histadine is just one of several secretalogues.