H2 receptor antagonists

Question 1

what causes peptic ulcers?

Answer 1

histamine causes erosions of mucus membranes of stomach or duodenum- pain

Question 2

what is the main functional group on histamine?

Answer 2

imadazole ring- with a pi and thio nirtogen attached

Question 3

what happens to histamines resonance form when in low ph?

Answer 3

it gets protinated on the pi nitrogen and the thio N is unaffected

Question 4

what happens to histamine in high PH?

Answer 4

it gets ionised- nh3-nh2 and the N on imadazole are unaddected

Question 5

do antihistamines work for peptic ulcers?

Answer 5

no

Question 6

what was the SAR for finding a new agonist?

Answer 6

H1:
1- a cationic N with at least one proton directly attached
2- flexible linker
3- aromatic ring with N- next to side chain

Question 7

what are the requirements for stimulating gastric acid release?

Answer 7

same as H2 but N-CH-NH required for acid release

Question 8

where do you extend the molecule to make it an antagonist?

Answer 8

• extension of a methyl group from the imidazole- h2 selectivity antagonist

Question 9

what is n- alpha guanylhistamine?

Answer 9

known to be a partial agonist- also antagonist- binds so that histamine binding is lowered

Question 10

how do histamine and N-alpha-guanylhistamine compare?

Answer 10

• both contain imidazole
  both have a cation
  guanidine is larger than a simple amine

Question 11

how do we remove partial agonist activity by variation?

Answer 11

• removing the charge from the amine- better antagonist activity/ partial agonist

Question 12

how do you improve antagonism through chain expansion?

Answer 12

• expanded guanidine- better antagonist

Question 13

is the binding mode better for longer or short chain?

Answer 13

longer chain is better for antagonist binding

Question 14

is sulfur a good binding agent as an antagonist?

Answer 14

no -NH is bettter

Question 15

what does ionic bonding promote?

Answer 15

agonist type binding

Question 16

what does replacing the charged group with an unionised analogue retain?

Answer 16

retains antagonist activity, while removing agonist activity

adds a pair of H bonds to target

Question 17

does burmaide display low or high activity orally? and why

Answer 17

low- due to equilibria between its imidazole tautomers

Question 18

how do you use the electronic effect to solve the tautomer problem burmaide has orally?

Answer 18

• thiaburimaide fixes this issue through strategic placement of an electronic withdrawing atom
• adding an el donating group next to Nt

Question 19

what are other examples of burimamides?

Answer 19

4-methylburimamide- no better

oxaburimamide-worse

Question 20

what kind of activity does metiamide have?

Answer 20

10x activity of burimamide

- was useful until kidney damage/ higher suspecibility to infection

Question 21

what activity did the urea analogue display?

Answer 21

reduced activity

Question 22

what does a 2 and a 3 atom linker produce?

Answer 22

partial agonists

Question 23

what does a 4 atom linker produce?

Answer 23

pure, albeit moderate, agonist activity

Question 24

what are the features of guanidines?

Answer 24

highly basic as they share the cationic charge across all 3 N atoms and central carbon atom

Question 25

how did they search for r a biocompatible, unionised, guanidine analogue ?

Answer 25

Depending on their inductive properties these can modulate the pKa of the guanidine.
•Electron withdrawing substituents could produce a guanidine analogue that is essentially unionised even in the stomach!
•Of the two strongly electron withdrawing iptions available, the cyano compound was found to be better in vivo.

Question 26

how is cimetidine metabolised?

Answer 26

• Largely excreted in the unchanged form.
• Main metabolites found are oxidation products of the ring and the thioether.
• However, cimetidine inhibits liver CYP450 enzymes.

Question 27

what drugs do you have to be cautioys of with cumetidine?

Answer 27

theophylline, warfarin, lidocaine, and diazepam

Question 28

what was the steric preference for the substituted cyanoguanidine unit?

Answer 28

• All of the N-C bonds in the guanidine unit have partial double bond character.
• This leads to at least some restricted rotation, and makes the E/Z designation valid.
• Urea analogue, which would favour the Z,Z type structure produced weak binding too

Question 29

what provides scope for elaboration?

Answer 29

Isocytosine

Question 30

what effect does increasing hydrophobicity within the aminal unit?

Answer 30

•Replacing N with C provides a potential alternative to adding a hydrophobic extension

Question 31

how can the correct tautomer be promoted ?

Answer 31

by addition of a strong electron withdrawing group on the new carbon atom.

Question 32

what was the result if a nitroketene?

Answer 32

Active, but no improved activity.
•Presence of nitro group made the compound more hydrophilic than anticipated
.•Therefore, logP is still lower than optimal

Question 33

what was the factor that allowed it to favour the correct tautomer?

Answer 33

it was the orientation of the dipole

Question 34

what is the optimum angle for binding?

Answer 34

•Optimal angle for binding is 30o, q represents deviation from this ideal angle

Question 35

what is the final product called that took over the market with less side effects?

Answer 35

Ranitidine (Zantac, Glaxo

Question 36

what can imidazole be replaced by?

Answer 36

other heterocycles, breaking the established dogma.

Question 37

what about the sulfur is important for activity?

Answer 37

Presence and location of the sulphur atom is important for activity

Question 38

what lowers the activity of ranitidine?

Answer 38

Replacement of furan with more hydrophobic heterocycles lowers activity

Question 39

when is 2,5-substitution best?

Answer 39

in these ring systems- imeadazole

Question 40

what are other members of the ranutidine family?

Answer 40

Famotidine

Nizatidine

Question 41

what are the differences in H1 and H2 binding in SAR?

Answer 41

H1 agonist: only one aromatic with positive charge
antagonist- two aromatics with positive charge

h2 agonist- imadazole with extra H
antagonist an aryl or heteroaryl ring and extension

Question 42

what is a shorter route to ranitidine?

Answer 42

Thiol not isolated.

•In air oxidises to corresponding symmetrical disulphide.