GI Diseases MedChem Flashcards
What can the parietal cell be stimulated by?
Histamine
Ach
Gastrin
How is HCl produced by the parietal cell?
Stimulation of the parietal cell leads to formation of a canaliculus invagination
H+ is pumped out into the canaliculus
Cl- flows through an ion channel so HCl passes into the lumen of the stomach
Describe the different tautomers of the histamine ligand:
2 different tautomers
T:π = 4:1
Adding a substituent can make it more in favour for π, but has less of an agonist action
Describe histamine at physiological pH:
Histamine is charged, the aliphatic amine is primarily charged
96% monocation (aliphatic) 3% dication (ring charged aswell)
Charge increases with lower pH, increased acidity
Describe the SAR for a H2 agonist:
Groups need to be separated by a 2 carbon spacer
Heteroaromatic ring must contain an amidine group, H1 agonists don’t need this
Why is N^a guanylhistamine a partial agonist?
Due to resonance delocalisation
+ve charge can be shared
Can be closer or further away from imidazole ring
It can separately access both agonist and antagonist binding sites
What is the binding interaction in cimetidine?
2 point interaction to two separate binding sites
Describe the properties of ranitidine which makes it a good H2 antagonist:
No longer has imidazole ring, not essential for antagonists
Neutral polar group had been modified, better activity x10, doesn’t inhibit p450
Can have other N containing ring, or a non N containing ring (furan ring= O)
No methyl group on furan ring as decreases activity
Ketenaminal
Why is a ketenaminal needed in ranitidine?
Keeps the 2 amines for binding changing N to C (less polar)
NO2 is essential as e- withdrawing group stabilises tautomer for amine binding interaction
Describe how HCl for stomach acid is produced:
The canaliculus has a pH of less than 2
H+ generated by action of carbonic anhydrase in parietal cells (reaction of CO2 and H2O)
H+ is pumped out into the canaliculus (against gradient)
K+ is pumped into the parietal cell (against gradient)
Cl- flows through an ion channel with its gradient and so does K+ in a seperate channel into canaliculus
HCl passes into lumen of the stomach
Why can PPIs be taken orally?
They can pass through systemic circulation
They can do this because they are lipophilic and neutral
How do PPIs work?
Reach parietal cell and flow into the canaliculus
Undergo a metabolic transformation in low pH of canaliculus and become charged
Enables a cascade reaction where PPI is transformed into active species
Active species forms a disulphide bond with one or more of the three available cysteine residues on the proton pump-> irreversible inhibition, no H+ into the canaliculus
How can acid production be restored when taking a PPI?
If new proton pumps are synthesised by cell or regenerated through glutathione
Describe the mechanism of omeprazole:
- In canaliculus, PPI picks up a proton, benzimidazole ring becomes protonated
2+3. Intramolecular reaction, nucleophilic pyridine N can attack C adjacent to charged N giving 5 membered ring, known as Spiro derivative - Benzimadazole ring is reformed, cleavage of S bond, formation of sulfinic acid derivative, highly reactive so second intramolecular reaction occurs
- Forms an intermediate which can react with protein
Describe the structure of omeprazole:
It is chiral
Sulfur is tetrahedral, the lone pair can be considered a bond, S enantiomer is more effective as it is metabolised more slowly so longer DoA (esomeprazole)
