H2 receptor antagonists Flashcards
what causes peptic ulcers?
histamine causes erosions of mucus membranes of stomach or duodenum- pain
what is the main functional group on histamine?
imadazole ring- with a pi and thio nirtogen attached
what happens to histamines resonance form when in low ph?
it gets protinated on the pi nitrogen and the thio N is unaffected
what happens to histamine in high PH?
it gets ionised- nh3-nh2 and the N on imadazole are unaddected
do antihistamines work for peptic ulcers?
no
what was the SAR for finding a new agonist?
H1:
1- a cationic N with at least one proton directly attached
2- flexible linker
3- aromatic ring with N- next to side chain
what are the requirements for stimulating gastric acid release?
same as H2 but N-CH-NH required for acid release
where do you extend the molecule to make it an antagonist?
- extension of a methyl group from the imidazole- h2 selectivity antagonist
what is n- alpha guanylhistamine?
known to be a partial agonist- also antagonist- binds so that histamine binding is lowered
how do histamine and N-alpha-guanylhistamine compare?
- both contain imidazole
both have a cation
guanidine is larger than a simple amine
how do we remove partial agonist activity by variation?
- removing the charge from the amine- better antagonist activity/ partial agonist
how do you improve antagonism through chain expansion?
- expanded guanidine- better antagonist
is the binding mode better for longer or short chain?
longer chain is better for antagonist binding
is sulfur a good binding agent as an antagonist?
no -NH is bettter
what does ionic bonding promote?
agonist type binding
what does replacing the charged group with an unionised analogue retain?
retains antagonist activity, while removing agonist activity
adds a pair of H bonds to target
does burmaide display low or high activity orally? and why
low- due to equilibria between its imidazole tautomers
how do you use the electronic effect to solve the tautomer problem burmaide has orally?
- thiaburimaide fixes this issue through strategic placement of an electronic withdrawing atom
- adding an el donating group next to Nt
what are other examples of burimamides?
4-methylburimamide- no better
oxaburimamide-worse
what kind of activity does metiamide have?
10x activity of burimamide
- was useful until kidney damage/ higher suspecibility to infection
what activity did the urea analogue display?
reduced activity
what does a 2 and a 3 atom linker produce?
partial agonists
what does a 4 atom linker produce?
pure, albeit moderate, agonist activity
what are the features of guanidines?
highly basic as they share the cationic charge across all 3 N atoms and central carbon atom
how did they search for r a biocompatible, unionised, guanidine analogue ?
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.
how is cimetidine metabolised?
- Largely excreted in the unchanged form.
- Main metabolites found are oxidation products of the ring and the thioether.
- However, cimetidine inhibits liver CYP450 enzymes.
what drugs do you have to be cautioys of with cumetidine?
theophylline, warfarin, lidocaine, and diazepam
what was the steric preference for the substituted cyanoguanidine unit?
- 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
what provides scope for elaboration?
Isocytosine
what effect does increasing hydrophobicity within the aminal unit?
•Replacing N with C provides a potential alternative to adding a hydrophobic extension
how can the correct tautomer be promoted ?
by addition of a strong electron withdrawing group on the new carbon atom.
what was the result if a nitroketene?
Active, but no improved activity.
•Presence of nitro group made the compound more hydrophilic than anticipated
.•Therefore, logP is still lower than optimal
what was the factor that allowed it to favour the correct tautomer?
it was the orientation of the dipole
what is the optimum angle for binding?
•Optimal angle for binding is 30o, q represents deviation from this ideal angle
what is the final product called that took over the market with less side effects?
Ranitidine (Zantac, Glaxo
what can imidazole be replaced by?
other heterocycles, breaking the established dogma.
what about the sulfur is important for activity?
Presence and location of the sulphur atom is important for activity
what lowers the activity of ranitidine?
Replacement of furan with more hydrophobic heterocycles lowers activity
when is 2,5-substitution best?
in these ring systems- imeadazole
what are other members of the ranutidine family?
Famotidine
Nizatidine
what are the differences in H1 and H2 binding in SAR?
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
what is a shorter route to ranitidine?
Thiol not isolated.
•In air oxidises to corresponding symmetrical disulphide.
